Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:20][C:21]1[C:22]([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]2)=[CH:23][C:24]([O:53][CH3:54])=[C:25]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[N:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][C:35]=3[C:43]3[CH:44]=[C:45]([CH:50]=[CH:51][CH:52]=3)[C:46](OC)=[O:47])[CH:31]=[CH:30][N:29]=2)[CH:26]=1.CO>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:46](=[O:47])[C:45]1[CH:50]=[CH:51][CH:52]=[C:43]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:34]=2[C:32]2[CH:31]=[CH:30][N:29]=[C:28]([NH:27][C:25]3[CH:26]=[C:21]([F:20])[C:22]([CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]4)=[CH:23][C:24]=3[O:53][CH3:54])[N:33]=2)[CH:44]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(F)c(CCN4CCCCC4)cc3OC)n2)c1
Reactant: Nc1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To 2,6-difluoroaniline (133 mg, 1 mmol) was added 1N NaHMDS in THF (1 mL, 1 mmol). The mixture stirred for 15 min at rt. Methyl 3-{3-[2-({5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]phenyl}amino)-4-pyrimidinyl]imidazo[1,2-a]pyridin-2-yl}benzoate (120 mg, 0.206 mmol) in 3 mL of dry THF was added. The mixture stirred at rt for 30 min. 1 mL of MeOH was added followed by 1 g of silica gel. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (52 mg, 0.0767 mmol, 37%). 1H NMR (400 MHz, CDCl3) δ ppm 9.46 (d, J=7.33 Hz, 1H), 8.21-8.29 (m, 3H), 8.11 (s, 1H), 8.02 (d, J=7.70 Hz, 1H), 7.74-7.83 (m, 2H), 7.66 (d, J=8.80 Hz, 1H), 7.47-7.56 (m, 1H), 7.32-7.40 (m, 1H), 7.22 (dd, J=8.43, 5.87 Hz, 1H), 6.91-7.01 (m, 3H), 6.76 (d, J=6.60 Hz, 1H), 6.63 (dd, J=5.32, 3.12 Hz, 1H), 3.92 (s, 3H), 2.79-2.87 (m, 2H), 2.54-2.61 (m, 2H), 2.45-2.54 (m, 4H), 1.59-1.68 (m, 4H), 1.42-1.52 (m, 2H). MS (ESI): 678 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:29][CH:30]=1)[CH:3]([NH:18]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:18][CH:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:14])[F:15])[CH:6]=1)[CH:2]([C:26]1[N:27]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:29][CH:30]=1)[OH:1]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of tert-butyl (1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate (1.67 g, 3.17 mmol) in chloroform (20 ml) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was basified with saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give (1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol (1.17 g, 87%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.CCN(C(C)C)C(C)C.[O:31]1[CH2:35][C@@H:34]([NH2:36])[C@@H:33]([NH2:37])[CH2:32]1>CN(C=O)C.CO>[NH2:36][C@H:34]1[CH2:35][O:31][CH2:32][C@H:33]1[NH:37][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1
Reactant: N[C@@H]1COC[C@@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2COC[C@@H]2N)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (40 mg, 0.133 mmol) in DMF (1 mL) was added DIPEA (0.046 mL, 0.265 mmol) and (3R,4S)-tetrahydrofuran-3,4-diamine (13.54 mg, 0.133 mmol). The mixture was stirred at RT overnight. Additional amine was added and the reaction mixture was stirred at RT for an additional day. The reaction mixture was diluted in MeOH (10 mL) and purified by reverse phase preparative HPLC. The fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (35.5 mg, 73%). [M+H] calc'd for C19H21N5O3, 368. found, 368.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:31][CH:32]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3=CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CC=C(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.24 mmol), N,N-dimethylglycine (27 mg, 0.26 mmol), EDCl (50 mg, 0.26 mmol), HOBt (35 mg, 026 mmol), and N,N-diisopropylethylamine (124 μL, 0.71 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 24 mg (20%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.96 (s, 1 H), 7.81 (d, 1 H), 7.61 (s, 1 H), 7.27-7.37 (m, 5 H), 7.14 (dd, 1 H), 7.03-7.10 (m, 1 H), 6.80-6.84 (m, 1 H), 5.65 (s, 2 H), 4.25 (d, 2 H), 3.69 (dt, 2 H), 3.13 (d, 2 H), 2.63-2.70 (m, 1 H), 2.53-2.60 (m, 1 H), 2.17 (m, 6 H); ES-MS m/z 507.17 [M+H]+, HPLC RT (min) 1.36.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:9].[Na+].[CH3:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH2:18][CH2:19][CH3:20]>CC(C)=O>[CH2:1]([I:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:9].[CH2:1]([N+:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][CH3:20])=[C:12]([CH3:11])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CCCc1ccncc1C
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCc1cc[n+](Cc2ccccc2)cc1C
Product: ICc1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzyl iodide in acetone was prepared from benzyl chloride (823 g.) and sodium iodide (975 g.). 3-Methyl-4-propylpyridine (879 g.) was added and the mixture was stirred at room temperature. Crystallization of the product from acetone-isopropyl acetate afforded 1-benzyl-3-methyl-4-propylpyridinium iodide in two crops (1334 g. and 162 g.), which melted at 94°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[S:22])[CH3:6]
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(Br)cccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(C)C(=S)c1cccc2c(Br)cccc12
Temperature: 25 °C

