Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]1=[O:20])[O:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C1COCC1>[O:20]=[C:12]1[C:11](=[C:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:10][CH:9]=3)[CH2:5][O:6]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 3 h, the mixture was concentrated in vacuo and the solid triturated with MeOH. Filtering the mixture and rinsing with MeOH and hexanes/EtOAc (7:3) afforded the title compound (42.2 mg, 73%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:24]2[S:25][C:26]([I:30])=[C:27]([CH3:29])[CH:28]=2)=[CH:20][S:21][C:22]=1[NH2:23])=[O:17])[CH3:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:24]2[S:25][C:26]([I:30])=[C:27]([CH3:29])[CH:28]=2)=[CH:20][S:21][C:22]=1[NH:23][C:4](=[O:5])[CH2:3][C:1]#[N:2])=[O:17])[CH3:14]
Reactant: N#CCC(=O)O
Reactant: CCOC(=O)c1c(-c2cc(C)c(I)s2)csc1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cc(C)c(I)s2)csc1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.5 %

Procedure:
Cyanoacetic acid (1.2 g, 14.0 mmol) and CH2Cl2 (14 ml) were combined at rt under N2. The solids do not dissolve. PCl5 (2.9 g, 14.0 mmol) was added as a solid portion wise (bubbles vigorously). The suspension was heated at reflux for 30 min and all solids dissolve to give a clear, light yellow solution. The acyl chloride solution was cooled and added directly to 5′-Amino-5-iodo-4-methyl-[2,3′]bithiophenyl-4′-carboxylic acid ethyl ester (2.0 g, 5.1 mmol) in CH2Cl2. The solution was stirred at rt for 2.5 h. The reaction was poured into NaHCO3 (aq, sat.) and washed a second time with NaHCO3 (aq, sat.). The organics were washed with brine and dried (Na2SO4), filtered and concentrated by rotary evaporation to give a light yellow solid which was then triturated with CH3CN and filtered to give 5′-(2-Cyano-acetylamino)-5-iodo-4-methyl-[2,3′]bithiophenyl-4′-carboxylic acid ethyl ester (1.7 g, 3.7 mmol) as a white solid. This material was taken to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(C(=O)O)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc(CO)c1F
Temperature: 0 °C
Yield: 50.1 %

Procedure:
3-amino-2-fluorobenzoic acid (APIN, 250 mg, 1.612 mmol) was dissolved in 10 mL of anhydrous THF under N2 atmosphere. Solution was cooled at 0° C. in an ice-water bath. LiAlH4 (FLUKA, 183 mg, 4.83 mmol) was added. Reaction was stirred under nitrogen at room temperature. After 2 h one equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added to the mixture and reaction was stirred at room temperature overnight. Another equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added. After 5 h The reaction mixture was quenched by adding MeOH. Solvent was evaporated to obtain an orange syrup that was dissolved in EtOAc and partitioned with saturated NaHCO3 (aqueous) (10 mL of saturated solution+15 mL of distilled water). Aqueous phase was extracted with EtOAc, organic layers were combined and dried with MgSO4 (anh), filtered off and concentrated. Crude was purified using silica gel cartridge with linear gradient 0-85% DCM/MeOH to yield the title compound (114 mg, 0.808 mmol, 50.1% yield) as yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.50-6.85 (m, 3H), 4.95-5.08 (m, 3H), 4.44 (d, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5])#[N:2].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.N1CCCCC1>N1C=CC=CC=1>[OH:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCC(=O)NCCCCCC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)cc1)C(=O)NCCCCCC(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
7.5 g (38 mmol 6-(cyanacetamido) hexanoic acid was dissolved in 50 ml pyridine. 4.6 g (38 mmol) 4-hydroxybenzaldehyde and 0.7 ml (7 mmol) piperidine were added to the solution and the reaction mixture was stirred for 2 hours at 50° C. A further aliquot of 0.4 ml piperidine was then added to the reaction and the solution was stirred at RT for 60 hours. The residue after evaporation of the pyridine was acidified with HCl (2N) and was extracted with ethyl acetate. The organic layer was poured into 300 ml of a saturated solution of sodium hydrogen carbonate. The aqueous layer was then carefully acidified with HCl (2N). The precipitated residue was filtered and washed with water. The dried product was crystallized from dioxane.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([CH2:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]([NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[OH:19])[CH3:15])=[C:10]([Cl:29])[CH:9]=1)=[O:6].Cl>O.CO>[C:5]([CH2:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]([NH:16][CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[OH:19])[CH3:15])=[C:10]([Cl:29])[CH:9]=1)([OH:6])=[O:4]
Reactant: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(COc1ccc(CC(=O)O)cc1Cl)NCC(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A solution of 6.0 g of potassium hydroxide in 10 ml of water was added to a solution of 2.3 g of 2-[2-(4-methoxycarbonylmethyl-2-chlorophenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described in Example 22) in 90 ml of methanol, and the resulting mixture was allowed to stand overnight. At the end of this time, the reaction mixture was poured into ice-water and the pH of the mixture was adjusted to a value of 7 by the addition of 1N aqueous hydrochloric acid, after which it was irradiated with ultrasonic waves. The crystals which precipitated were collected by filtration and recrystallized from methanol, to give 0.97 g of the title compound as crystals, melting at 188°-192° C.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:20][C:21]1[N:25]([CH:26]2[CH2:32][CH:31]3[N:33]([CH2:34][CH2:35][C:36]4([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:28]([CH2:29][CH2:30]3)[CH2:27]2)[C:24]2[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=2[N:22]=1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:6][C:2]([OH:1])([CH3:7])[C:3]([N:39]1[CH2:38][CH2:37][C:36]([CH2:35][CH2:34][N:33]2[CH:28]3[CH2:29][CH2:30][CH:31]2[CH2:32][CH:26]([N:25]2[C:24]4[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=4[N:22]=[C:21]2[CH3:20])[CH2:27]3)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40]1)=[O:4]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: CC(C)(O)C(=O)O
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)C(C)(C)O)CC1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
2-hydroxy-2-methylpropanoic acid (36 mg, 0.35 mmole) was dissolved in 0.92 ml of 1,2-dichloroethane. To this was added 1,1′-carbonyldiimidazole (37 mg, 0.23 mmole) and shaken for 30 min. 2-Methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (50 mg, 0.12 mmole) was added as a dry powder and shaking was resumed overnight. 1 ml of NaHCO3 sat. was added to the reaction mixture and shaken, followed by filtration through a hydrophobic frit and concentrated to an oil. The oil was separated on silica using gradient flash chromatography (0-8% MeOH in CHCl3) to afford 2-methyl-1-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)-1-oxo-2-propanol 20 23.7 mg (38%) as a white glassy solid. 1H NMR (300 MHz, CDCl3) δ 7.7-7.6 (m, 1H), 7.1-7.4 (m, 8H), 4.7 (s, 1H), 4.0 (s, 2H), 3.2-3.4 (m, 4H), 2.6 (s, 3H), 2.2-2.5 (m, 5H), 2.1-1.7 (m, 11H), 1.7-1.5 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].C(=O)(O)[O-].[Na+]>C(O)C>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CC(C)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNc1ccc(C(C)C)cc1)OCC
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A solution of 4-isopropylaniline (7.6 mL, 56 mmol), 2-bromoacetaldehyde diethyl acetal (5.5 mL, 36 mmol) and sodium bicarbonate (4.8 g, 57 mmol) in ethanol (60 mL) was stirred at reflux for 3 days under argon. After cooling to room temperature, the ethanol was removed in vacuo and the product was partitioned between ether and water, washed sequentially with water and brine, and dried over sodium sulfate. After removal of the solvent in vacuo, flash chromatography (silica, 10% ethyl acetate in hexanes) yielded 4-isopropyl-N-(2,2-diethoxyethyl) aniline (8.23 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.C1C(=O)N([Br:40])C(=O)C1>>[Br:40][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 59.6 %

Procedure:
Following General Procedure I, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (600 mg, 1.3 mmol) was reacted with NBS (280 mg, 1.5 mmol) to afford the desired product (410 mg, 60%) as a reddish brown solid. ESI MS m/z 529 [C25H25BrN2O4S H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15]N.O.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.Cl>C(O)C(F)(F)F>[N+:12]([C:9]1[C:8]2[C:20]3[CH2:19][NH:18][CH2:23][CH2:22][C:21]=3[NH:15][C:7]=2[C:6]([S:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: O=C1CCNCC1
Reactant: NNc1cc([N+](=O)[O-])ccc1SCCCCl
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCCCl)c2[nH]c3c(c12)CNCC3
Temperature: 25 °C
Yield: 96.9 %

Procedure:
1-{2-[(3-Chloropropyl)sulfanyl]-5-nitrophenyl}hydrazine (100 mg, 0.38 mmol) and 4-piperidone mono hydrate (58 mg, 0.38 mmol) were dissolved in trifluoroethanol (1 mL) andheated at reflux for 1 hour. To this was added 12 N HCl (3 mL) and the reaction allowed to heat at reflux for 2 hours. The product percipatated out upon cooling to room temperature, it was filtered off and washed with cold 2-propanol to give 3-chloropropyl 9-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl sulfide (120 mg, 75.4%). 1H NMR (CD3OD, 300 MHz): δ8.00 (d, 1H, J=8.4 Hz), 7.30 (d, 1H, J=8.4 Hz), 4.68 (s, 2H), 3.69 (t, 2H, J=6.2 Hz), 3.60 (t, 2H, J=6 Hz), 3.23 (t, 2H, J=6.2 Hz), 2.08 (q, 2H, J=6.2 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1OC
Product: CCOC(=O)C(=CNc1ccc(OC)c(OC)c1)C(=O)OCC
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10 g of 3,4-dimethoxyaniline in 13.2 cm3 of diethyl ethoxymethylenemalonate was stirred for 1.5 hours at a temperature in the region of 110° C. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. 21.1 g of diethyl 2-[(3,4-dimethoxyphenylamino)methylene]malonate were obtained in the form of a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].N1CCCC1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1/[CH:12]=[CH:15]/[N:16]([CH3:18])[CH3:17]
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CN(C)/C=C/c1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitrobenzene (5.0 g, 21.37 mmol) in N,N-dimethylformamide (50 mL) was added N,N-dimethylformamide dimethyl acetal (8.58 mL, 64.1 mmol) and pyrrolidine(1.767 mL, 21.37 mmol). The reaction mixture was heated at 110° C. for 4 hours. After cooling to room temperature, the N,N-dimethylformamide was removed by evaporation. The residue was taken up in diethyl ether and water. After separation of the organic layer, the aqueous layer was re-extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated to give a red/brown oil which was used directly in the following reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:11][CH2:10][C:9]#[N:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Product: N#CCCSc1cccc(Br)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
3-Bromothiophenol (10 g, 52.9 mmmol) was dissolved in acrylonitrile (11.28 g, 213 mmol). Triton B (1 mL) was added, at which time the reaction mixture became exothermic and began to reflux without added heat. The mixture was allowed to cool to room temperature, poured into cold aqueous sodium hydroxide (2%; 200 mL), and extracted with diethyl ether. The organic layer was dried, filtered and evaporated to provide 12 g (93%) of 3-[(3-bromophenyl)thio]propionitrile as a tan oil; 1H NMR (CDCl3) δ7.54 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 7.25-7.15 (m, 2H), 3.15 (t, 2H), 2.62 (t, 2H); Mass spectrum m/z 261, 259 (M+NH4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br.[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27]Br)[CH2:21]1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2-c2ccccc2)C1
Yield: 43.4 %

Procedure:
A mixture of 2-hydroxybiphenyl (3.0 g, 17.6 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (6.1 g, 17.6 mmol, EP 374801), potassium carbonate (9.7 g, 71 mmol) and methyl isobutylketone (50 ml) was heated at reflux for 22 h. The reaction mixture was allowed to cool, diluted with methyl isobutylketone and filtered. The solvent was evaporated in vacuo and the residue was purified by column chromatography (heptane/ethyl acetate=2/3) to give 2.7 g of (R)-1-(2-(2-phenylphenoxy) ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc(-c2cc[nH]n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Compound 17a (1 g, 6.9 mmol) obtained from the aforesaid process and 3,4-difluoro-nitrobenzene (0.74 mL) were dissolved in N,N-dimethylformamide (20 mL), and then anhydrous potassium carbonate (1.9 g) was added thereto. The mixture was reacted at 100° C. for 4 hours. After completion of the reaction, the reactant mixture was cooled to room temperature. Water was added to the mixture, resulting in a substantial amount of precipitate. Then, the precipitate was suction-filtered, and the filter cake was recrystallized with acetone to get the product 18a as a white powder (1.7 g), with a yield of 93.4%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][OH:19].C(N(CC)C(C)C)(C)C.[CH2:29](Cl)[O:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([Cl:17])=[CH:4][C:3]=1[CH2:18][O:19][CH2:29][O:30][CH3:31]
Reactant: COCCl
Reactant: CCc1ccc(Cc2cc(Br)c(CO)cc2Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)c(COCOC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a cooled (0° C.) solution of (2-bromo-5-chloro-4-(4-ethylbenzyl)phenyl)methanol (4.0 g, 11.8 mmol) in CH2Cl2 (60 mL), was added N,N-Diisopropylethylamine (DIPEA) (10.5 mL, 59.0 mmol) and MOMCl (4.5 μL, 59.0 mmol) successively. The reaction mixture was kept at 0° C. for 1 h, and then warmed to room temperature and kept at that temperature for 4 h. The reaction was quenched with H2O, the organic layer was separated and the aqueous layer was extracted 2× with CH2Cl2. The combined organic layers were washed 1× with brine prior to drying over Na2SO4. The volatiles were removed using a rotary evaporator and the resulting residue was purified by a silica gel column (50:1 petroleum ether:ethyl acetate as eluent) to give 4.05 g of pure product as colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.52 (s, 1H), 7.33 (s, 1H), 7.12 (q, 4H), 4.77 (s, 2H), 4.60 (s, 2H), 4.03 (s, 2H), 3.44 (s, 3H), 2.64 (q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:14])=[N:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]2[N:6]=[C:5]([NH2:14])[CH:4]=[N:3][C:2]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: Nc1cnc(Br)c(-c2cccnc2)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccncc2)c(-c2cccnc2)n1
Temperature: 150 °C
Yield: 93.4 %

Procedure:
A mixture of 5-bromo-6-pyridin-3-ylpyrazin-2-amine (Preparation 6, 0.4 g, 1.59 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.424 g, 2.07 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride dichloromethane complex (1:1) (76 mg, 0.095 mmol) and cesium carbonate (1.55 g, 4.77 mmol) in dioxane (14 mL) and water (3.72 mL) was heated to 150° C. for 10 minutes in the microwave oven. The mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and evaporated. Silica gel flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.37 g, 74%) as a solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C>>[OH:23][CH2:22][CH2:21][CH2:20][N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1B from 4-(2,2,2-trifluoro-ethylamino)-2-trifluoromethyl-benzonitrile and [(3-bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane: MS (APCI) m/z 327 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1ccc(-c2cc(O)no2)cc1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Yield: 66.4 %

Procedure:
3-Hydroxy-5-(4-hydroxyphenyl)isoxazole (0.1 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.12 g, 67%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH2:31])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1OC
Product: COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1OC

Procedure:
The product from Example 1d (277 mg, 1.56 mmol) was reacted with the product from Example 51b (430 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (628 mg, 79%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.35 (s, 3H) 2.76 (s, 3H) 3.56 (s, 3H) 3.68 (s, 3H) 6.24 (d, J=6.99 Hz, 1H) 6.82 (m, 3H) 7.29 (m, 3H) 7.79 (d, J=8.46 Hz, 1H) 8.38 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.46 Hz, 1H) 10.97 (s, 1H) 14.35 (s, 1H); MS (ESI+) m/z 418 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[C:3]1[C:20]1[CH:38]=[CH:37][C:23]([N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.Br[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>>[C:25]1([N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][C:20]([C:3]3[N:2]([CH3:1])[C:6]([C:40]4[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=4)=[CH:5][CH:4]=3)=[CH:21][CH:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)n1C
Reactant: O=Cc1ccc(Br)cc1
Product: Cn1c(-c2ccc(C=O)cc2)ccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
As shown in scheme 1, 4-bromo-N,N-diphenylaniline (11) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12). n-butyl lithium is reacted with 4-(1-methyl-1H-pyrrole-2-yl)-N,N-diphenylaniline (12), and then tributylstannylchloride is added thereto to obtain 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13). 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) is reacted with 4-bromobenzaldehyde by Stille coupling reaction to obtain 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a). Finally, 4-(5-(4-(diphenylamino)phenyl)-1-methyl-1H-pyrrol-2-yl)benzaldehyde (14a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[4-(5-(4-(diphenyl-amino)phenyl)-1-methyl-1H-pyrrol-2-yl)]phenyl)acrylic acid (15a) is synthesized.