Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6](I)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1N1CCCC1
Temperature: 120 °C
Yield: 27 %

Procedure:
The 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (0.20 g, 0.57 mmol) was combined with pyrrolidine (0.052 mL, 0.63 mmol) in N,N-dimethylformamide (2.0 mL) with cesium carbonate (0.19 g, 0.57 mmol) and heated to 120° C. in a sealed tube. After heating for 18 hrs the reaction was allowed to cool, taken up in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a dark oil. The product was purified by FCC on silica gel eluting with hexane:ethyl acetate gradient to give 4-acetyl-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile as an oil (0.045 g, 27%). LCMS calculated for C15H18ClN2O2(M+H)+: m/z=293.1; found 293.1.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:22]=3)[CH:6]=2)[CH2:3][CH2:2]1.[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][N:40]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:22]=[C:17]([C:7]4[CH:6]=[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)[N:10]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=5)[CH:8]=4)[CH:18]=[N:19][CH:20]=3)=[CH:30][CH:29]=2)[CH2:39]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=Cc1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(6′-cyclopropylamino-[2,2′;4′,3″]terpyridin-5″-yl)-benzaldehyde (Example 2.64)(1 eq, 0.204 mmol, 80 mg) in DCM (3 ml) is treated with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.2 eq, 0.448 mmol, 83.2 mg) followed by AcOH (1.2 eq, 0.245 mmol, 0.14 ml) and sodium triacetoxyborohydride (3.1 eq, 0.632 mmol, 134 mg). The reaction mixture is stirred at room temperature overnight and then extracted with DCM. The organic portion is washed with water, dried (MgSO4) and concentrated in vacuo to afford the title compound which is used in the next step without further purification; [M+H]+ 563.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:32])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:27][CH2:28]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol) was suspended in methylene chloride (5 ml), and diisopropylethylamine (72 μl, 0.41 mmol) and acetyl chloride (29 μl, 0.41 mmol) were added. The mixture was stirred for half an hour at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. The solid was suspended in methanol and filtered off to give 7-[(1-acetylpiperidin-4-yl)methoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (117 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:23]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:15][CH2:14]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: N#Cc1ccc(N2CCNCC2)cc1F
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-fluoro-4-(piperazin-1-yl)-benzonitrile (0.53 g, 2.56 mmol) and triethylamine (0.5 ml, 3.59 mmol) in CH2Cl2 (13 ml) is added dropwise to a cooled solution (0-5° C.) of acryloyl chloride (0.25 ml, 3.15 mmol) in CH2Cl2 (3 ml). After complete addition, the mixture is stirred at rt for 1 h, sat. aq. Na2CO3 solution is added and stirring is continued for 20 min. The organic layer is separated off, dried over Na2SO4 and evaporated. Upon addition of AcOEt, 4-(4-acryloyl-piperazin-1-yl)-2-fluoro-benzonitrile crystallizes out, is filtered off, washed with AcOEt and air-dried.
Reaction SMILES: Cl.N[OH:3].[OH-].[K+].[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8][N:7]=1>C(O)C>[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([NH2:17])=[O:3])=[CH:8][N:7]=1
Reactant: NO
Reactant: N#Cc1cnnc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cnnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.76 g of hydroxylamine hydrochloride was added to a stirred solution of 0.72 g of 85% aqueous potassium hydroxide in 25 ml of absolute ethanol at room temperature. The mixture was stirred at room temperature for 20 minutes, then 1.55 g of 27C was added and the mixture was heated at reflux for 3 hours, held overnight at room temperature, and filtered. The filtrate was stripped of solvent to give a dark oil, from which a yellow solid precipitated on standing. The solid was separated, and stirred in hot ethyl acetate. The resulting mixture was filtered, the solvent was stripped from the filtrate and the residue was recrystallized from ethanol to give 27, as a yellow solid, m.p.: 223° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[C:19]([O:27][CH3:28])[CH:18]=1>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:23]=[C:21]([C:20]3[CH:25]=[CH:26][C:17]([OH:16])=[CH:18][C:19]=3[O:27][CH3:28])[N:22]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: COc1cc(O)ccc1C(=N)NO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(O)cc3OC)no2)cc1C
Yield: 16 %

