Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN>O.S([O-])([O-])(=O)=O.[Cu+2].CO>[OH:1][C:2]1[C:7]2[C:8]([CH3:16])=[C:9]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(/C=C/C(=O)O)oc2cccc(O)c12
Agent: [Cu+2]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: O
Product: Cc1c(CCC(=O)O)oc2cccc(O)c12
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of E-3-(4-hydroxy-3-methylbenzofuran-2-yl)propenoic acid (4.5 g, 20 mmoles), methanol (250 ml), 99% hydrazine hydrate (5 ml) and copper sulfate monohydrate (3 crystals) was stirred at room temperature for several days. The mixture was filtered and concentrated to remove methanol. The aqueous residue was acidified with 20% citric acid solution and extracted with diethyl ether. The ether solution was dried with Na2SO4, filtered, concentrated and chromatographed to obtain 950 mg of the title compound, m.p. 114°-117° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:46][CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CC(C)c1ccccc1N1CCS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 90 °C
Yield: 61.2 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (214 mg, 0.407 mmol) and potassium carbonate (225 mg, 1.63 mmol) in butanone (4 ml) was added 1-bromo-2-chloroethane (70.0 mg, 0.489 mmol). The reaction was heated to 90° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was cooled, diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were filtered through a phase separator and concentrated. Separation by flash column chromatography and drying the recovered solid at 55° C. under vacuum provided the title compound as a white solid (137 mg, 0.249 mmol, 61%): mp 193-196° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.22 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.80 (ddd, J=9.5, 6.9, 4.9 Hz, 4H), 7.43-7.33 (m, 4H), 7.31-7.21 (m, 2H), 4.05 (td, J=9.4, 7.1 Hz, 1H), 3.97-3.87 (m, 1H), 3.42-3.33 (m, 1H), 3.33-3.24 (m, 1H), 3.12 (heptet, J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H); ESIMS m/z 552 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([C:23]#[N:24])=[C:4](S(C)=O)[N:3]=1.[CH3:28][NH2:29]>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([C:23]#[N:24])=[C:4]([NH:29][CH3:28])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(SCC(=O)Nc2cccc(C(F)(F)F)c2)c1C#N
Reactant: CN
Solvent: CC#N
Product: CNc1nc(N)nc(SCC(=O)Nc2cccc(C(F)(F)F)c2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask were added 2-(2-Amino-5-cyano-6-methanesulfinyl-pyrimidin-4-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-acetamide (0.2 mmol, 1.0 eq.), methyl amine (2M in THF, 0.3 mmol), and acetonitrile (1 mL). The reaction mixture was stirred at room temperature for overnight. The crude material was purified by column chromatography (18 mg). LC-MS: (ES+) m/z 383 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.47 (s, 1H), 8.07(s, 1H), 7.75 (d, 1H), 7.55 (t, 1H), 7.40 (d, 1H), 7.36 (d, 1H), 7.25 (s, 1H), 3.95 (s, 2H), 2.73 (d, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7]2.P(Cl)(Cl)([Cl:21])=O.CN(C)[CH:26]=[O:27]>>[Cl:21][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[OH:1])[O:7][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[CH:26]=[O:27]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: O=C1CC(c2ccccc2)Oc2cccc(O)c21
Product: O=CC1=C(Cl)c2c(O)cccc2OC1c1ccccc1

Procedure:
As in example 1, but using 2.4 g 5-hydroxy-flavanone, 20 ml dimethylformamide and 2.8 ml phosphorous oxychloride. Reaction time is forty hours at 75° C. After hydrolysis and usual work up the residual solid is purified by column chromatography. The best fractions are recrystallised in a mixture of toluene and hexane to give pure yellow crystalline 4-chloro-3-formyl-5-hydroxy-flav-3-ene; m.p. 165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[S:23][C:24]([CH3:30])=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[S:23][C:24]([CH3:30])=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: Cc1sc(Br)nc1C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(-c2nc(C(=O)O)c(C)s2)cccc1[N+](=O)[O-]
Yield: 26 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (1.7 g, 6.08 mmol), 2-bromo-5-methyl-thiazole-4-carboxylic acid (900 mg, 4.05 mmol), tetrakis(triphenylphosphine)palladium (233 mg, 0.2 mmol) and sodium carbonate (1.29 g, 12.16 mmol) were dissolved in 30 mL of 1,4-dioxane. The reaction mixture was heated to reflux for 4 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 20 mL of hydrochloric acid (1 N) and 30 mL of ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain the title compound 2-(2-methoxy-3-nitro-phenyl)-5-methyl-thiazole-4-carboxylic acid 47a (310 mg, yield 26%) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[NH2:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:21][C:22]4[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(CN)o1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ccc2c(I)cccc2n1
Product: Cc1cc(Nc2cccc3nc(NCc4ccc(C)o4)ccc23)n[nH]1

Procedure:
The title compound, MS: m/e=334.5 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 3-amino-5-methylpyrazole.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([CH2:11][CH2:10][C@H:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:8]2)[NH:4][C:3]1=[O:20].[NH2:21][OH:22]>C(O)C.O>[OH:22]/[N:21]=[C:16](\[NH2:17])/[C:15]1[CH:18]=[CH:19][C:12]([C@H:9]2[CH2:10][CH2:11][C:5]3([NH:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]3=[O:7])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: NO
Reactant: CN1C(=O)NC2(CC[C@H](c3ccc(C#N)cc3)C2)C1=O
Solvent: O
Solvent: CCO
Product: CN1C(=O)NC2(CC[C@H](c3ccc(/C(N)=N/O)cc3)C2)C1=O
Temperature: 60 °C
Yield: 97.9 %

Procedure:
4-((7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl)benzonitrile (0.88 g, 3.27 mmol) was suspended in ethanol (20 ml). To this was added hydroxylamine (0.240 ml, 3.59 mmol) as 50% weight solution in water, and the reaction was heated to 60° C. under an atmosphere of nitrogen for about 20 hours. The reaction mixture was left to cool down to ambient temperature. Solvent was partially removed. The resulting white precipitate was filtered, rinsed with cold ethanol and vacuum-dried to afford (Z)-N′-hydroxy-4-{(7S)-3-methyl-2,4-dioxo-1,3-diazaspiro[4.4]nonan-7-yl}benzimidamide as light brown solid (1.12 g, 3.20 mmol).
Reaction SMILES: [C:1]([PH2:5])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15]OS(=O)(=O)O1.[OH:24]O>C1COCC1>[C:1]([P:5]1(=[O:24])[CH2:11][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)(C)P
Reactant: O=S1(=O)OCc2ccccc2CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)P1(=O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of tert-butyl phosphine (1.40 mL, 11.5 mmol) in THF (40 mL) was added dropwise n-BuLi (11.5 mmol) at −78° C. The resulting yellow solution was allowed to warm to rt and stirred at rt for 1 h. A solution of 40 (2.29 g, 11.5 mmol) in THF (20 mL) was added at −78° C. via cannula. The resulting solution was allowed to warm to rt and stirred at rt for 5 h. After being cooled to −78° C. again, n-BuLi (11.5 mmol) was added dropwise. The reaction mixture was warmed to rt and stirred overnight. 2.5 mL H2O2 (30% aq.) was added at 0° C. After being stirred at 0° C. for 1 h, the reaction was quenched with saturated Na2SO3 solution (10 mL) at 0° C. for 1 h. After usual workup, the crude product was purified by recrystallization (CH2Cl2 and hexane) to give 50 as white crystals (2.26 g, 94%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[N:17]1([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9](=[O:16])[NH:10]3)=[O:4])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: O=C(CN1CCCCC1)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 6 h

Procedure:
10 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) prepared in Example 4 or 8 was suspended in 50 ml of benzene, and 10 ml of piperidine (III) was added to the suspension followed by allowing the mixture to react while heating under refluxing and stirring for 6 hours. The reaction mixture was filtered to recover the reaction product which was then washed with benzene and then with 50 ml of isopropanol. The resulting insoluble material was dissolved in 150 ml of a 2% aqueous hydrochloric acid. The solution was concentrated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol to obtain 7.5 g of white amorphous 5-piperidinoacetyl-8-hydroxycarbostyril (II) hydrochloride 1/2 hydrate having a melting point of 239° - 241° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1.[C:16]1([CH2:22][CH2:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:22][CH2:23][CH2:24][NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]23[O:15][CH2:14][CH2:13][O:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CCCc1ccccc1
Reactant: Nc1ccc2c(c1)C1(OCCO1)C(=O)N2
Product: O=C1Nc2ccc(NCCCc3ccccc3)cc2C12OCCO2

Procedure:
By reaction of 5-amino-3,3-ethylenedioxy-2-oxindole with 3-phenylpropanal using the procedure of Example 1, the title compound was prepared.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]1[O:32][C:31]2[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][C:23]=2[O:22]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C.O.C(OCC)(=O)C>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][C:31]4[O:32][CH2:21][O:22][C:23]=4[CH:24]=3)[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OCC2CCNC2)c2ccccc2)cc1
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc(C(OCC2CCN(CCc3ccc4c(c3)OCO4)C2)c2ccccc2)cc1
Yield: 52.3 %

Procedure:
A mixture of 3-(diphenylmethoxymethyl)pyrrolidine (267 mg) (Preparation 7), 3,4-methylenedioxyphenethyl bromide (250 mg), sodium carbonate (1.0 g) and sodium iodide (100 mg) in acetonitrile (30 ml) was heated under reflux for 24 hours, diluted with water and ethyl acetate and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatogrpahy on silica using dichloromethane plus 0-20% ethyl acetate followed by dichloromethane plus 20% ethyl acetate plus 1-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (217 mg) as a colourless oil which was characterised containing 0.25 equivalents of water.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[C:6](I)[CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([C:32]4[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=4)[CH:6]=[C:7]3[N:8]=2)[N:13]=[C:14]([NH2:19])[CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2c(I)ccnc2N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(C(F)(F)F)cc4)cnc3[nH]2)c1
Temperature: 110 °C
Yield: 54.1 %

Procedure:
96 mg N-(2-amino-iodo-pyridin-3-yl)-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A10) is dissolved in 3.0 ml anoxic dioxane under a nitrogen atmosphere. Subsequently, 0.7 ml of an aqueous sodium bicarbonate solution (2.0 M), 52 mg 4-(trifluoromethyl)phenyl-boronic acid, and 14 mg trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 20 h. Thereafter, the volatile components are removed in vacuo and the remaining residue is re-dissolved in a mixture of water/dichloromethane (1:1). The aqueous phase is extracted several times with dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield 161 mg of a colourless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethanol 8:1) to afford 52 mg of the title compound. M.p. 170° C. ESI-MS: 398.3 (MH+). TLC: Rf=0.25 (dichloromethane/methanol 8:1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48](O)=[O:49])[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].NC(C1C=C[C:58]([Cl:61])=[CH:57][CH:56]=1)C#N.C(N(C(C)C)C(C)C)C>CC(N(C)C)=O>[Cl:61][C:58]1[CH:16]=[CH:15][C:14]([N:13]([CH2:12][C:11]#[N:10])[C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:49])=[CH:56][CH:57]=1
Reactant: N#CC(N)c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N(CC#N)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.456 g) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.361 g), 2-amino-2-(4-chlorophenyl)acetonitrile (Intermediate 4) (0.167 g) and N-ethyldiisopropylamine (0.523 mL, 3.00 mmol) in DMA (5 mL) at 25° C. The resulting solution was stirred at 50° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford tert-butyl 4-((4-chlorophenyl)(cyano)methylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate as a white solid (0.343 g, 67.3%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH3:17])[C:15]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:18]1[C:15]2[N:16]([CH3:17])[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:13][C:14]=2[CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCc1nc2cccc(Cl)c2n1C
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cn1c(CCC#Cc2ccccn2)nc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
In a dry reaction tube containing copper iodide (1 mg, 0.0055 mmol) and triethylamine (0.50 mL, 0.1 mmol), were added 2-iodopyridine (22 mg, 0.11 mmol) and Pd(PPh3)2Cl2 (2.4 mg, 0.0055 mmol). A yellow suspension was obtained and after a few minutes of stirring at room temperature, 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (compound 191(E), 24 mg, 0.11 mmol) in triethylamine (0.2 mL) was added. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 50° C. for 3 h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 2 g, DCM/MeOH:98/2 as eluent) to afford 2 mg g of 7-chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 6%) as brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH2:12][CH2:13][CH2:14][NH2:15])([CH3:11])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[C:16](Cl)(Cl)=[O:17].[C:20](OCCCC)(=[O:22])C>>[N:1]([CH2:2][CH2:3][CH2:4][Si:5]([CH2:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17])([CH3:11])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8])=[C:20]=[O:22]
Reactant: C[Si](C)(C)O[Si](C)(CCCN)CCCN
Reactant: CCCCOC(C)=O
Reactant: O=C(Cl)Cl
Product: C[Si](C)(C)O[Si](C)(CCCN=C=O)CCCN=C=O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Twenty parts of bis(3-aminopropyl)tetramethyldisiloxane obtained in Example 1, (1) was dissolved in 400 parts of butyl acetate. Thirty parts of butyl acetate was put in a flask equipped with a stirrer, a dropping funnel, a reflux condenser, a thermometer and a phosgene introducing tube, and cooled to 10° C. with an ice bath. Phosgene passed through the flask, and the polyamine solution prepared as above was added dropwise from the dropping funnel over the course of 30 minutes. After the addition, phosgene was further passed through the flask for 30 minutes to continue the reaction between the polyamine and phosgene. The ice bath was then replaced by an oil bath, and the reaction mixture was heated to 110° C. The reaction was continued by passing phosgene for 1 hour. After the reaction, dry nitrogen was passed through the flask at 110° C. to remove dissolved gases. The unreacted materials and the solvent were evaporated off, and the residue was distilled under reduced pressure to give 4 parts of bis(3-isocyanatopropyl)tetramethyldisiloxane of the following formula having a boiling point of 131° C. at 2 mmHg. ##STR41##
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]3[C:12]([C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18](/[C:21](=N/O)/[CH3:22])=[CH:17][CH:16]=4)=[C:4]2[CH:3]=[CH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C[O:26]/N=C(/C1C=CC(NC2C3C(=CC=CC=3)N=C3OC=CC=23)=CC=1)\C.COC1C=C(NS(C)(=O)=O)C=CC=1NC1C2C=CC=CC=2N=C2C=CC=CC=12>>[O:1]1[C:5]2=[N:6][C:7]3[C:12]([C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:26])[CH3:22])=[CH:17][CH:16]=4)=[C:4]2[CH:3]=[CH:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CO/N=C(\C)c1ccc(Nc2c3ccccc3nc3occc23)cc1
Reactant: C/C(=N\O)c1ccc(Nc2c3ccccc3nc3occc23)cc1
Agent: COc1cc(NS(C)(=O)=O)ccc1Nc1c2ccccc2nc2ccccc12
Product: CC(=O)c1ccc(Nc2c3ccccc3nc3occc23)cc1

Procedure:
In addition, (E)-1-(4-(furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone oxime (a hydroxyimino derivative of compound 1, referred to as compound 2 hereinafter) and (E)-1-(4-(furo[2,3-b]quinolin-4-ylamino)phenyl)ethanone O-methyloxime (a methoxyimino derivative of compound 1, referred to as compound 3 hereinafter) were also shown to have an antiproliferative potency comparable to that of amsacrine. The applicants even further found that compound 1 is able to induce mitotic arrest and apoptosis by binding to tubulin and inhibiting tubulin polymerization (Huang Y. T. et al. (2005), J. Med. Chem., 280:2771-2779).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:23][CH:19]2[CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: NC1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(NC2CCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(-2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.53 g, 2 mmol) and cyclobutylamine (1.387 g, 19.5 mmol) in methanol (15 mL) was heated at 70°-75° C. (oil bath) for 29 hours. After cooling to room temperature, 2 mL of 1.0N NaOH was added. The solution was concentrated and the residue chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as colourless foam which solidified to white powder in acetonitrile (454 mg, 75.7%), m.p. 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12](O)=[O:13].B.C1COCC1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:12][OH:13]
Reactant: O=C(O)c1cccc2cc(Cl)ncc12
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cccc2cc(Cl)ncc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroisoquinoline-8-carboxylic acid (0.5 g, 1.803 mmol) in THF (18.03 ml) at 0° C. was treated with BH3.THF (5.41 ml, 5.41 mmol). After stirring for 2 hours at 0° C., 1N NaOH was added. The reaction was stirred for 30 minutes then diluted with EtOAc and the layers were separated. Aqueous layer was washed with EtOAc three times. All combined organic layers were washed with brine, then dried with sodium sulfate. Filtered and concentrated in vacuo. Purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (3-chloroisoquinolin-8-yl)methanol.