Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:23])[CH2:21]N)=[CH:16][CH:15]=1>C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:21][CH:20]([C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1)[OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCC(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Reaction time: 8 h

Procedure:
28 g of t-butoxycarbonyl azide were added at room temperature to 200 ml of a methylene chloride solution containing 25.3 g of DL-2-amino-1-phenylethanol and 45 ml of triethylamine, and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was then condensed by evaporation under reduced pressure, and water and diisopropyl ether were added to the condensate. The mixture was thoroughly stirred. yielding the title compound in the form of insoluble crystals melting at 123°-124° C. in a yield of 20.6 g. These crystals were filtered off. The organic layer in the filtrate was separated and washed with an aqueous solution of potassium hydrogen sulfate and with an aqueous solution of sodium bicarbonate. The resulting solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The crystals of the title compound in the residue were collected by filtration and washed with a mixture of diisopropyl ether and petroleum ether, yielding a further 18.7 g.
Reaction SMILES: [CH2:1]([S:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=O)[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[CH2:1]([S:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:7])[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCSC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCSC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 16 was prepared from (ethylsulfanyl) (diphenyl)acetic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}-2-methylpropan amide according to the procedures described in Scheme 9: ESMS m/e: 658.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:4][CH:3]=1.[C:27]([NH:29][C:30](=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]1[N:44]=[C:45]([NH:48][C:49]([NH2:51])=[NH:50])[S:46][CH:47]=1)OC1C=CC=CC=1)#[N:28]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:30]([NH:29][C:27]#[N:28])=[N:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[N:44]=[C:45]([NH:48][C:49]([NH2:51])=[NH:50])[S:46][CH:47]=2)[CH3:20])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (1.9 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,7-heptanediamine and 0.7 g (1.9 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography (eluant: methylene chloride/methanol 95+5) analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=655 ([M+H]+ 2), 230 (18), 154 (100); IR (KBr): 2161 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 150° C. with decomposition.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([OH:43])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41](=[O:43])[N:2]([CH3:1])[C@@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CN[C@H](CN1CCCC1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C(=O)Cc1ccccc1CNC(=O)OC(C)(C)C)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl-[1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl]-amine in acetonitrile (0.3 M) at 0° C. under nitrogen was added diisopropylethylamine (2.2 eq), 6a (1.1 eq) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.1 eq). The reaction was stirred at room temperature overnight. The acetonitrile was removed under reduced pressure. The remaining oil was partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (2×), brine (1×), dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using the ISCO (1-15% gradient methanol/dichloromethane) to afford the product. (65%) 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 9H), 6.21 (m, 1H), 5.62 (m, 1H), 4.31 (m, 2H), 3.95 (m, 1H), 3.71 (m, 1H), 3.05 (m, 1H), 2.82 (m, 5H), 2.55 (m, 2H), 1.85 (m, 5H), 1.46 (s, 9H). Mass Spectral Analysis m/z=452.3 (M+H)+ tR=4.92 min (96%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=[CH:4][C:3]=1[NH:21][C:22]([CH:24]1[CH2:26][CH2:25]1)=O>C(O)(=O)C>[CH:24]1([C:22]2[NH:1][C:2]3=[N:7][C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)=[C:5]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])[CH:4]=[C:3]3[N:21]=2)[CH2:26][CH2:25]1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)C1CC1
Solvent: CC(=O)O
Product: Fc1cnccc1-c1cc2nc(C3CC3)[nH]c2nc1-c1cccnc1
Yield: 12.5 %

Procedure:
A solution of N-(6′-amino-3″-fluoro-3,2′:3′,4″-terpyridin-5′-yl)cyclopropanecarboxamide (0.2 g, 0.58 mmol) in acetic acid (2.5 mL) was heated in a sealed tube at 130° C. for 16 h. The solvent was evaporated and water (1 mL) was added and the solution was neutralised with 4% sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (100:8:1 dichloromethane/methanol/NH3) to give the title compound (0.024 g, 12% of yield).
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34]/[CH:35]=[CH:36]/[C:37](O)=[O:38])[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][N:31]([CH2:34]/[CH:35]=[CH:36]/[C:37]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:27][CH:26]=3)[CH:20]=2)=[O:38])[CH2:30][CH2:29]1
Reactant: O=C(O)/C=C/CN1CCOCC1
Reactant: Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Product: O=C(/C=C/CN1CCOCC1)Nc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 34 %