Procedure:
To a stirred solution of N-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (35.5 g, 106 mmoles, described in Example 2) in dry pyridine (100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise. The mixture was stirred and refluxed for 1.5 hr and then poured into a liter of water at 50° to 80° C. (caution: evolution of copious quantities of H2S). The mixture was allowed to cool to 20° to 22° C. (room temperature), filtered and the filtrate was extracted with ethyl acetate. The extract was washed with 1 N aqueous HCl solution, brine, a saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethanol-water (4:1) to give the title compound; mp 85°-86° C.; NMR (CDCl3) δ3.0 (s, 3H), 3.85 (s, 3H), 4.58 & 5.37 (2d, J=17, 2H), 7.1-8.3 (m, 6H); UVλmax (EtOH) 281 nm (ε14,480), 218 (14,480).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][N:3]1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: COC(=O)c1ccn(C(C)c2ccccc2)c(=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(c1ccccc1)n1ccc(C(=O)O)cc1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate (90 mg, 0.35 mmol), lithium hydroxide monohydrate (57.1 mg, 1.36 mmol), tetrahydrofuran (5 mL), methanol (1 mL) and water (1 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with acetic ether (15 mL×3). The combined organic phase was dried by sodium sulfate, then filtered. The filtrate was concentrated in vacuum to give 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid as a white solid (60 mg, 70%). LRMS (M+H)− m/z: cald. 243.09. found 243.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)([O-])=O.I[CH3:21]>CC(C)=O.C1C=CC=CC=1.CO.[Pt](=O)=O>[CH3:21][N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=2[NH2:1])[CH2:15]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1-c1cccnc1
Reactant: CI
Agent: O=[Pt]=O
Solvent: c1ccccc1
Solvent: CO
Solvent: CC(C)=O
Product: CN1CCCC(c2ccc(C(F)(F)F)cc2N)C1
Reaction time: 120 h

Procedure:
To an orange solution of 3-(2-nitro-4-(trifluoromethyl)phenyl)pyridine (1.4 g, 5.2 mmol) in 2 ml acetone and 1 mL benzene was added iodomethane (1.0 ml, 16 mmol). The solution was allowed to stand for 5 days, and was concentrated in vacuo to give an orange solid. A portion of this material was treated with platinum (IV) oxide (0.11 g, 0.49 mmol) in 5 ml MeOH under an atmosphere of hydrogen for approximately 24 h. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Purification by silica gel chromatography (MC/MeOH/conc. NH4OH) provided the title compound. MS (m/z): 259.0 (M+H)+. Calc'd for C13H17P3N2: 258.28.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[C:6]2=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20](O)=[O:21]>>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][N:25]=1)[C:20]([NH:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:12])([CH3:13])[C:6]2=[CH:5][CH:4]=1)=[O:21]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)nc21
Reactant: Cc1cc(C(=O)O)ccn1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc3c(n2)N(C)C(=O)C3(C)C)ccn1

Procedure:
Prepared in analogy to example 26 using 6-amino-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (example 76c) and 2-methylisonicotinic acid. The title compound was obtained as light brown viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.[Br-].Br[CH2:19][C:20]1[CH:25]=[CH:24][NH+:23]=[CH:22][CH:21]=1>C(O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cc[nH+]cc1
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(O)nc(SCc2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (300 mg, 2.1 mmol) was dissolved in absolute ethanol (10 mL), then triethylamine (650 μL, 4.6 mmol) and 4-(bromomethyl)pyridin-1-ium bromide (587 mg, 2.3 mmol) were added. The mixture was stirred overnight at room temperature, and the solvent was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford, after washing with water, 6-methyl-2-[(pyridin-4-ylmethyl)sulfanyl]pyrimidin-4-ol as white solid (128 mg, 26% yield); 1H NMR (400 MHz, MeOd4): δ 2.24 (s, 3H), 4.47 (s, 2H), 6.00 (s, 1H), 7.52 (dd, J=4.5 Hz, J=1.6 Hz, 2H), 8.45 (dd, J=4.5 Hz, J=1.6 Hz, 2H).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[N:10]=[C:11]([CH3:18])[O:12][C:13]=1[C:14]([F:17])([F:16])[F:15])=[O:8]>C(OCC)C>[CH3:18][C:11]1[O:12][C:13]([C:14]([F:15])([F:16])[F:17])=[C:9]([C:7](=[O:8])[CH3:1])[N:10]=1
Reactant: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(=O)c1nc(C)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.7 %

Procedure:
Under an atmosphere of nitrogen, a solution of methylmagnesium bromide (3M in diethylether; 0.63 ml, 1.89 mmol) was cooled to 0° C. A solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid methoxy-methyl-amide (300 mg, 1.26 mmol) in diethylether (3 ml) was added dropwise. The reaction mixture was left to warm to room temperature and stirring was continued for 15 minutes. For the workup, the reaction mixture was cooled to 0° C. and quenched with hydrochloric acid (1N, 3 ml). After 5 minutes of stirring, the mixture was extracted with diethylether. The organic layer was dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a 4:1-mixture of cyclohexane and ethyl acetate as the eluent. The 1-(2-methyl-5-trifluoromethyl-oxazol-4-yl)-ethanone (155 mg, 64% yield) was obtained as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25](CC)[CH2:26][C:27]2C=CC(OC)=CC=2)[C:22]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:21]2[N:20]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)CCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH3:27])[C:22]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:21]2[N:20]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3C[C@@H]4C[C@H]3CN4C)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N3C[C@@H]4C[C@H]3CN4C)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (163 mg, 0.186 mmol) (crude, <=0.190 mmol) was dissolved in ClCH2CH2Cl (10 mL). Anisole (1 ml, 9.15 mmol) and TFA (2 ml, 26.0 mmol) were added and the mixture stirred at room temperature for 3 hours. The reaction mixture was evaporated to a sticky oil, dissolved in DMSO and purified by prep HPLC to give 48.5 mg of 2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](C=O)=[CH:8][CH:9]=2)[N:4]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[C:22]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:24][CH3:25])=[O:23].O.[C:47]1(C)C=CC=CC=1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:47]=[CH:26][C:22]([O:24][CH3:25])=[O:23])=[CH:8][CH:9]=2)[N:4]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:3]=1
Reactant: Cc1ccccc1
Reactant: Cc1cn(CCCc2ccccc2)c2cc(C=O)ccc12
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc2c(C)cn(CCCc3ccccc3)c2c1
Temperature: 80 °C

Procedure:
A stirred 3-methyl-1-{3-(phenyl)propyl}-1 H-indole-6-carboxaldehyde (0.283 g, Reference Example 40) in dry toluene (20 ml), under argon, was treated with carbomethoxymethylene triphenylphosphorane (0.409 g). The mixture was heated at 80° C. for 4 hours then cooled to room temperature and then poured into water (20 ml). The organic phase was separated and the aqueous phase was extracted three times with ethyl acetate (30 ml). The combined organic phases were dried over magnesium sulphate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of diethyl ether and hexane (10:1, v/v) to yield the title compound (0.263 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11])=[O:3].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:11][C:5]1[CH:6]=[C:7]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc(-n2cncn2)cc1F

Procedure:
A solution of 2,4-difluoroacetophenone (2.43 mL), 1,2,4-triazole (1.59 g) and potassium carbonate (5.32 g) in toluene (10 mL) was stirred at 100° C. overnight. The reaction solution was returned to room temperature, and then water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 187 mg of the title compound. Properties data of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.Cl[CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12]([C:11]1[N:4]2[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([Br:1])[C:3]2=[N:9][C:16]=1[CH2:17][CH3:18])=[O:13]
Reactant: Cc1cnc(N)c(Br)n1
Reactant: CCC(=O)C(Cl)C(=O)OC
Product: CCc1nc2c(Br)nc(C)cn2c1C(=O)OC
Temperature: 130 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
3-Bromo-5-methyl-2-pyrazineamine (3.5 g, 18.6 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and the mixture was heated under stirring at 130° C. for 1 hour. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (0.32 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].C[Al](C)C.C(N[C:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[NH:30][C:31]1[C:32]2[CH:39]=[CH:38][NH:37][C:33]=2[N:34]=[CH:35][N:36]=1)=[O:24])C1C=CC=CC=1.O>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][NH:7][C:23]([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[NH:30][C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[O:24])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCCc1cccc(F)c1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(NCCc1cccc(F)c1)c1sccc1Nc1ncnc2[nH]ccc12
Reaction time: 0.25 h
Yield: 12.4 %

Procedure:
To a solution of 3-fluorophenethylamine (130 μL; 134 mg; 0.97 mmol) in anhydrous toluene (3 mL) placed in a microwave tube under nitrogen was added a solution of trimethylaluminum (390 μL; 2.00 M; 0.77 mmol) in toluene. The colorless solution was stirred at 25° C. for 15 min, before 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide (60 mg; 0.19 mmol), was added. The resulting green solution was stirred for 15 min under a flow of nitrogen, and microwaved to 120° C. for 30 min. The reaction mixture was allowed to cool down before water (0.1 mL) was added. The resulting beige suspension was stirred at 25° C. for 2 h, diluted with methanol and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid [2-(3-fluorophenyl)-ethyl]-amide (9 mg, 12%) as a white solid (HPLC: 98%, RT: 6.33 min). 1H NMR (DMSO-d6) 11.97 (br s, 1H), 11.37 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.33 (t, J=5.5 Hz, 1H), 7.75 (d, J=5.5 Hz, 1H), 7.37 (dd, J=3.7, 2.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.13-7.08 (m, 2H), 7.03 (td, J=8.1, 2.6 Hz, 1H), 6.45 (dd, J=3.7, 1.8 Hz, 1H), 3.53 (q, J=6.6 Hz, 2H), 2.90 (t, J=7.1 Hz, 2H); MS (m/z) 382 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[O-:9])=[CH:4][CH:3]=1.[CH2:11](N(CC)CC)[CH3:12].[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](/[N:10]=[C:23](/[C:22]2[CH:26]=[CH:27][C:19]([Br:18])=[CH:20][CH:21]=2)\[O:24][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: N=C([O-])c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCO/C(=N\C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Bromobenzenecarboximidate (25 g, 0.10 mole) is added to toluene (225 ml). Then triethylamine (25 ml, 0.17 mole) is added. The reaction mixture is stirred at room temperature for 10 minutes. 4-bromobenzoyl chloride (25 g, 0.12 mole) in toluene (25 ml) is added to the reaction mixture in 30 minutes at room temperature. After stirring the reaction mixture overnight, it is filtered and the toluene layer is concentrated. The product, 4-Bromo-N-[1-(4-bromo-phenyl)-1-ethoxy-meth-(z)-ylidene]benzamide, from the toluene concentrate is then washed with methanol (30 ml) and dried in vacuum (Yield=30 g (62%)). The product is used without further purification in the next reaction step.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:19][CH2:18][O:17][CH:16]([CH:20]([CH3:22])[CH3:21])[O:15][CH2:14]2)[CH2:8][C:7]1=[O:23])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:25]([O:27][NH3+:28])[CH3:26].C(=O)(O)[O-].[Na+]>CO>[CH2:25]([O:27][NH:28][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH:13]2[CH2:19][CH2:18][O:17][CH:16]([CH:20]([CH3:22])[CH3:21])[O:15][CH2:14]2)[CH2:8][C:7]1=[O:23])[CH2:2][CH2:3][CH3:4])[CH3:26]
Reactant: CCCC(=O)C1C(=O)CC(C2CCOC(C(C)C)OC2)CC1=O
Reactant: CCO[NH3+]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCCC(NOCC)=C1C(=O)CC(C2CCOC(C(C)C)OC2)CC1=O

Procedure:
6.5 parts by weight of 2-butyryl-5-(2-isopropyl-1,3-dioxepan-5-yl)-cyclohexane-1,3-dione, 2.1 parts by weight of ethoxyammonium chloride and 1.8 parts by weight of sodium bicarbonate in 80 parts by volume of methanol are stirred for 16 hours at room temperature. The solvent is distilled off under reduced pressure, the residue is stirred with 50 parts by volume of water and 50 parts by volume of dichloromethane, the organic phase is separated off, the aqueous phase is extracted once with 50 parts by volume of dichloromethane, the combined organic phases are dried over sodium sulfate, and the solvent is distilled off under reduced pressure. 6.2 parts by weight of 2-(1-ethoxyamino-n-butylidene)-5-(2-isopropyl1,3-dioxepan-5-yl)-cyclohexane-1,3-dione are obtained as an oil (active ingredient No. 1).