Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:28][CH2:29][CH2:30][NH2:31]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([NH:31][CH2:30][CH2:29][OH:28])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(NCc4ccccc4)ncnc23)CC1
Product: O=S1(=O)CCN(c2nc(NCCO)nc3c(NCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 2 from 8-benzylamino-2-chloro-4-(1,1-dioxido-thiomorpholino)pyrimido[5,4-d]pyrimidine (melting point: 213°-215° C.) and 2-hydroxyethyl-amine.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[C:10]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][C:12]2[N:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:13]=2[CH:23]=1.[Cl:31]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:31][C:15]1[N:14]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:13]2[CH:23]=[C:9]([Cl:8])[C:10]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][C:12]=2[N:16]=1
Reactant: COCCOCn1cnc2cc(Oc3ccccc3)c(Cl)cc21
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCOCn1c(Cl)nc2cc(Oc3ccccc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of diisopropylamine (260 L, 1.85 mmol) in dry THF (2 mL) cooled in −78° C. bath was added n-buthyllithium in hexanes (1.16 mL of a 1.6 M solution). After 45 min, the contents of the flask were added via syringe to a −78° C. solution of 6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole (0.560 g, 1.68 mmol) in dry THF (2 mL). After 60 min, N-chlorosuccinimide (0.247 g, 1.85 mmol) in THF (3 mL) was added via syringe to the dark solution at which time the color changed to light brown. The reaction mixture was allowed to warm to ambient temperature then was added to saturated aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with 0.5 M citric acid, 5% aq. NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.251 g, 41%; orange oil). MS (ESI/CI): mass calcd. for C17H16Cl2N2O3, 366; m/z found, 367 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.62 (s, 1H), 7.37 (s, 1H), 7.36-7.29 (m, 4H), 7.18 (s, 1H), 7.14-7.04 (m, 2H), 6.98-6.90 (m, 4H), 5.63 (s, 2H), 5.54 (s, 2H), 3.72-3.63 (m, 2H), 3.63-3.57 (m, 2H), 3.57-3.50 (m, 2H), 3.49-3.42 (m, 2H), 3.38 (s, 3H), 3.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>CN(C)C=O.CCCCC>[CH2:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.2 g of methyl4-hydroxybenzoate (100 mmol) in 125 mL of N,N-dimethylformamide was added under stirring 33.13 g of potassium carbonate (240 mmol). Then 17.45 g of benzyl bromide (102 mmol) was added within 5 minutes. The mixture was stirred at 25° C. using a water bath. The reaction was complete after 3 hours. The reaction mixture was poured into a mixture of 180 g of ice and 200 mL of ethyl acetate. After extraction, the aqueous phase was separated and extracted with three portions of 80 mL of ethyl acetate. The organic phase was washed with two portions of 150 mL of water, combined, dried (MgSO4) and partially concentrated to give a thick suspension. 60 mL of pentane was added and the suspension was stirred during 2 hours at room temperature. The crystalline methyl 4-benzyloxybenzoate was collected on a filter, washed with pentane and dried.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[CH2:20]([NH2:22])[CH3:21]>CN1CCCC1=O.O>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[NH:22][CH2:20][CH3:21]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Reactant: CCN
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 4-chloro-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine (1.330 g, 4.822 mmol) and 20 ml of ethyl amine in 13 ml of 1-methyl-2-pyrrolidinone was heated at 150° C. at 250 psi overnight in a pressure reactor. The reaction was heated an additional 24 hours at 175° C. and 300 psi. The reaction mixture cooled to room temperature and diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using chloroform to 2% methanol in chloroform as eluent to give 0.820 g (60%) of the title compound as a white solid, mp 115–116° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[C:34]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[C:34]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:31])(=[O:40])=[O:41])=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: NS(=O)(=O)c1ncccc1Cl
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ncccc3Cl)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-chloro-2-pyridinesulfonamide (U.S. Pat. No. 4,490,380): 1H-NMR (DMSO-d6) δ 8.62 (1H, d, J=4.3 Hz), 8.20 (1H, d, J=7.9 Hz), 7.71-7.67 (1H, m), 7.49-7.31 (9H, m), 6.57 (1H, br.s), 3.37-3.28 (2H, m), 2.79-2.74 (2H, m), 2.27 (3H, s), 2.23 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:25][N:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:35])[C:29]=2[CH:28]=[CH:27]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:29]=1[CH:28]=[CH:27][N:26]2[CH3:25])#[N:9]
Reactant: Cn1ccc2c(N)cccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1ccc(C#N)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1ccc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ccc3C#N)cccc21
Reaction time: 16 h
Yield: 39.5 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(3-bromo-4-cyanophenylamino)cyclohexylcarbamate (200 mg, 0.507 mmol), 1-methyl-1H-indol-4-amine (160 mg, 1.09 mmol), BINAP (50 mg, 0.080 mmol), Pd(OAc)2 (25 mg, 0.11 mmol) and K2CO3 (150 mg, 1.08 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 100 C for 16 h. EtOAc and water were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with 10-40% EtOAc in hexane to give tert-butyl (1S,2R)-2-(4-cyano-3-(1-methyl-1H-indol-4-ylamino)phenylamino)cyclohexylcarbamate (92 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([O:26]C)=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[C:20]3[CH:21]=[CH:22][S:23][C:19]=3[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[OH-].[Na+].Cl>O>[F:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[C:20]3[CH:21]=[CH:22][S:23][C:19]=3[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3nccc4sccc34)s2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1nccc(Sc2cnc(Nc3nccc4sccc34)s2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of methyl 3-fluoro-4-(2-(thieno[3,2-c]pyridin-4-ylamino)thiazol-5-ylthio)picolinate (3.13 g, 7.48 mmol) was treated with aqueous sodium hydroxide (1N, 12 mL, 12.0 mmol) and was stirred at room temperature for 2 hours. The reaction was then acidified to pH ˜6 with 10% aqueous HCl and then poured into water (300 mL) and allowed to sit overnight for complete precipitation. The solid was collected by filtration, washed with water and air dried to give the title material (1.86 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.24 (1H, s), 8.22 (1H, d, J=5.56 Hz), 8.18 (1H, d, J=5.05 Hz), 8.15 (1H, d, J=5.81 Hz), 7.90 (1H, s), 7.87 (1H, d, J=5.56 Hz), 7.69 (1H, d, J=5.56 Hz), 6.94 (1H, t, J=5.31 Hz). LC/MS (M+H)+: 405. HPLC ret. time (Condition I): 1.28 min.
Reaction SMILES: C(N1CCN(C(=O)C([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=O)C(C)C1)(=O)C1C=CC=CC=1.COC1C=NC(OC)=C2C=1C(C(=O)C([O-])=O)=CN2.[K+]>>[CH3:28][O:27][C:25]1[CH:24]=[N:23][C:22]([O:29][CH3:30])=[C:21]2[C:26]=1[CH:18]=[CH:19][NH:20]2
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3C)c[nH]c12
Agent: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12
Agent: [K+]
Product: COc1cnc(OC)c2[nH]ccc12