Procedure:
(E)-4-morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide was prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and (E)-4-morpholinobut-2-enoic acid using Method E (34% yield). HPLC: 100%, RT=3.493 min. MS: m/z=508 [M+H]+, RT=2.27 min.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([CH:15]3[O:19][C:18](=[O:20])[N:17]=[N:16]3)[CH:12]=[C:11]([Cl:21])[N:10]=2)[CH2:5][CH2:4]1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:30])[NH:26][C:27]=1[CH3:28]>CC(N(C)C)=O>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[C:13]([CH:15]4[N:16]=[N:17][C:18](=[O:20])[O:19]4)[CH:12]=[C:11]([Cl:21])[N:10]=3)[CH2:5][CH2:4]2)=[O:30])[NH:26][C:27]=1[CH3:28]
Reactant: Cc1[nH]c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Br
Reactant: NC1CCN(c2cc(C3N=NC(=O)O3)cc(Cl)n2)CC1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C4N=NC(=O)O4)cc(Cl)n3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
TEA (0.10 ml, 0.70 mmol) and 5-[2-(4-aminopiperidin-1-yl)-6-chloropyridin-4-yl]-1,3,4-oxadiazol-2(5H)-one hydrochloride (Intermediate 51, 0.10 g, 0.33 mmol) were added to a solution of pentafluorophenyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 17) (0.12 g, 0.33 mmol) in DMA (2 ml). The mixture was stirred at room temperature overnight and was purified by semi-preparative HPLC eluting with water/acetonitrile and TFA mixtures to give the title compound (18 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13].O.CN(C)[CH:24]=[O:25]>>[CH3:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=[O:19])[C:17]([CH:24]=[O:25])=[C:16]([CH3:20])[NH:15]2)[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2[nH]c(C)c(C=O)c2=O)cc1C
Temperature: 100 °C
Yield: 79 %

Procedure:
Phosphorus oxychloride (4.82 mL, 51.6 mmol) was added dropwise to an ice-cooled, stirred suspension of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one (8.70 g, 43.0 mmol) in dimethylformamide (18.0 mL) at such a rate as to maintain the temperature below 20° C. After the addition, the mixture was heated at 100° C. for 2 h, then cooled, poured into iced water (200 mL). The resulting mixture was stirred for 18 h, then filtered. The solid was washed with water and dried to give the title compound (7.83 g, 79%) as a cream-coloured powder. 1H NMR (300 MHz, d6-DMSO) δ 9.63 (s, 1H), 7.47 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 2.23 (d, J=8.2 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[CH2:7][C@@H:6]1[C:8]1[CH:13]=[C:12]([N:14]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[N:15]2)[N:11]=[C:10]([CH3:21])[N:9]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:20][C:16]1[N:17]=[C:18]([CH3:19])[N:14]([C:12]2[N:11]=[C:10]([CH3:21])[N:9]=[C:8]([C@H:6]3[CH2:7][C@@H:5]3[C:3]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[CH:2]=3)[CH:13]=2)[N:15]=1
Reactant: Cc1nc([C@H]2C[C@@H]2C(=O)CCl)cc(-n2nc(C)nc2C)n1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc([C@H]2C[C@@H]2c2cn3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 80 °C

Procedure:
To a solution of 1-5 (30 mg, 0.10 mmol) and 2-aminopyridine (10 mg, 0.11 mmol) in ethanol (1 mL) was added sodium bicarbonate (16 mg, 0.20 mmol) in a single portion and the reaction was heated at 80° C. After 2 h the mixture cooled to room temperature, diluted with ethyl acetate (5 mL) and washed with saturated aqueous sodium bicarbonate (2×5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give Example 1 as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.03 (dt, J=6.7, 1.2 Hz, 1H), 7.57 (s, 1H), 7.52 (br d, J=9.1 Hz, 1H), 7.45 (s, 1H), 7.13 (ddd, J=9.0, 6.8, 1.2 Hz, 1H), 6.74 (td, J=6.8, 1.1 Hz, 1H), 2.88 (s, 3H), 2.81-2.76 (m, 1H), 2.68-2.62 (m, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 1.93-1.83 (m, 2H); MS: m/z=346.5 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C[Al](C)C.[NH:26](/[C:30](/[CH3:36])=[CH:31]\[C:32](OC)=[O:33])[C:27]([CH3:29])=O>C(Cl)Cl>[CH2:10]([N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:32](=[O:33])[CH:31]=[C:30]([CH3:36])[N:26]=[C:27]2[CH3:29])=[CH:7][C:2]=1[F:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1F
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a solution of 2-fluoro-N1,N1-di-n-hexyl benzene-1,4-diamine (0.58 g, 1.97 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (9.9 mL, 19.8 mmol, 2 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (341 mg, 2.17 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as pale yellow oil (500 mg, 63%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:4].[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCCC.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:28]#[C:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)c1sccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COC(=O)c1sccc1C#Cc1ccccc1

Procedure:
This product was prepared from 3-(toluene-4-sulfonyloxy)-thiophene-2-carboxylic acid methyl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (91 mg, 75%); 1H NMR δ (CDCl3): 7.53 (m, 2H), 7.39 (d, J=5.02 Hz, 1H), 7.3 (m, 3H), 7.12 (d, J=5.10 Hz, 1H), 3.82 (s, 3H); LCMS m/z: 242.
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([N+:19]([O-])=O)=[CH:14][C:13]=1[Cl:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:4]([O:11][C:12]1[C:13]([Cl:22])=[CH:14][C:15]([NH2:19])=[CH:16][C:17]=1[Cl:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 70 °C

Procedure:
Tin(II) chloride (22 g, 98 mmol) was added to a stirring solution of 2-(benzyloxy)-1,3-dichloro-5-nitrobenzene (5.8 g, 19 mmol) in ethanol (80 mL), and the resulting suspension was heated to 70° C. After 1 h the mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The mixture was poured into brine (100 mL) and the resulting emulsion stirred with sodium potassium tartrate solution (200 mL). The mixture was extracted with ethyl acetate and the combined organic layers dried (MgSO4), filtered and concentrated in vacuo to afford 4-(benzyloxy)-3,5-dichloroaniline that was used directly in the next step without purification.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17]([CH2:19][CH3:20])=[O:18])[CH3:16])[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[CH2:22]([O:24][NH2:25])[CH3:23]>C(O)C>[CH2:22]([O:24][NH:25][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17]([CH2:19][CH3:20])=[O:18])[CH3:16])[CH2:8][C:7]1=[O:21])[CH2:2][CH2:3][CH3:4])[CH3:23]
Reactant: CCCC(=O)C1C(=O)CC(CC(C)S(=O)CC)C(C)C1=O
Reactant: CCON
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC(C)S(=O)CC)C(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Into 20 ml of ethanol, 3.1 g of 2-butyryl-5-(2-ethylsulfinylpropyl)-4-methylcyclohexane-1,3-dione was dissolved and 0.61 g of ethoxyamine was dropped thereto at 0° C. and the resulting solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was treated as in Example 1 to obtain 2.65 g of the desired compound as yellow oily material. Yield 74%, nD19 1.5348.
Reaction SMILES: [Na+].[C:2]1(=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:4][C:3]1=O.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>O.Cl>[OH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:25]=[N:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1
Reactant: NNc1ccccn1
Reactant: O=C1C=C(S(=O)(=O)[O-])c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1cc(N=Nc2ccccn2)c(O)c2ccccc12

Procedure:
1,2-Naphthoquinone-4-sulfonic acid sodium salt (26 g) was dissolved in a mixture of water (500 ml) and concentrated hydrochloric acid (250 ml). To this solution was added 2-pyridylhydrazine (11 g) in water (100 ml). The reaction mixture became warm and the product started to precipitate. After 30 minutes of cooling, the product was filtered off and washed with a small volume of water, acetone and ether. Yield 32 g (96 percent).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:31](OC(C)(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])[CH:17]=[CH:31][N:32]([CH3:34])[CH3:33])=[C:11]3[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)nccc12
Temperature: 80 °C
Yield: 69 %

Procedure:
To 1-[7-(cyclopentylamino)-2-(4fluorophenyl)pyrazolo[1,5- c]pyrimidin-3-yl]ethanone (200 mg, 0.59 mmol) was added 1,1 -di-tert-butoxy-N,N-dimethylmethanamine (4 mL) and the mixture heated to 80° C. for 30 minutes. The reaction was let cool to room temperature and was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water and brine. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica chromatography eluting with ethyl acetate to yield 160 mg (69%) of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-3-(dimethylamino)prop-2-en-1-one. 1H NMR (CDCl3): δ 7.77 (m, 4H), 7.44 (d, 1H), 7.19 (t, 2H), 6.41 (d, 1H), 5.09 (d, 1H), 4.57 (m,1H), 3.07 (m, 3H), 2.60 (m, 3H), 2.25 (m, 2H), 1.85 (m, 6H). MS m/z 394 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:4][CH2:3]1.IC.[CH2:29](N(C(C)C)C(C)C)C>C(Cl)Cl>[O:26]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH2:17][CH2:16][N:15]([CH3:29])[CH2:14][CH2:13][C:12]=3[N:18]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCNCC3)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.2 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.060 g, 0.00016 mol), iodomethane (0.015 mL, 0.00016 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.056 mL, 0.00032 mol) in DCM (2 mL) was stirred at rt for 3 h. The mixture was diluted with DCM and washed with water (3×) and satd. aq. NaCl. The separated organic layer was dried and concentrated. The residue was purified by FCC [7 N NH3/MeOH)/DCM] to give 0.010 g (16%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2([OH:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2([OH:27])[CH2:22][CH2:23][N:24]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:25][CH2:26]2)[CH:16]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2cccnc2)CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OC1(c2cccnc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (24.29 g, 109.15 mmol), 4-(pyridin-3-yl)piperidin-4-ol (21.40 g, 120.07 mmol) and DIPEA (24.72 ml, 141.90 mmol) in DMF (95 ml) was heated at 80° C. for 1 hour. The solution was cooled to ambient temperature and slowly diluted with water, with seeding, to give a crystalline precipitate. The precipitate was collected by filtration, washed with water, acetonitrile and ether and dried under vacuum to afford 4-pyridin-3-yl-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (36.1 g, 91%) as a solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([N:30]2[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]2)[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]2[CH:15]=[C:16]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[C:22]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC(C)C)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 192-194° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.73 (1H, s), 8.33 (1H, s), 8.17-8.22 (2H, m), 7.94-7.96 (1H, d, J=7.2 Hz), 7.76 (1H, s), 7.54-7.57 (1H, d, J=7.8 Hz), 7.45-7.48 (1H, d, J=8.4 Hz), 7.15-7.18 (1H, d, J=7.5 Hz), 6.79-6.82 (1H, d, J=9.0 Hz), 4.14-4.20 (1H, m), 2.56 (3H, s), 2.19 (3H, brs), 1.20-1.22 (6H, d, J=6.3 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C28H26F3N6O: 519.2115. found: 519.2121.
Reaction SMILES: [C:1](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:5])[C:2]([CH3:4])=O.Cl.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C:30](=[NH:35])[O:31]C(C)C)=[CH:21]1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:4][C:2]1[C:1](=[O:5])[NH:31][C:30](=[O:35])[C:29]=1[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]([CH3:19])[CH:21]=1
Reactant: CC(=O)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(c2cn(C)c3ccccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
A solution of 802 mg of pentafluorophenyl pyruvate in 20 ml of dichloromethane was added dropwise to a solution of 266 mg (1 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 808 mg (8 mmol) of triethylamine in 20 ml of dichloromethane. After completion of the addition, the mixture was stirred at room temperature for 18 hours. Then, 1.9 g (10 mmol) of p-toluenesulfonic acid were added and stirring was continued for 1 hour. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using ethyl acetate/dichloromethane (1:8) for the elution to give 24 mg(10% ) of 3-methyl-4-(1 -methyl-3-indolyl)- 1H-pyrrole-2,5-dione in the form of a yellow solid of melting point 181° C.