Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[F:15].[CH2:16]([N:23]([CH2:29]OC)[CH2:24][Si](C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:23]1[CH2:29][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[C:3]([F:15])=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:13])([F:12])[F:11])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1c(Cl)cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (10 g, 38.61 mmol) in DCM (150 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (36.6 g, 154.44 mmol) at room temperature and reaction mixture was cooled to 0° C. followed by slow addition of TFA (0.29 mL, 3.861 mmol). Resulting reaction mixture was stirred at room temperature for 5 hours. After complete consumption of starting material, the reaction mixture was quenched with aqueous Na2CO3 and extracted with DCM (3×100 mL). Combined organic layer was dried over Na2SO4 and concentrated under vacuum to afford brown oil (9.7 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4% ethyl acetate in hexane to afford product as brownish solid (6.1 g, impure). Impure compound was used as such for next reaction. 1H-NMR (400 MHz, CDCl3) δ: 2.24-2.31 (m, 1H), 2.53-2.59 (m, 1H), 2.68-2.78 (m, 1H), 2.80-2.83 (m, 1H), 3.01-3.08 (m, 2H), 3.61-3.69 (m, 2H), 7.29-7.34 (m, 7H). (m/z): 280.4 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:3]#[CH:4].[Cl-].[NH4+].[OH2:19].O=O>C(O)C>[CH3:14][C:12](=[CH:11][CH2:10][CH2:9][C:8]([CH3:15])=[CH:7][CH2:6][CH2:5][C:2]([CH3:1])([OH:19])[C:3]#[C:4][C:4]#[C:3][C:2]([CH3:1])([OH:16])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:13]
Reactant: O
Reactant: C#CC(C)(O)CCC=C(C)CCC=C(C)C
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)=CCCC(C)=CCCC(C)(O)C#CC#CC(C)(O)CCC=C(C)CCC=C(C)C

Procedure:
In a 5-l. three-necked, and round-bottomed flask were placed 114.7 g of 3,7,11-trimethyldodeca-6,10-dien-l-yne-3-ol, 305.9 g of ammonium chloride, 765 ml of water and 76.5 ml of ethyl alcohol and the mixture was stirred at a room temperature by passing oxygen for 18 hours. After completion of the reaction, no starting material remained. The reaction mixture was centrifuged and was extracted with benzene. The organic layer was distilled off to remove benzene and ethyl alcohol. The residue was dissolved in benzene and washed with water. The benzene solution was dried over anhydrous calcium sulfate and the solid material was filtered off. The benzene solution thus obtained was distilled off to give 107.8 g of 2,6,10,15,19,23-hexamethyltetracosa-2,6,18,22-tetraene-11,13-diyne-10,15-diol as viscous liquid. A 3 g of this substance was further dissolved in 10 ml of benzene, treated with active carbon and purified by distilling the benzene.
Reaction SMILES: C([NH:3][C:4]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=O.O.[ClH:19]>O1CCOCC1>[ClH:19].[NH2:3][C:4]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)c1ccc(C(C)(C)NC=O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(N)c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-(1-formylamino-1-methyl-ethyl)-benzoate (2.97 g, 12.6 mmol) is added to a mixture of water (30 mL), dioxane (15 mL) and concentrated hydrochloric acid (3.01 mL, 36.1 mmol) and the mixture is heated to 100° C. for 12 h. The reaction mixture is evaporated and the residue is crystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1
Reactant: Nc1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: Fc1cc2c(Nc3ccc(OCc4cccc(Cl)c4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.0 g, 6.06 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 40 min to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-chloro-4-(3-chlorobenzyloxy)aniline (1.79 g, 6.67 mmol) and dry DMA (10 mL). The residue of 3-chloro-4-(3-chlorobenzyloxy)aniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 1 h 30 min. It was partitioned in between ethyl acetate (400 mL) and water (400 mL). The ethyl acetate layer was separated and washed further with water (2×200 mL), dried (MgSO4) and evaporated to give a crude product of N-(3-chloro-4-(3-chlorobenzyloxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (201). Chromatography on silica gel (dichloromethane/MeOH=25:1) gave pure 201 (2.52 g, 100%) as a yellow/orange solid, mp 196-198° C.; 1H NMR δ [(CD3)2SO] 10.03 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.75 (dd, J=9.0, 2.5 Hz, 1H), 7.57-7.54 (m, 1H), 7.49-7.39 (m, 3H), 7.31 (d, J=9.0 Hz, 1H). Anal. Calcd for C20H13Cl2FN4O: C, 57.85; H, 3.16; N, 13.49. Found C, 57.60; H, 3.45; N, 13.32.
Reaction SMILES: [C:1]([O:4][CH:5](Cl)[CH3:6])(=[O:3])[CH3:2].[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O-:21])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9].[K+].[I-].[Na+]>CN(C=O)C>[C:8]([NH:11][C:12]1[C:13]([I:28])=[C:14]([N:23]([C:25](=[O:27])[CH3:26])[CH3:24])[C:15]([I:22])=[C:16]([C:19]([O:21][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:20])[C:17]=1[I:18])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)Cl
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(C)=O)c(I)c(N(C)C(C)=O)c1I
Reaction time: 20 h

Procedure:
1-Chloroethyl acetate (Neuenschwander, Markus et. al., Helv. Chim. Acta, 61 (1978) 2047) (4.38 g, 35.7 mmol) in dry DMF (50 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6,-triiodobenzenecarboxylate (21.64 g, 32.5 mmol) and sodium iodide (0.26 g, 1.75 mmol) in dry DMF (320 ml). The precipitate is removed by filtration after stirring for 20 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (300 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solution is treated with activated carbon and the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[C:18]2[C:10]([C:11](=[O:20])[CH2:12][C:13]3([O:17]2)[CH2:16][CH2:15][CH2:14]3)=[C:9]([OH:21])[CH:8]=1)(=O)=O.[Cl-].[Li+].[CH:26]([Zn]C(C)C)([CH3:28])[CH3:27].[Cl-].[NH4+]>O.Cl.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[OH:21][C:9]1[CH:8]=[C:7]([CH:26]([CH3:28])[CH3:27])[CH:19]=[C:18]2[C:10]=1[C:11](=[O:20])[CH2:12][C:13]1([O:17]2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CC2(CCC2)Oc2cc(OS(=O)(=O)C(F)(F)F)cc(O)c21
Reactant: CC(C)[Zn]C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(O)c2c(c1)OC1(CCC1)CC2=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under argon, 16 g (45.42 mmol) of 5-hydroxy-4-oxo-3,4-dihydrospiro[chromen-2,1′-cyclobutan]-7-yl trifluoromethanesulfonate (Example 44A), 3.71 g (4.54 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 5.78 g (136.25 mmol) of lithium chloride are suspended in 400 ml of abs. dimethylformamide. The mixture is cooled to 0° C., 90.8 ml (90.8 mmol) of diisopropylzinc (1 M solution in toluene) are added and the mixture is stirred at this temperature for 4 hours. At 0° C., saturated ammonium chloride solution is then added to the mixture. The mixture is diluted with water, 1 N hydrochloric acid and ethyl acetate, the organic phase is separated off and the aqueous phase is extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is adsorbed on silica gel and purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 20:1). This gives 9.6 g (86% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.[CH2:38](Cl)Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:38])[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2CC(=O)Nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc32)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(O)c1)cc(=O)n2C)c1ccc(Cl)s1
Yield: 66 %

Procedure:
Following the same procedure as that described in Example 34A, the title compound of example 31 (100 mg, 0.203 mmol) was treated with BBr3 in CH2Cl2 (1M, 1.02 ml, 1.02 mmol) to give the title compound (64 mg, 67% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([O:18]CC)=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[N:9]=1)=[O:4].C(N(CC)C(C)C)(C)C>CO>[CH3:15][O:14][C:10]1[N:9]=[C:8]([CH2:7][CH:6]2[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:16]2=[O:18])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CN
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CC2NC(=O)CNC2=O)n1
Temperature: 70 °C
Reaction time: 48 h
Yield: 53.9 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-(6-methoxy-2-pyridinyl)alaninate (945 mg, 3.36 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.36 mmol) in MeOH (20 mL). The reaction mixture was stirred at 70° C. for two days. The mixture was allowed to cool to room temperature. The solid that formed was collected by filtration, washed with MeOH, and dried to give 3-((6-methoxy-2-pyridinyl)methyl)-2,5-piperazinedione (426 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Br:18][C:19]1[C:20]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])=[N:21][N:22]([CH3:24])[CH:23]=1.Cl>O.C(O)C>[Br:18][C:19]1[C:20]([C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH:28][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[N:21][N:22]([CH3:24])[CH:23]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1cc(Br)c(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)n1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)aniline (97 mg, 0.386 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature, extracted with ethyl acetate (50 ml) and washed with water (1×25 ml). The ethyl acetate solution was acidified with aqueous 2N HCl (1×25 ml). The resulting precipitate was collected by filtration, washed with water and isolated as a pale white solid (59 mg, 64%). 1H NMR (DMSO-d6): 10.54 (s, 1H), 9.44 (d, J=2.1 Hz, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.62–8.58 (m, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.65 (t, J=8.3 Hz, 1H), 7.59–7.54 (m, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:35])=[O:34])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3].Cl[C:47]([O:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:48]>O1CCCC1.O>[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:34])=[O:35])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[N:26][C:47]([O:49][CH:50]4[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)=[O:48])=[CH:28][CH:29]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3]
Reactant: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OC3CCCCC3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and cyclohexyl chloroformate in tetrahydrofuran/water.
Reaction SMILES: [O:1]=[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O>N1C=CC=CC=1>[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[CH:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])=[O:1]
Reactant: O=Cc1cccs1
Reactant: O=C(CC(=O)Nc1ccccc1C(=O)O)Nc1ccccc1C(=O)O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)O)C(=Cc1cccs1)C(=O)Nc1ccccc1C(=O)O
Yield: 57.3 %

Procedure:
2,2'-[(1,3-Dioxo-1,3-propanediyl)diimino]bisbenzoic acid (1.0 g, 2.92 mmol) and 2-thiophenealdehyde (0.49 g, 4.38 mmol) were heated under reflux in dry pyridine (8 ml) for 16 hours. After removing pyridine, the mixture was treated with water, made alkaline with 10% aqueous ammonia under ice cooling, and washed with ether. The aqueous layer was made acidic with 1N.HCl under ice cooling, and the precipitated crystals were collected on filter and washed with water. The resulting solid was purified by silica gel column chromatography and the effluent containing the desired compound was collected. After removing solvent, the residue was crystallized by treating water, collected by filtration, washed with water, and dried to give the title compound (0.730 g, yield, 57%), which was recrystallized from the mixed solvent of CH3OH--H2O to give the pale yellow crystals (0.602 g). m.p.: 213°-215° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:8][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]3)=[CH:16][N:15]=2)=[CH:10][CH:11]=1)(=O)C.[OH-].[Na+].O.Cl>O1CCOCC1>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:9]3[S:8][C:7]([CH2:6][CH2:5][OH:4])=[CH:11][CH:10]=3)=[N:15][CH:16]=2)[CH2:21][CH2:22]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCCc1ccc(CCc2ccc(N3CCN(C(C)=O)CC3)cn2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCO)s3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethyl acetate (719.0 mg, 1.791 mmol) in dioxane (6.3 ml) were added 1M aqueous sodium hydroxide solution (6.27 ml, 6.27 mmol) and water (6.3 ml) at 0° C. After stirring at room temperature for 1 hr, the mixture was cooled to 0° C., and 1M hydrochloric acid (8.0 ml, 8.0 mmol) was added. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:acetone=7:3→5:5) to give 2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethanol (608.7 mg, yield 94.5%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:13]1[N:17]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[N:21][C:16]2=[N:15][CH:14]=1)CCC>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[N:17]2[CH:18]=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[N:21][C:16]2=[N:15][CH:14]=1
Reactant: Clc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3ccccn3)cnc2n1
Yield: 26.8 %

Procedure:
2-Chloropyridine (361 μl, 3.78 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.89 mmol) by the method of Example 1 to give 3-(pyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (134 mg) as a white solid: δH (400 MHz, CDCl3) 7.24-7.30 (1H, m), 7.33 (1H, d, J 7.0), 7.82-7.84 (2H, m), 8.51 (1H, s), 8.68-8.70 (1H, m), 10.54 (1H, d, J 7.0); m/z (ES+) 265 (M++H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[C:12]1([S:18]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
1H-Indole-4-carbaldehyde (0.300 g, 2.01 mmol), benzensulfonyl chloride (0.47 g, 2.67 mmol) and tetrabutylammonium hydrogen sulfate (0.070 g, 0.21 mmol) were dissolved in dichloromethane (10 mL) and NaOH (413 mg, 10.33 mmol) in water (3 mL) was added. The mixture was stirred overnight and diluted with water and extracted with dichloromethane (1×). The combined organics were dried (MgSO4) and the crude product was purified with a plug of silica using 1% MeOH in dichloromethane as the eluent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]([C:26]#[C:27][CH2:28][NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:19][C:18]=1[Cl:35].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:35][C:18]1[CH:19]=[C:20]([C:26]#[C:27][CH2:28][NH:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])[C:21]2[O:25][CH2:24][O:23][C:22]=2[C:17]=1[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CN(C)C(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)c2cc1OC
Yield: 77.1 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6,7-dimethoxyquinazoline (160 mg, 0.71 mmol), N′-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N,N-dimethylurea (232 mg, 0.78 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.5 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (265 mg, 77%) as a pale brown solid; NMR Spectrum:DMSOd6) 2.81 (s, 6H), 3.91 (s, 3H), 3.92 (s, 3H), 4.09 (d, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.18 (s, 1H), 7.82 (s, 1H), 8.33 (s, 1H), 9.47 (s, 1H); Mass Spectrum: M+H+ 484/486.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(N(C(C)C)CC)(C)C.C(Cl)(Cl)Cl>CN(C=O)C.O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][N:4]1[CH2:3][CH2:2][NH2:1])([O-:19])=[O:18]
Reactant: NCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: NCCN1CCCCC1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine (10.0 g, 78.0 mmol) and 2-fluoro-1-nitrobenzene (22.0 g, 156.0 mmol) in DMF (250 mL) was added diisopropylethylamine (12.5 mL) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into a mixture of CHCl3 and water. The water layer was extracted with CHCl3 and the combined organic layers were washed with water and brine, dried (Na2SO4), and evaporated, and the residue was purified by silica gel column chromatography to give 1 (17.6 g, 91%) as a yellowish solid.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=S.Cl.[Cl:7][CH:8]([C:14]([CH3:16])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[S]>C(O)C.O>[ClH:7].[NH2:5][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([CH3:16])[NH:1][N:2]=1
Reactant: NNC(N)=S
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [S]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(N)n[nH]c1C
Temperature: 0 °C
Yield: 55.9 %

Procedure:
A stirred mixture of 9.1 g (0.1 mole) of 3-thiosemicarbazide and 1 mL of concentrated hydrochloride acid in 150 mL of absolute ethanol was cooled to 0° C. in an ice bath and 16.5 g (0.1 mole) of ethyl 2-chloroacetoacetate was added dropwise. The thiosemicarbazide dissolved as the reaction mixture was allowed to slowly come to ambient temperature, it then became yellow and a new precipitate formed. The reaction mixture was heated at reflux for 3 hr. All the material had not dissolved so the reaction mixture was diluted with water and made acidic with 3N hydrochloric acid to dissolve all the solids but sulfur. After filtering, the filtrate was concentrated in vacuo leaving an orange-red oil which slowly crystallized when acetone was added to give 11.5 g of orange powder, mp 186°-188° C., with decomposition.
Reaction SMILES: [O:1]=[C:2]1[CH:9](C(OCC)=O)[C:8](=[O:15])[C:5]2([CH2:7][CH2:6]2)[CH2:4][NH:3]1.O>C(#N)C>[CH2:6]1[C:5]2([C:8](=[O:15])[CH2:9][C:2](=[O:1])[NH:3][CH2:4]2)[CH2:7]1
Reactant: CCOC(=O)C1C(=O)NCC2(CC2)C1=O
Solvent: CC#N
Solvent: O
Product: O=C1CC(=O)C2(CC2)CN1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
Ethyl 6,8-dioxo-5-azaspiro[2.5]octane-7-carboxylate (4.0 g, 18.95 mmol) was taken up in ACN containing 1% v/v water (40 mL) and the resulting solution was heated at 90° C. for 3 h. The mixture was cooled to RT and concentrated in vacuo. The residue was diluted with water (40 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 80% EtOAc/petroleum ether) furnished 5-azaspiro[2.5]octane-6,8-dione (1.2 g, 8.62 mmol, 46% yield) as a pale pink solid: 1H NMR (400 MHz, CDCl3): δ 8.24 (br s, 1H), 3.41 (s, 2H), 3.33-3.31 (m, 2H), 1.11-1.05 (m, 2H), 0.98-0.96 (m, 2H). m/z (ESI, +ve) 140.3 (M+H)+.