Procedure:
Compound 5ap, {circle around (R)}N-(benzoyl)-3-methyl-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]piperazine (white solid) was prepared using the same method used to prepare compound 5a except that Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was used as the starting material. MS m/z: (M+H)+ calcd for C23H25N4O5: 437.18; found 437.24. HPLC retention time: 1.37 minutes (column B).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:6][C@H:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[C:15](=[O:37])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:4]1>O1CCOCC1>[OH:25][NH:24][C:22](=[O:23])[C@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:20][CH2:19][N:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C@H:5]3[CH2:4][C@@H:3]([OH:2])[CH2:6]3)=[CH:8][CH:9]=2)=[CH:14][C:15]1=[O:37]
Reactant: C[C@@](CCn1ccc(-c2ccc([C@H]3C[C@@H](O)C3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc([C@H]3C[C@@H](O)C3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
HCl (1.0 N in water, 3.58 mL) was added to a solution of (2R)-4-{4-[4-(cis-3-hydroxycyclobutyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (620 mg, 1.20 mmol) in 1,4-dioxane (10 mL). After 2 hours the reaction was concentrated to give a brown solid. The solid was triturated with ethanol at 50° C., for 30 minutes. After cooling, filtration afforded the title compound as a white solid (384 mg, 74%). LCMS m/z 435.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 1.83-1.98 (m, 2H) 2.11-2.24 (m, 1H) 2.44 (d, J=17.95 Hz, 1H) 2.54-2.69 (m, 2H) 2.83-3.00 (m, 1H) 3.11 (s, 3H) 3.65-3.84 (m, 1H) 3.98-4.18 (m, 2H) 6.65 (dd, J=7.02, 2.15 Hz, 1H) 6.69 (d, J=1.95 Hz, 1H) 7.34 (d, J=8.20 Hz, 2H) 7.62-7.71 (m, 2H) 7.74 (d, J=7.02 Hz, 1H) 11.17 (br. s., 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][C:22]=1[F:29].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:11])[CH:9]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([F:29])[CH:23]=1)[OH:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C=O)c1ccc(Cl)nc1
Reactant: Fc1cc([Mg]Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(c1ccc(Cl)nc1)C(O)c1ccc(Cl)c(F)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
A tetrahydrofuran (20 ml) solution of the compound (6.47 g, 22.7 mmol) obtained in Step 3 above was added dropwise to 4-chloro-3-fluorophenyl magnesium bromide (0.5 M tetrahydrofuran solution) (100 ml, 50.0 mmol) under ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. An aqueous solution of saturated ammonium chloride was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. An n-hexane/ethyl acetate mixed solvent was added to the residue obtained and the resulting precipitate was collected by filtration and dried to give the title compound (7.92 g, 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22].O>C(Cl)Cl>[CH3:18][O:19][CH2:20][C:21]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:22]
Reactant: CNc1cccc(N)c1C#N
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CNc1cccc(NC(=O)COC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzonitrile (3.3 g) in methylene chloride (50 ml) is added pyridine (3.6 ml) and thereto is added dropwise methoxyacetyl chloride (4.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (1.9 g) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([OH:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]=1[CH3:7]
Reactant: C1COCCN1
Reactant: Cc1c(Br)cnn1CC1(OCC(=O)O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cnn1CC1(OCC(=O)N2CCOCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 174B (331 mg) in dichloromethane (10 mL) was added morpholine (174 mg), 4-dimethylaminopyridine (122 mg) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (287 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][C:18]([C:20]1[CH:36]=[CH:35][C:23]2[CH2:24][CH2:25][N:26]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:27][CH2:28][C:22]=2[CH:21]=1)=[O:19]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:17][C:18](=[O:19])[C:20]2[CH:36]=[CH:35][C:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:34])[C:30]([F:33])([F:31])[F:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.00 g (4.97 mmol) 4-benzyloxy-1H-pyridin-2-one in THF at 0° C. is added subsequently 613 mg (5.47 mmol) potassium-tert-butylate, 92 mg (0.25 mmol) tetra-butylammonium-iodide and 2.38 g (7.46 mmol) 1-[7-(2-chloro-acetyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is taken up in DCM and aqueous 2M sodium hydroxide solution. The layers are separated, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via chromatography (silica gel; DCM/MeOH 95:5) and then via reverse HPLC purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][S:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21]>O1CCCC1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:10]1[CH:11]=[N:12][C:8]([S:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[N:9]1)=[O:24])[CH3:21]
Reactant: C=CCOCCSc1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOCCSc1ncn(C(=O)N(CC)CC)n1

