Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][NH:6][CH2:5]2.[N:11]([O-])=[O:12].[Na+].Cl[Sn]Cl.O[C:19]1[C:20](=[O:38])[N:21]([C:31]2[CH:36]=[CH:35][C:34]([I:37])=[CH:33][CH:32]=2)[CH2:22][CH2:23][C:24]=1[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]>Cl.O.CO.CC(O)=O>[I:37][C:34]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1.[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]3[C:19]4[C:20](=[O:38])[N:21]([CH3:31])[CH2:22][CH2:23][C:24]=4[C:25]([C:26]([F:29])([F:28])[F:27])=[N:11]3)=[CH:10][CH:9]=2)[CH2:5][NH:6]1.[CH3:26][C:25]([OH:30])=[O:12]
Reactant: Nc1ccc2c(c1)CNC2
Reactant: O=N[O-]
Reactant: O=C1C(O)=C(C(=O)C(F)(F)F)CCN1c1ccc(I)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2c(C(F)(F)F)nn(-c3ccc4c(c3)CNC4)c2C1=O
Product: Ic1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Part C. The 5-aminoisoindoline (700 mg, 4.11 mmol) made above was dissolved in 6 M HCl (4.6 mL) at rt, then cooled to 0° C. A solution of NaNO2 (340 mg, 4.93 mmol) in water (0.8 mL) was added dropwise, maintaining the reaction temperature below 5° C. After 40 min, AcOH (1.4 mL) was added to the mixture, followed by the dropwise addition of SnCl2 (1.79 g, 9.44 mmol) in concentrated HCl (2.7 mL) at 0° C. The mixture was warmed to 10° C. and stirred for 2 h, then a solution of 3-hydroxy-1-(4-iodophenyl)-4-(2,2,2-trifluoroacetyl)-5,6-dihydro-1H-pyridin-2-one (1.78 g, 4.31 mmol) in MeOH (16 mL) was added and the reaction mixture was heated at 50° C. for 16 h. Methyl alcohol was removed under vacuum and the solid was collected by filtration to give 1-(2,3-dihydro-1H-isoindol-5-yl)-6-methyl-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one; compound with iodo-benzene as an AcOH salt (2.07 g, 86% yield): 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, br, 2H), 7.75 (d, 2H), 7.66-7.62 (m, 2H), 7.51 (d, 1H), 7.19 (d, 2H), 4.56 (m, 4H), 4.11 (t, 2H), 3.12 (t, 2H); ESI MS m/z 585 (M+H)+.
Reaction SMILES: [Na+].[Br:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:5][CH:4]=1.[CH3:16]I.O>CN(C)C=O>[CH3:16][O:13][C:12](=[O:14])[C:11](=[O:15])[CH:10]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([Br:2])=[CH:4][CH:5]=1
Reactant: O=C([O-])C(=O)C=Cc1ccc(Br)nc1
Reactant: CI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)C=Cc1ccc(Br)nc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A mixture of the 4-(6-bromo-pyridin-3-yl)-2-oxo-3-butenoic acid sodium salt (900.0 mg, 3.2 mmol) in the form of a pale yellow solid, methyl iodide (400.0 mL, 6.47 mmol) in N,N-dimethylformamide (20.0 mL) was stirred at 75° C. for 3 hours. Distilled water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 615.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[Cl:12][CH2:13][C:14]([O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][N:23]2[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19][CH:18]=1)=[O:15]>ClC(Cl)C>[C:5]([C:21]1[C:20]2[C:24](=[CH:25][C:17]([O:16][C:14](=[O:15])[CH2:13][Cl:12])=[CH:18][CH:19]=2)[N:23]([C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[CH:22]=1)(=[O:7])[CH3:6]
Reactant: CC(C)(C)C(=O)n1ccc2ccc(OC(=O)CCl)cc21
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1cn(C(=O)C(C)(C)C)c2cc(OC(=O)CCl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a suspension of 9.5 g (72 mmol) of aluminum chloride in dichloroethane (47.5 ml) was added dropwise 3.64 g (36 mmol) of acetic anhydride. After stirring for 15 min at room temperature, to the above mixture was added dropwise 3.3 g (11 mmol) of 6-chloroacetoxy-1-pivaloylindole (prepared in accordance with the literature (SYNTHESIS, p1018, 1994) in dichloroethane (33 ml). After stirring for 1 hour at room temperature, the mixture was poured into ice-water. The mixture was extracted with ethyl acetate. The extract was washed twice with water and aqueous sodium bicarbonate, and dried. The solution was concentrated and the obtained residue was chromatographed on silica gel (ethyl acetate as eluant) to give 1.23 g of 3-acetyl-6-chloroacetoxy-1-pivaloylindole as an oil. Yield: 36%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]C)[CH2:26][CH2:25]1.[C:33](=O)([O-])[O-:34].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:34][CH3:33])[CH2:26][CH2:25]3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CCCN1CCN(CCCCl)CC1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCN(CCCOc2ccc3nc(C#N)nc(NCC(C)(C)C)c3c2)CC1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31 mmol), 1-(3-chloro-propyl)-4-propyl-piperazine (0.62 mmol) and cesium carbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 92-94° C., Rf=0.45 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][N:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:14])(=O)=O>>[CH3:14][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[C:2]1=[CH2:1]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC1=NCCCC1(C)C
Product: C=C1N(C)CCCC1(C)C

Procedure:
A mixture of 5 g of 2,3,3-trimethyl-3,4,5,6tetrahydropyridine and 12 g of methyl tosylate was reacted at 100° C. for 4 hours. The reaction mixture was cooled and extracted with water/chloroform. Then, 2 g of sodium hydroxide was added to the water layer and the mixture was stirred. The liquid was extracted with chloroform. The chloroform layer was concentrated to obtain a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.O=O.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CS(C)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)[N:12]=[CH:11]3)=[CH:5][CH:4]=1.[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[CH:11][N:12]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[N:13]=3)[CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Reactant: c1ccncc1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)cc1
Product: COc1ccc(Oc2ccc3nn(-c4cccnc4)cc3c2)cc1
Reaction time: 336 h

Procedure:
A mixture of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) and 1.7 mL of anhydrous dimethyl sulfoxide (previously saturated with oxygen) was treated with 3-pyridylboronic acid (0.25 grams, 1.7 mmol), copper (II) acetate (0.23 grams, 1.2 mmol), pyridine (0.34 mL, 0.33 grams, 4.2 mmol) and 4A molecular sieves (0.17 grams). After stirring for 14 days under an oxygen atmosphere, the mixture was diluted with water, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (0-100%), affording 5-(4-Methoxy-phenoxy)-1-pyridin-3-yl-1H-indazole (0.11 grams) (1H NMR (CDCl3, 400 MHz): δ 9.07 (d, 1H, J=2.1 Hz), 8.60 (d, 1H, J=4.2 Hz), 8.12 (s, 1H), 8.10 (dd, 1H, J=1.3, 5.8 Hz), 7.65 (dd, 1H, J=1.1, 9.6 Hz), 7.50 (dd, 1H, J=5.0, 8.3 Hz), 7.25 (m, 2H), 7.00-6.80 (m, 5H), 3.80 (s, 3H) ppm) and 5-(4-Methoxy-phenoxy)-2-pyridin-3-yl-2H-indazole (0.050 grams) (1H NMR (CDCl3, 400 MHz): δ 9.12 (bs, 1H), 8.50 (b, 1H), 8.32 (d, 1H, J=8.3 Hz), 8.29 (s, 1H), 7.73 (d\d, 1H, J=9.5 Hz), 7.54 (dd, 1H, J=4.6, 7.9 Hz), 7.16 (dd, 1H, J=2.1, 9.1 Hz), 7.01 (d, 2H, J=9.1 Hz), 6.96 (s, 1H), 6.90 (d, 2H, J=8.7 Hz), 3.81 (s, 3H) ppm) as colorless syrups.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].CCCCCC>O1CCCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]([C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH:11]=[C:12]([O:18][CH3:19])[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(CC(=O)Oc2ccccc2)cc(OC)c1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(OC)cc(C(C(=O)Oc2ccccc2)C(=O)Oc2ccccc2)c1
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (400 mL, 1M in tetrahydrofuran obtained commercially from Aldrich Chem. Co.) was added a solution of 3,5-dimethoxybenzeneacetic acid phenyl ester (53.1 g) in tetrahydrofuran (65 mL) dropwise over 20 min while cooling in a dry ice bath at −70° C. The resulting slurry was stirred at dry ice temperature for 45 min. Phenyl chloroformate (26 mL) was added all at once followed by 50 mL of tetrahydrofuran. The resulting thick slurry was stirred for 2.5 h at 0° C. while cooling in an ice bath before quenching with diluted aqueous HCl (50 mL of conc. HCl diluted to 150 mL with water). The bulk of tetrahydrofuran was removed under vacuum and diethyl ether (550 mL) and water (80 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). The combined ether layers were dried over magnesium sulfate and concentrated under vacuum to yield a crude solid which was stirred with hexane (250 mL) for 24 h. The solid was then collected by filtration, washed with hexane (100 mL), and vacuum dried to yield 62 g of the title compound. 1H NMR (CDCl3) δ 7.37 (t, 2H), 7.26 (q, 1H), 7.13 (d, 2H), 6.73 (s, 2H), 6.45 (s, 1H), 5.02 (s, 1H), 3.82 (s, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][NH:28][C:27]1=S>CN(C=O)C.[Hg](Cl)Cl>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:27]4[NH:28][CH2:29][CH2:30][N:26]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: S=C1NCCN1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: Cl[Hg]Cl
Solvent: CN(C)C=O
Product: c1cc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)ccc1NC1=NCCN1
Temperature: 140 °C
Yield: 18.3 %

Procedure:
A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline (40 mg, 0.12 mmol), imidazolidine-2-thione (15 mg, 0.15 mmol) and mercury(II) chloride (40 mg, 0.15 mmol) in 2 mL of DMF was stirred at 140° C. 16 hr. Then the reaction mixture was cooled to room temperature and filtered through Celite™. The filtration was concentrated and purified by reverse phase chromatography to give N-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]-4,5-dihydro-1H-imidazol-2-amine (9.0 mg, 22% yield). HPLC: Rt=1.74 min; MS 411 [M+H].
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[N:28]=[C:27](Cl)[S:26][N:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:27]3[S:26][N:25]=[C:24]([Cl:23])[N:28]=3)[CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCNCC2)n1
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3nc(Cl)ns3)CC2)n1

Procedure:
A solution of (4-benzyl-6-methyl-pyrimidin-2-yl)-piperidin-4-yl-amine hydrochloride (159 mg, 0.5 mmol), 3,5-dichloro-[1,2,4]thiadiazol (39 mg, 0.25 mmol) and N,N-diisopropylethylamine (85 L, 0.5 mmol) in tetrahydrofurane (2 mL) was heated to 95° C. 4 hours under nitrogen. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using Et2O as eluent. The title compound was obtained as a colorless oil (52 mg, 52%).
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:3].[Cl:12][Si:13](Cl)([CH3:15])[CH3:14]>O1CCCC1>[Cl:12][Si:13]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:2][CH3:3])=[CH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: C[Si](C)(Cl)Cl
Reactant: CCOc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 3.5 g (0.14 mole) of magnesium powder in 100 mL of dry tetrahydrofuran was added dropwise 17.5 g (0.14 mole) of p-bromophenyl ethyl ether during a one hour period. The mixture was warmed for one hour and then cooled to room temperature. The reaction mixture was added dropwise to a solution of dichlorodimethylsilane in 100 mL of dry tetrahydrofuran which was cooled to -78° C. Upon completion of addition the reaction mixture was allowed to warm to room temperature. Stirring was continued overnight. After dilution with hexane, the reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure, leaving a liquid residue. Distillation of this residue yielded 18 g of chloro(4-ethoxyphenyl)dimethylsilane as a clear, colorless oil, b.p. 79-81° C./0.09 mm of Hg.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH2:2][CH:3]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCNCC1CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 95.1 %

Procedure:
A mixture of 7.7 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, 12 g of N-methylpiperazine, 3.5 g of potassium carbonate, 150 ml of dioxane and 60 ml of water was heated overnight at 80°-90° C. and then evaporated. The residual gum was dissolved in dichloromethane, washed with water, dried, filtered and evaporated, giving 8.8 g of 2-[(N-methylpiperazinyl)methyl]-1,4-bis(phenylmethyl)piperazine.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][NH:9][C@H:8]([C:18]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COCCN
Product: C=CCON=C1CN[C@H](C(=O)NCCOC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and 2-methoxyethyl-amine the title compound was obtained in 100% purity by LC/MS. MS(ESI+): m/z=242.0.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25])[O:26][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: CCc1ccc(O)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Temperature: 150 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (984 mg, 3.0 mmol), 3-amino-4-ethylphenol (617 mg, 4.5 mmol), potassium carbonate (829 mg, 6.0 mmol) and N,N-dimethylformamide (9 mL) was stirred at 150° C. for 24 hr. The reaction mixture was diluted with water and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (3:1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) and recrystallized from a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound (706 mg, yield 70%) as a khaki solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>O>[CH2:25]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:24]=[CH2:23]
Reactant: COC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)OC)cc1

Procedure:
A solution of N-[4-(1-hydroxyiminoethyl)phenyl]-N'-methoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield N-[4-(1-allyloxyiminoethyl)phenyl-N'-methoxycarbonylmethylurea.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=O)=[N:9][NH:10][CH:11]=1)=[O:5].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:12]([C:8]2[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:2]=3[F:1])=[CH:11][NH:10][N:9]=2)=[O:14])[CH2:22][CH2:23]1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2n[nH]cc2NC(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), 4-amino-N-methylpiperidine (50.0 μl, 0.45 mmol), EDAC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (3 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO4) and reduced in vacuo to give 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (1-methyl-piperidin-4-yl)-amide as a white solid (113 mg, 69%). (LC/MS: Rt 2.52, [M+H]+ 364.19).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14][Mg]Br.[O:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[NH4+]>O1CCCC1>[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14][C:4]([CH2:3][CH2:2][CH:1]1[O:6][CH2:2][CH2:3][CH2:4][O:5]1)([OH:5])[CH2:18][CH2:19][CH2:20][CH2:21][OH:17]
Reactant: Br[Mg]CCC1OCCCO1
Reactant: O=C1CCCO1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: OCCCCC(O)(CCC1OCCCO1)CCC1OCCCO1
Yield: 105.9 %

Procedure:
430 mg (5 mmol) of γ-butyrolactone was dissolved in 10 ml of tetrahydrofuran, and 22 ml (11 mmol) of 0.5 M (1,3-dioxan-2-ylethyl)magnesium bromide/tetrahydrofuran solution was added thereto with stirring under ice-cooling, followed by stirring for 3 hours at 50° C. After the reaction solution was cooled with ice, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate:ethanol=10:1) to give 880 mg of the title compound as a colorless oil (yield: 55%).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.Br[C:21]1[CH:22]=[C:23]([O:32][CH3:33])[C:24](=[CH:26]N(CC)CC)[N:25]=1.[O-:34]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O.CCO>[CH3:33][O:32][C:23]1[CH:22]=[C:21]([C:9]2[NH:8][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[NH:25][C:24]=1[CH:26]=[O:34]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cccnc21
Reactant: O=P([O-])([O-])[O-]
Reactant: CCN(C=C1N=C(Br)C=C1OC)CC
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cc3cccnc3[nH]2)[nH]c1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-2-ylboronic acid (150 mg, 0.57 mmol), N-((5-bromo-3-methoxy-2H-pyrrol-2-ylidene)methyl)-N-ethylethanamine (114 mg, 0.44 mmol, provided by Chemzon Scientific Inc, Montreal, Canada), Pd(dppf)2Cl2CH2Cl2 (16 mg, 0.02 mmol) and K3PO4 (187 mg, 0.88 mmol) in a 20 mL sealed-tube flask was vented 4 times with nitrogen. 1,4-Dioxane (2.2 mL) and water (0.3 mL) were introduced by syringe and the mixture was vented twice with nitrogen. The reaction mixture was then heated at 80° C. for 2 h and TLC showed no starting materials were left. EtOH (15 mL) and water (5 mL) were added and the reaction mixture was stirred for 0.5 h at r.t. and then extracted with 2×15 mL of EtOAc. The extracts were dried over Na2SO4, filtered through a pad of silica gel. The filtrate was concentrated under vacuum to give 15 mg of the title compound as a dark solid.