Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[C:19](B(O)O)=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O.O1CCOCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:19]3[C:14]([O:13][CH3:12])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ncccc1-c1cnc2ccc(Cl)nn12
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (Preparation 1b, 6.0 g, 25.81 mmol), (2-methoxypyridin-3-yl)boronic acid (3.3 g, 21.58 mmol), cesium carbonate (30 mL of a 2M solution in water, 60 mmol) and 1,4-dioxane (250 mL) in a Schlenk vial was subjected to three cycles of evacuation backfilling with argon. [1,1′-Bis(diphenyl phosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (1:1) (1.8 g, 2.16 mmol) was then added and the resulting mixture was again subjected to three further cycles of evacuation backfilling before being heated at 100° C. for 2 hours. Subsequently, the reaction was cooled down, diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was treated with ethyl acetate and the solid formed was filtered, washed with dichloromethane and dried in vacuo to yield the title compound (3.5 g, 62%) as a yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[C:50]([CH2:52][O:53][Si](C(C)(C)C)(C)C)[CH:51]=1)[N:31]([CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH3:48])[CH2:32][C:33]([CH3:38])([S:35][S:36][CH3:37])[CH3:34])(C(C)(C)C)(C)C>C1COCC1>[CH3:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][N:31]([CH2:32][C:33]([CH3:38])([S:35][S:36][CH3:37])[CH3:34])[C:30]1[CH:29]=[C:28]([CH2:27][OH:26])[CH:51]=[C:50]([CH2:52][OH:53])[CH:49]=1
Reactant: COCCOCCOCCN(CC(C)(C)SSC)c1cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCOCCOCCN(CC(C)(C)SSC)c1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (10.57 ml, 10.57 mmol) was added dropwise to stirring solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5 g, 5.29 mmol) in anhydrous THF (65 ml) at 0° C. in an ice bath. Following addition the mixture was stirred at ambient temperature for two hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The extracts were washed with water and brine, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)(2-methyl-2-(methyldisulfanyl)propyl)amino)-1,3-phenylene)dimethanol (2 g, 87%). 1H NMR (400 Hz, CDCl3): δ 6.76 (s, 2H), 6.63 (s, 1H), 4.55 (s, 4H), 3.65-3.51 (m, 14H), 3.35 (s, 3H), 2.44 (s, 3H), 1.33 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 149.0, 142.35, 114.0, 111.1, 71.98, 70.7, 70.6, 70.5, 67.6, 65.5, 59.75, 59.1, 53.9, 51.9, 26.6, 25.7, 20.75; MS (m/z). found 456.2 (M+Na)+. See FIG. 46.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CC1CCCO1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-chloropyridin-3-ol (2.41 g) in 2-methyltetrahydrofuran (20 mL) and N,N-dimethylformamide (4 mL) was added potassium tert-butoxide (1.0M in tetrahydrofuran) (18.60 mL). The reaction was stirred for 15 minutes, then methyl 2,4-difluorobenzoate (3.52 g) was added as a solution in 2-methyltetrahydrofuran (2 mL). The reaction was then heated to 80° C. and stirred under a nitrogen atmosphere for 3 days. The reaction was cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g), eluting with 10% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:17][C:15]([O:14][CH3:13])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CN(C(=O)OC(C)(C)C)C1

Procedure:
3-Oxo-azetidine-1-carboxylic acid tert-butyl ester (1.67 g; 9.7 mmol) and methoxycarbonyl-methylene-triphenylphosphorane (3.42 g; 10.25 mmol) are dissolved in toluene (5 ml), refluxed for 2.5 hours and left over night at room temperature. The precipitate is filtered off, washed with TBME, and the filtrate purified via chromatography (TBME/hexane 2:8>3:7) to yield the title compound as colorless crystals. 1H-NMR (400 MHz; DMSO-d6): 5.90 (m, 1H); 4.71 (bs, 2H); 4.58 (bs, 2H); 3.67 (s, 3H); 1.42 (s, 9H). MS (m/z) ES+: 171 (10; MH+ minus tert-butyl); 57 (100).
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12]([CH2:15][P:16](=[O:21])([O:19]C)[O:17]C)(O)=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]12([NH:11][C:12]([CH2:15][P:16](=[O:17])([OH:21])[OH:19])=[O:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COP(=O)(CC(=O)O)OC
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CP(=O)(O)O)NC12CC3CC(CC(C3)C1)C2

Procedure:
Adamantylamine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide was added portionwise. The solution was stirred overnight, and the mixture filtered. The filtrate was concentrated to a solid. It was recrystallized from an appropriate solvent such as methanol. m.p. 190°-4° C.; yield, 32%
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][C@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: C[C@@H](N)C(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H](NC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), D-alanine (1061 mg, 11.9 mmol) and NaOMe solution (18 mL, 9 mmol, 0.5 M in MeOH) was refluxed for 48 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated to give a crude solid. The solid was dissolved in saturated NaHCO3 and washed with ether. 4 M HCl was added to the aqueous layer until pH was about 1, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as an off-white solid. MS: (+) m/z 393.25 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CN(C=O)C.CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:16][CH3:17])[CH:4]=1
Reactant: CCI
Reactant: Oc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(Br)ccc1Cl
Temperature: 55 °C
Yield: 99 %

Procedure:
To a solution of 2-chloro-5-bromophenol (WO98/003464 which is incorporated herein by reference, 3.43 g, 16.5 mmol) and K2CO3 (4.57 g, 33.0 mmol) in DMF (20 mL) was added ethyl iodide (1.78 mL, 22.3 mmol) at rt. The mixture was heated at 55° C. for 3.0 h. After cooling to rt, the reaction was diluted with ether, washed with water and brine, and dried over MgSO4. The crude residue was purified by flash column chromatography to give 3.85 g (99%) of 31A as viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.03 Hz, 3H) 4.08 (d, J=7.03 Hz, 2H) 7.03 (m, 2H) 7.22 (d, J=6.15 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:40]1[CH2:44][CH2:43][O:42][C:41]1=[O:45]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:40]3[CH2:44][CH2:43][O:42][C:41]3=[O:45])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCOC3=O)cc2n1Cc1ccccc1
Yield: 14 %

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1 H-indole-3-carboxamide (Compound 8, 19mg, 0.044 mol) in DMF (1.0 ml) was reacted with K2CO3 (30 g, 0.22 mmol), 3-bromodihydrofuran-2(3H)-one (20 mg, 0.22 mmol) to yield the title compound (16mg, 71%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.Cl[CH2:10][C:11]([N:13]([C:15]1[C:16](=[O:31])[C:17]2[C:22]([C:23](=[O:30])[C:24]=1[NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])=[O:12].O>O1CCCC1>[CH3:29][O:28][CH2:27][CH2:26][NH:25][C:24]1[C:23](=[O:30])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:31])[C:15]=1[N:13]([CH3:14])[C:11](=[O:12])[CH2:10][N:2]([CH3:3])[CH3:1]
Reactant: COCCNC1=C(N(C)C(=O)CCl)C(=O)c2ccccc2C1=O
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: COCCNC1=C(N(C)C(=O)CN(C)C)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 M Dimethylamine/tetrahydrofuran solution (3.0 ml) was added to a solution of 2-chloro-N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methylacetamide (0.5 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to give N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methyl-2-(dimethylamino)acetamide (0.19 g) as a brown powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:25]
Reactant: CNC
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(CN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and dimethylamine by a procedure similar to Example 76. 1H NMR (DMSO-d6): 7.71 (d, J=8.7 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.09 (t, J=8.1 Hz, 1H), 7.00-6.96 (m, 3H), 3.78 (s, 3H), 3.63 (s, 2H), 3.50 (s, 3H), 2.33 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O1CCOCC1>[Cl:9][C:4]1[N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: Nc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 2,6-dichloro-pyrimidin-4-yl-amine (0.492 g, 3.0 mmol) and 4-chloro-aniline (1.54 g, 12.0 mmol) in dioxane (25 ml) was heated under reflux for 3 hours. After cooled to room temperature, the mixture was filtered. Concentration of the filtrate under reduced pressure provided the crude product which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide 6-chloro-N*2*-(4-chloro-phenyl)-pyrimidine-2,4-diamine (0.32 g, 42% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1I.[Br-].C[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Zn+])[CH:26]=1.[CH2:32]1COCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:21])=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[O:10])=[CH:4][C:3]=1[C:27]1[CH:26]=[CH:25][C:30]([CH3:32])=[CH:29][N:28]=1
Reactant: C1CCOC1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(I)c1
Reactant: Cc1ccnc([Zn+])c1
Agent: [Br-]
Product: Cc1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide (150 mg, 0.34 mmol) was used in Procedure B with 4-methyl-2-pyridylzinc bromide (1.7 mL of a 0.5 M in THF). Purified by silica gel chromatography (5-75% Ethyl acetate/Hexanes) to yield N-(4-chloro-3-(5-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxamide as a white solid: TLC Rf=0.23 (35% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) δ 10.62 (bs, 1H), 8.12 (dd, 1H), 7.89 (d, 1H), 7.58 (d, 1H), 7.47 (m, 3H), 7.18 (d, 1H), 6.89 (d, 1H), 2.62 (s, 3H), 2.38 (s, 3H); MS (Q1) 406.3 (M)+.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][C:3]=1[C:9]#[N:10].[C:11](=O)([O-])[O-].[K+].[K+].[I-].FC(F)(F)C1NC(Br)=C(Br)C=1C#N>CC(C)=O.C(COC)OC.O>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH3:11])[C:3]=1[C:9]#[N:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1[nH]c(Br)c(Br)c1Br
Agent: N#Cc1c(C(F)(F)F)[nH]c(Br)c1Br
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COCCOC
Product: Cn1c(Br)c(Br)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Tribromo-pyrrole-2-carbonitrile (1.0 g, 0.003 mo1) is dissolved in a mixture of acetone (20 mL) and dimethoxyethane (10 mL). Potassium carbonate (0.45 g, 0.0033 mol) is added followed by methyl .iodide (0.478 g, 0.0033 mo1). After stirring overnight at room temperature, the mixture is poured into water precipitating a white solid. The solid (0.S g, 80%) has mp 115°-119° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:21]([CH3:22])=[CH:20][C:19]([Br:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:7]2[N:6]3[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Cc1cc(Br)cc2c1-n1c(Br)nnc1CN=C2c1ccccn1
Reactant: CN1CCNCC1
Product: Cc1cc(Br)cc2c1-n1c(nnc1N1CCN(C)CC1)CN=C2c1ccccn1

Procedure:
In the manner given in Example 1, 1,8-dibromo-10-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-bromo-10-methyl-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[CH:12]=[C:11]([CH:13]=O)[N:10]=[CH:9][C:8]=2[N:15]=1)([CH3:3])[CH3:2].[NH4+].[OH-].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([N+:36]#[C-:37])S(C1C=CC(C)=CC=1)(=O)=O.[NH:38]1CCNCC1>C1COCC1.CCOC(C)=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:36]=[CH:37][NH:38][C:13]=1[C:11]1[N:10]=[CH:9][C:8]2[N:15]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[S:6][C:7]=2[CH:12]=1
Reactant: C1CNCCN1
Reactant: CC(C)Nc1nc2cnc(C=O)cc2s1
Reactant: [C-]#[N+]C(c1ccccc1F)S(=O)(=O)c1ccc(C)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc2cnc(-c3[nH]cnc3-c3ccccc3F)cc2s1
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A solution of 2-(isopropylamino)thiazolo[4,5-c]pyridine-6-carbaldehyde (example 10, step 4) (presumed 0.244 mmol, 1.0 eq.) and concentrated aqueous NH4OH (0.050 mL) in THF (1 mL) was stirred overnight. 1-Fluoro-2-(isocyano(tosyl)methyl)benzene (0.0880 g, 0.304 mmol, 1.2 eq.) and piperazine (0.0371 g, 0.431 mmol, 1.8 eq.) were added, and the reaction mixture was stirred overnight. It was then diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 6-(4-(2-fluorophenyl)-1H-imidazol-5-yl)-N-isopropylthiazolo[4,5-c]pyridin-2-amine as a light orange solid (0.0212 g, 25% yield). LC/MS (MH)=354.18.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[CH:7]=[C:8]([C:10]#[N:11])[O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:32])([F:31])[F:30])[NH2:24]>CN(C=O)C.CCOC(C)=O.O>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][CH2:2][C:3]2[CH:13]=[CH:12][C:6]3[CH:7]=[C:8]([C:10]#[N:11])[O:9][C:5]=3[CH:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:31])([F:32])[F:30]
Reactant: N#Cc1cc2ccc(CBr)cc2o1
Reactant: Nc1ccc(OC(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc2ccc(CNc3ccc(OC(F)(F)F)c(Br)c3)cc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
6-(bromomethyl)benzofuran-2-carbonitrile (0.5 g, 2.12 mmol) was dissolved in DMF (21.2 ml). K2CO3 (0.44 g, 3.18 mmol) was added, followed by 3-bromo-4-(trifluoromethoxy)aniline (314 μL, 2.12 mmol), and the mixture was stirred at RT for 18 hr. The reaction was diluted with EtOAc and water. The organic layer was washed with water×6, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was diluted with DCM and silica gel was added. The mixture was concentrated under reduced pressure to dry-load material for purification. The crude mixture was purified via silica gel FCC, 100% Heptane-50% EtOAc/50% Heptane to give 6-(((3-bromo-4-(trifluoromethoxy)phenyl)amino)methyl)benzofuran-2-carbonitrile (651 mg). LCMS retention time=1.57 minutes (LC method 1); MS (m+1)=412.1. 1H NMR (400 MHz, DMSO-d6) δ 4.46 (d, J=6.0 Hz, 2H), 6.62 (dd, J=9.0, 2.8 Hz, 1H), 6.88-6.95 (m, 2H), 7.17 (dq, J=9.0, 1.3 Hz, 1H), 7.44 (dd, J=8.2, 1.4 Hz, 1H), 7.70 (s, 1H), 7.80 (dd, J=8.1, 0.7 Hz, 1H), 8.08 (d, J=1.0 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH2:12](N(CC)CC)[CH3:13].C([CH:21](O)[C:22]([O-:24])=[O:23])C>C1COCC1.C1(C)C=CC=CC=1>[CH2:12]([O:24][C:22](=[O:23])[CH:21]=[N:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[CH3:13]
Reactant: CCN(CC)CC
Reactant: CCC(O)C(=O)[O-]
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=NNc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A suspension of 4-methoxy-phenylhydrazine hydrochloride (32, 14.0 g, 80.2 mmol) in anhydrous THF (100 mL) was treated with triethylamine (TEA, 8.10 g, 11.2 mL, 80.2 mmol, 1.0 equiv) before a solution of ethylglycolate (50% solution in toluene, 16.4 g, 80.2 mmol, 1.0 equiv) in toluene was dropwise added into the reaction mixture at 0–5° C. under N2. The resulting reaction mixture was then stirred at 0–5° C. for 30 min before being gradually warmed to 25° C. for 12 h. When TLC and HPLC showed the reaction was deemed complete, the reaction mixture was filtered to collect triethylamine hydrochloride salt. The filtrates were concentrated in vacuo, and the resulting solids were collected by filtration. The crude solids were washed with water (2×50 mL) and 20% of EtOAc/hexane (2×50 mL), and dried at 40–45° C. in vacuo for 12 h to afford the crude, desired [(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (33, 16.0 g, 17.80 g theoretical, 90%), which was found to be pure enough to do the following reaction without further purification. For 33: CIMS m/z 221 (M+−H, C11H14N2O3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH:32]1(I)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:10][C:9]([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: IC1CCCC1
Reactant: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)nc1OC1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester (90 mg, 0.2 mmol), cyclopentyl iodide (46 μL, 0.4 mmol), and potassium carbonate (138 mg, 1 mmol) in DMF (1 mL) was heated to 90° C. for 1 day. The reaction mixture was then filtered and purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.58 (m, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.84 (m, 1H), 3.04 (m, 4H), 2.73 (m, 4H), 1.83 (m, 8H), 1.40 (m, 6H); HPLC ret. time 2.80 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 519.5 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].C([O:33][CH:34]([CH3:36])C)(C)C>C(O)(=O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:34]([O-:10])(=[O:33])[CH3:36]
Reactant: CC(C)OC(C)C
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
Sunitinib base (1.3 g) was dissolved in acetic acid (10 ml) by stirring for 5 min at 20° C. Then diisopropyl ether (20 min) was added within 30 min with stirring. Then the solution was filtered and t-butyl methyl ether (50 ml) was added to the stirred solution within 5 min. The orange precipitate thus formed was recovered by filtration, washed with t-butyl methyl ether (50 ml) and dried on air for 12 h at 20° C. (yield 1.425 g).