Procedure:
A solution of 7.4 C. 3-(2-allyloxyethylthio)-1,2,4-triazole, 8 ml. triethylamine 6.0 g. diethylcarbamoyl chloride in 40 ml. of tetrahydrofuran was heated under reflux for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated under vacuum to remove the solvent. Further precipitation of amine hydrochloride was filtered off. The filtrate was dissolved in 50 ml. methylene chloride and washed with ice-cold N/ 10 sodium hydroxide, with N/ 10 hydrochloric acid and finally with ice-cold water. The solvent was removed by vacuum distillation to give a liquid product, 1-diethylcarbamoyl-3-(2-allyloxyethylthio)-1,2,4-triazole, b.p. 148°-153° C./0.05 mm. GLC assay showed that the 1-isomer was present to the extent of 98.33%. Elemental analysis was satisfactory.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]([CH:30]=O)=[CH:22][CH:21]=1.N1CCCCC1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:30][C:23]1[CH:22]=[CH:21][C:20]([OH:19])=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[N:28]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=Cc1ccc(O)c3ncccc13)C(=O)N2
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of 5-t-butoxycarbonylamino-2-oxindole (630 mg, 2.5 mmol) and 8-hydroxyquinoline-5-carbaldehyde (450 mg, 2.6 mmol) in absolute alcohol was added piperidine (0.26 g, 2.6 mmol). The reaction was carried out at 80° C. for 3 h. The solvent was evaporated and the residue was purified by silica gel chromatography (eluant cyclohexane/ethylacetate 2:3) thus giving 800 mg of 5-(t-butoxycarbonylamino)-3-(8-hydroxyquinol-5-ylmethylen)-2-oxindole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([Br:16])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1cc(OCc2ccccc2)ccn1
Solvent: CC(=O)O
Product: Nc1cc(OCc2ccccc2)c(Br)cn1
Yield: 47 %

Procedure:
A flask was charged with 4-(benzyloxy)pyridin-2-amine (10.69 g, 53.39 mmol) and 20 mL acetic acid was added. Bromine (2.735 ml, 53.39 mmol) and the reaction was stirred for 10 minutes. The reaction mixture was concentrated and purified using silica gel column chromatography eluting with 50%-100% ethyl acetate/hexane provide the desired product (7.0 g, 42.28% yield) as brown solid
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: BrBr
Reactant: c1cncc(-c2c3ccccc3cc3ccccc23)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 26 h

Procedure:
In a 200 μL three-neck flask, 1.0 g (4.0 mmol) of 3-(9-anthryl)pyridine and 25 mL of carbon tetrachloride were placed. Then, 10 μL of a carbon tetrachloride solution containing 0.83 g (5.1 mmol) of bromine was dripped into the solution under nitrogen stream, and the solution was stirred for 26 hours at room temperature. After a certain period, 100 mL of a 1.0 M sodium thiosulfate solution was added into the mixture. Then, an aqueous layer of the mixture was extracted with chloroform. The obtained extracted solution and the organic layer were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. A chloroform solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina, and the filtrate was condensed to give a solid. The solid was recrystallized with ethyl acetate/hexane, so that 0.74 g of target pale yellow powder was obtained in a yield of 53%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)=[CH:4][N:3]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N

Procedure:
A stirred solution of 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine [prepared by the method of Taylor and Ray--JOC, 52, 3997 (1987)], 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid commercially available or prepared by the method of Thompson and Gaudino--JOC, 49, 5237 (1984)], 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine.