Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:18][C:17]=1[CH3:28]>C1(C)C=CC=CC=1.[Pd](Cl)Cl.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>[CH3:28][C:17]1[CH:18]=[C:19]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)[CH:20]=[CH:21][C:16]=1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc([Sn](C)(C)C)nc1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(-c3nnc(C)o3)cc2C)nc1
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Methyl 6-(trimethylstannyl)nicotinate (D11, 0.300 g, 1.00 mmol) was dissolved in dry toluene (15 ml) and was treated with 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268A1) (0.211 g, 0.834 mmol). The mixture was flushed with argon and bis(triphenyl phosphine)pallalladium (II) chloride (0.029 g, 0.042 mmol) was added. The mixture was then heated to reflux under argon. After 2 h, further methyl 6-(trimethylstannyl)nicotinate (0.030 g, 0.100 mmol) in toluene (2 ml) and bis(triphenylphosphine) palladium (II) chloride (0.010 g, 0.014 mmol) was added. Reflux was continued for a further 2 h before the reaction mixture was allowed to cool. The reaction mixture was then filtered through kieselguhr. The kieselguhr was washed with toluene (2×20 ml) and the filtrate was evaporated under reduced pressure to give a yellow/brown solid which was dried in vacuo (0.450 g). The solid was then purified by silica-gel chromatography (1:1 Petrol 60-80: EtOAc as eluant) to give the title compound as a cream coloured solid (0.140 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O>CC(O)=O.CCO.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(F)ccc1Br

Procedure:
To a solution of 1-bromo-4-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) in HOAc/EtOH (20 mL/20 mL) was added iron powder in one portion at room temperature. The mixture was bubbled with N2 for 5 min, and then refluxed for 2 hrs. Partial of the solvents were removed on rotary vacuum, then the residue was partitioned between aqueous NaOH (10N, 200 mL) and Et2O (200 mL). After separation, the organic phase was washed with H2O (50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, as an light tan oil (quantitative yield), which was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δppm 4.15 (s, 1 H), 6.34 (td, J=8.44, 2.77 Hz, 1 H), 6.46 (dd, J=10.20, 2.90 Hz, 1 H), 7.31 (dd, J=8.81, 5.79 Hz, 1 H); Mass spec. 189.94 (MH+), Calc. for C6H5BrFN 188.96
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9]C)=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23]C)C(O)=O>>[Br:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]2[N:6]=[C:12]([C:16]3[CH:20]=[CH:21][C:22]([OH:23])=[C:14]([F:13])[CH:15]=3)[O:11][C:4]=2[CH:3]=1
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: COc1cc(Br)c(OC)cc1N
Product: Oc1ccc(-c2nc3cc(O)c(Br)cc3o2)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 4-bromo-2,5-dimethoxyaniline, and 3-fluoro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 224-226° C.; MS m/e 322 (M−H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[F:11])[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=[O:13])[C:10]=1[F:11])[NH:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)c(F)c(C(=O)O)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c(F)c(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a stirred solution of 5-bromo-1-{[(1,1-dimethylethyl)oxy]carbonyl}-6-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (8.3 g, 0.023 mol) in DCM (90 mL) was added TFA (90 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated. The residue was partitioned between EtOAc (100 mL) and water (100 mL), and the aqueous fraction was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (1×50 mL) and brine (1×50 mL). dried (Na2SO4) and concentrated under reduced pressure, giving 5.9 g (99%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([Br:17])=[CH:9][C:6]=1[CH2:7]Br)(=[O:3])[CH3:2].[CH3:18][NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(Cl)(Cl)(Cl)[Cl:27]>>[ClH:27].[C:1]([NH:4][C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([Br:17])=[CH:9][C:6]=1[CH2:7][N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:18])(=[O:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)Nc1cc(C(C)(C)C)c(Br)cc1CBr
Reactant: CNC1CCCCC1
Product: CC(=O)Nc1cc(C(C)(C)C)c(Br)cc1CN(C)C1CCCCC1
Product: Cl

Procedure:
A mixture of 25 gm of 2-acetylamino-5-bromo-4-tert.butyl-benzyl bromide, 1.5 liters of carbon tetrachloride and 23 gm of N-methyl-cyclohexylamine was refluxed for 1 hour. After cooling, the precipitated N-methyl-cyclohexylamine hydrobromide was filtered off and the filtrate was evaporated. The residue was admixed with 2 N hydrochloric acid, and the mixture was extracted twice with benzene. The acid phase was made alkaline with concentrated ammonia, extracted three times with chloroform, and the organic phase was dried and evaporated. The residue was purified by column-chromatography on silicagel with ethylacetate/chloroform (1:1), and 2-acetylamino-5-bromo-4-tert.butyl-N-cyclohexyl-N-methylbenzylamine hydrochloride was precipitated from a solution of the purified residue in ethanol/ether with ethanolic hydrochloric acid. The crude product was recrystallized from ethanol-ether, whereupon it had a melting point of 231°-234° C.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:26][CH2:27][C:28]#[N:29]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:29][CH2:28][C:27]#[N:26])=[O:14])=[CH:7][CH:8]=1
Reactant: N#CCN
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1cccnc1)C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1cccnc1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (132 mg, 0.35 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 10% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.C(N(CC)CC)C.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>[Pt].C1(C)C=CC=CC=1.C(O)C>[CH2:30]([O:32][CH2:33][C:34]1[N:14]([CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=1)[CH3:31]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Reactant: CCOCC(=O)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol prepared above (87%, 7.00 g, 20.3 mmol) and 5% platinum on carbon (0.60 g) in toluene (160 mL) and ethanol (20 mL) was hydrogenated at 20-30 psi (1.4×105 to 2.1×105 Pa) on a Parr apparatus for 2 h. The mixture was filtered through CELITE filter agent, which was rinsed with toluene. The filtrate was concentrated to a golden oil. The oil was concentrated twice from toluene. To the oil was added CH2Cl2 (200 mL) and the resulting solution was cooled in an ice bath. Triethylamine (3.11 mL, 22.3 mmol) was added followed by dropwise addition of ethoxyacetyl chloride (88%, 2.96 g, 21.3 mmol). The solution was allowed to warm to rt and stir for 1 h, during which time a precipitate formed. The reaction mixture was concentrated to a yellow foam to which ethanol (200 mL) and triethylamine (11 mL) were added. The resulting solution was heated at reflux for 13 h. The solution was concentrated to a yellow solid, which was dissolved in CH2Cl2 (150 mL) and washed with water (50 mL) and brine (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated to a solid that was crystallized from CDCl3/CH2Cl2 to yield 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as pale orange crystals after drying (1.94 g, 28%).
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].O1CCOCC1.S(=O)(=O)=O.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>ClC(Cl)C>[CH2:15]([O:19][S:1](=[O:3])(=[O:2])[OH:4])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CO
Reactant: O=S(=O)=O
Solvent: CC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)COS(=O)(=O)O

Procedure:
609 g sulfur trioxide-dioxane addition product, which contained 143.9 g (1.8 mols) sulfur trioxide and was dissolved in 400 g dichloroethane, was reacted with 137.1 g (1.85 mols) isobutanol, and a solution of sulfuric acid monoisobutylester in dichloroethane was obtained. 66 g of this solution, which contained 49 g (0.32 mol) sulfuric acid monoisobutylester, was added dropwise within 1 hour to 59.5 g (0.33 mol) dichlorophenylphosphane. The whole was initially heated for a short while to 30° C. and then cooled with water to maintain the reaction temperature at 20° C. Next, the reaction mixture was stirred for 4 hours at room temperature, stripped under a vacuum of 1 mm mercury and at a temperature of up to 30° C. 79 g of a brown, medium-viscous crude product was obtained. 31P-NMR-spectroscopy indicated that 41% of the phosphorus used was present in the crude product in the form of benzenephosphonic acid isobutylester chloride.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([CH3:20])[C:6]=2[CH:5]=[C:4]([CH3:21])[C:3]=1[CH3:22].N(S([O-])(=O)=O)(S([O-])(=O)=[O:26])[O].[K+].[K+]>CC(C)=O.OP([O-])(O)=O.[K+]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:8]2[O:9][C:10]3[C:2](=[O:1])[C:3]([CH3:22])=[C:4]([CH3:21])[C:5](=[O:26])[C:6]=3[C:7]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: COc1ccc(Cc2oc3c(O)c(C)c(C)cc3c2C)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3c(c2C)C(=O)C(C)=C(C)C3=O)cc1
Temperature: 45 °C

Procedure:
A solution of 7-hydroxy-2-(-4-methoxybenzyl)-3,5,6-trimethylbenzofuran from Step 4 (8.6g, 29 mmol) in acetone (1.5 L) was added rapidly to a solution of potassium nitrosodisulfonate (Fremy's salt) (25 g, 93 mmol) in 0.055 M KH2PO4 buffer (1.5 L) at room temperature. The reaction was slowly heated to 45° C. over a period of 2 hr. The reaction was then cooled and the quinone was extracted with EtOAc (2×, 500 mL). Evaporation of the organic solvent gave a solid residue which was crystallized and re-crystallized from EtOH, to give the title compound, mp 111°-113° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19](C(O)(C)C)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.[CH2:27]1[O:29][CH:28]1[CH2:30][OH:31].C(N(CC)CC)C.C([OH:41])C>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19]([O:29][CH2:27][C@@H:28]([OH:41])[CH2:30][OH:31])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2
Reactant: CCO
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(C(C)(C)O)c(C)c34)ccc2[nH]1
Reactant: OCC1CO1
Solvent: CCN(CC)CC
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OC[C@@H](O)CO)c(C)c34)ccc2[nH]1
Yield: 48 %

Procedure:
A mixture of Example 1 (45 mg, 0.14 mmol), S-(−) glycidol (330 mg, 4.2 mmol ) and triethylamine (5 μL) in ethanol (15 mL) was heated at 75° C. for 2 h. The reaction was concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with 100% ethyl acetate to provide the title compound (26 mg, 48% yield) as a white solid. MS: (M+H)+=387.2
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]O)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Br)(Br)(Br)[Br:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][Br:38])=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of N-dodecyl-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.996 g, 1.74 mmol, 1 eq) in CH2Cl2 (9 mL) was added carbon tetrabromide (0.760 g, 2.29 mmol 1.3 eq) and triphenylphosphine (0.603 g, 2.29 mmol, 1.3 eq). The reaction was stirred at overnight at rt and concentrated in vacuo. The residue was purified by flash chromatography (15% EtOAc:hexane) to afford N-dodecyl-3-bromo4-(2-bromo-ethoxy)-5(m-trifluoromethylphenyl)-benzamide (0.951 g, 89%) as a colorless oil. 1H NMR (CDCl3) δ 7.98 (d, 1H); 7.78-7.40 (m, 5H); 6.20 (bt, 1H); 4.52 (dd, 2H); 3.95 (dd, 2H); 3.42 (dd, 2H); 1.50 (m, 2H); 1.30 (m, 18H); 0.92 (t, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:25]([C:26]5[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=5)=[CH:24][N:23]([CH3:32])[N:22]=4)=[CH:17][CH:16]=3)=[N:10]2)=[CH:5][CH:4]=1.ClCC1C=CC2C(=CC=C([F:45])C=2)N=1>>[ClH:2].[F:45][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:3]=1)[N:10]=[C:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:24][N:23]([CH3:32])[N:22]=3)=[CH:17][CH:16]=1)[CH:8]=[CH:7]2
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccc(Cl)cc4n3)cc2)n1
Reactant: Fc1ccc2nc(CCl)ccc2c1
Agent: Cl
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4cc(F)ccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 7-Chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline hydrogen chloride but substituting 2-chloromethyl-6-fluoro-quinoline provided the title compound. 1H NMR (400 MHz, DMSO) δ 8.67 (d, J=6.6 Hz, 2H), 8.55 (s, 1H), 8.42 (d, J=8.3, 1H), 8.04 (m, 1H), 7.82 (m, 1H), 7.71 (m, 4H), 7.36 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7, 2H), 5.37 (s, 2H), 3.91 (s, 3H); MS: (M+H m/z=411.2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.CS(C)=[O:15].[ClH:17]>>[ClH:17].[NH2:12][CH2:11][CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:15]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CS(C)=O
Agent: Cl
Product: NCCC1C(=O)Nc2ccccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 2-(1H-indol-3-yl)ethanamine (6.00 g, 37.50 mmol) in DMSO (8.0 mL, 112.50 mmol) was added concentrated hydrochloric acid (9.5 mL, 112.50 mmol) slowly. The resulting reaction mixture was stirred at 50° C. in a sealed tube for 16 h. After cooling to room temperature, the reaction mixture was filtered. The resulting cake was stirred in EtOH (15 mL). The mixture was filtered and dried to give the desired title compound as a brown solid (5.00 g, 23.64 mmol, 63% yield). MS (ESI) m/z 177.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[N:18][CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].CCN=C=NCCCN(C)C>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]3[N:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[O:24])=[N:18][CH:19]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A mixture of (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (209 mg), O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (89 mg), HOBt (111 μg) and EDCI (158 mg) in DMF (4.5 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5) to give (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (198 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:32][NH:33][C:34](=[O:37])[CH2:35]Cl>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:35][C:34]([NH:33][CH3:32])=[O:37])[CH2:23][CH2:24]2)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=CC=CC(=O)N2CCNCC2)cc(OC)c1OC
Reactant: CNC(=O)CCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)CN1CCN(C(=O)C=CC=Cc2cc(OC)c(OC)c(OC)c2)CC1
Yield: 71.7 %

Procedure:
To a solution of 302 mg of 1-[5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl]-piperazine in dry toluene (12 ml) were added in an atmosphere of argon 1.3 ml of triethylamine and subsequently a solution of 254 mg of N-methylchloroacetamide in dry toluene-chloroform (1:1, 2 ml). The mixture was refluxed for 8 hours. To the reaction mixture was added water, and extraction was made with methylene chloride. The organic layer was concentrated under reduced pressure, and the residue thus obtained was chromatographed on silica gel column. There was obtained 263 mg of 1-[5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl]-4-(methylaminocarbonylmethyl)-piperazine. Spectrophotometric data of the product support the structure of the formula (V) shown below. ##STR5##
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[N:20]3[C:15]([CH:16]=[N:17][C:18](O)=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:22]([S:24](C1C=C(C2N3C(C=NC(SC)=N3)=CC=2)C=CC=1)(=[O:26])=[O:25])C.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>CO.CC(O)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[N:20]3[C:15]([CH:16]=[N:17][C:18]([S:24]([CH3:22])(=[O:26])=[O:25])=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc3cnc(SC)nn23)c1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCS(=O)(=O)c1cccc(-c2ccc3cnc(S(C)(=O)=O)nn23)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
7-(3-Ethanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol: To a mixture of Na2WO4.2H2O (62 mg, 0.19 mmol) and 7-(3-Ethanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.25 g, 3.76 mmol) in methanol (40.0 mL) was added 50% H2O2 (0.65 mL, 11 mmol) and the reaction was stirred at 60° C. for 5 h. The mixture was treated with HOAc (700 uL), 50% H2O2 (0.65 mL, 11 mmol) and Na2WO4.2H2O (65 mg, 0.2 mmol) and warmed at 60° C. until reaction was completed as analyzed by LC/MS. At this time, the mixture was treated with 10% aqueous solution of Na2S2O3 (5 mL) and the resultant solids were collected on a Buchner funnel, washed with water (5×5 mL) and dried in vacuo to afford 7-(3-ethanesulfonyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (1.33 g; Yield=97%, HPLC RT=2.51). To the above sulfone in 1,4-dioxane (4 mL) and DMSO (2.5 mL) was added an aqueous solution of 5N NaOH (11.1 mL, 55.4 mmol). The mixture was heated at 80° C., O/N, cooled in an ice bath and treated with 3M HCl until pH 4. The resulting solids were collected on a Buchner funnel, washed with water (5×5 mL) and dried in vacuo to afford the title compound (0.675 g; Yield=88%). LC/MS: 304 (M+H); HPLC: RT=1.81 min; 1H NMR: (DMSO, δ) 11.88 (br s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 8.59 (d, J=7.7, 1H), 7.87 (d, J=7.7, 1H), 7.80 (t, 1H, J=7.7), 7.45 (d, J=4.9, 1H), 7.06 (d, J=4.9, 1H), 3.39 (q, J=7.2, 2H), 1.15 (t, J=7.2, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52][CH:51]=1>CN(C=O)C>[N:50]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52][CH:51]=1
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cncnc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 61.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.015 g of product in 62% yield: LCMS (ESI) m/z 374 (MH+).