Procedure:
The title compound (7 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and 4,N-dihydroxy-2-methoxy-benzamidine (21 mg, 117 μmol) according to Method A; LC-MS: tR=0.50 min; [M+1]+=374.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:22](I)[CH2:23][CH3:24].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH2:22][CH2:23][CH3:24])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCI
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(-c2ccc(OC)c(OC)c2)cc(=O)n1C
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.0 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 0.5 g). The mixture was heated at 60° C. with stirring for 20 minutes and cooled to 0° C. To the mixture was added n-propyl iodide (15 ml) with stirring, which was continued at 0° C. for 2 hours and at ambient temperature for 3 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether and the resulting precipitates were collected by filtration to give 6-(3,4-dimethoxyphenyl)-3-methyl-2-propoxy-4(3H)-pyrimidinone (1.15 g) as by-product.
Reaction SMILES: Br[C:2]1[N:6]2[C@@H:7]([CH3:15])[CH2:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:16][CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].N.O.[CH3:25][N:26](C)C=O>>[C:25]([C:2]1[N:6]2[C@@H:7]([CH3:15])[CH2:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:16][CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:26]
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)[C@@H](C)CN(C(C)C)C2=O
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: CCOC(=O)c1c(OC)c2n(c1C#N)[C@@H](C)CN(C(C)C)C2=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
(S)-ethyl 6-bromo-2-isopropyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine-7-carboxylate (1.2 mol) and Cu(I)CN (2.4 mol) were dissolved in dimethylformamide (DMF; 2.2 l) at 20° C. under N2. The mixture was stirred for 2 h at 110° C. Concentrated NH3.H2O (650 ml) was added at 60° C. The mixture was stirred for 30 min at 60° C. and then cooled to 20° C. The mixture was filtered off. Ethyl acetate (3000 ml) and H2O (2000 ml) were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×1000 ml). The combined organic layers were washed with brine, dried and concentrated in vacuo. The crude product and a small batch of an earlier preparation were combined and washed with methyl tert-butyl ether to give a solid. Yield: 350 g of Intermediate I-3 (95% purity, 80% yield total).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[S:8])[NH:6][N:7]=1.[OH-].[Na+].[CH3:12]I>C(O)C>[CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5]([S:8][CH3:12])=[N:6][N:7]=1
Reactant: Cc1n[nH]c(=S)[nH]c1=O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(C)c(=O)[nH]1
Temperature: 40 °C
Yield: 47.9 %

Procedure:
To a solution of 6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (4, 5.80 g, 40.6 mmol) in absolute ethanol (250 mL) was added NaOH (1.96 g, 49.1 mmol) followed by MeI (11.5 g, 81.2 mmol). The mixture was heated at 40° C. for 15 h. Most of the solvent was evaporated under reduced pressure. Water was added to the residue. The precipitated white solid was collected by filtration and washed with ethanol to give 5 (3.06 g). The aqueous phase was extracted with CH2Cl2 (80 mL×4). The combined extracts were dried over Na2SO4 and concentrated to give 3.34 g crude product. This was purified by column chromatography on silica gel, and eluted with 1:1 to 1:2 petroleum ether-ethyl acetate to provide 6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (5). MS: m/z, 158 (100%, M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:10]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)C1

Procedure:
The title compound was prepared by following the similar procedure as described in intermediate-6, using 6-chloropyridin-3-ol and tert-butyl 3-hydroxypyrrolidine-1-carboxylate; MS: 299.0 (M+1)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:15]([NH2:17])=O>>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[CH:15][N:17]=[C:7]([OH:8])[C:6]=2[CH:5]=1)[CH2:13][CH3:14]
Reactant: NC=O
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Product: CCCc1cc2c(O)ncnc2s1

Procedure:
The product of example 3a was reacted with excess formamide at reflux for 3 hours. The reaction mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water and dried under vacuum to provide the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH:8]=1)#[N:2].[H][H]>CO.[Ni]>[O:7]1[CH:8]=[C:4]([CH2:3][CH2:1][NH2:2])[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]1=2
Reactant: [H][H]
Reactant: N#CCc1coc2ccccc12
Agent: [Ni]
Solvent: CO
Product: NCCc1coc2ccccc12
Yield: 69.2 %

Procedure:
To a solution of 3.1 g of 3-cyanomethylbenzo[b]furan in 40 mL of methanol was added 2.4 g of Raney nickel. The reaction was agitated at 25° C. in a Parr apparatus under 40 psi hydrogen for 21/2 hours. The suspension was filtered through a pad of filter aid and the filtrate was evaporated to give 2.2 g (71% yield) of oily product.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([NH:4][CH:5]([C:11]1[CH:12]=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[CH:15][CH:16]=1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(NC(C)=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)NCC(NC(C)=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h
Yield: 61 %

Procedure:
3 g, 0.014 mol of N,N'-Diacetyl-1-phenylethylenediamine was added slowly to 10 ml of 90% HNO3 at -40°. After stirring 5 hr at -40°, the solution was poured over ice and neutralized with NaHCO3. The product was extracted into ethyl acetate, and that was dried with MgSO4 and then evaporated to dryness under reduced pressure. The product was recrystallized from acetone/hexane, yielding 2.2 g (61%) of N,N'-Diacetyl-1-(p-nitrophenyl)-ethylenediamine mp 178°-180°. Anal. (C12H15N3O4) C, H, N were within 0.4% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
2-Amino-5-hydroxy-benzoic acid (3.0 g) was dissolved in a 1N aqueous solution of sodium hydroxide (50 ml), to which was added dropwise carbobenzyloxy chloride (3.5 g). The mixture was stirred for one hour at room temperature, which was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure to leave 2-benzyloxycarbonylamino-5-hydroxybenzoic acid as blackish brown crystals (2.9 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[I:17].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:7]2[C:2]([I:1])=[C:3]([CH2:8][CH2:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[I:17])[CH:4]=[CH:5][CH:6]=2)=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Ic1ccccc1CCNc1ccccc1I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cccc(CCNc2ccccc2I)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of 0.90 g of 2-iodo-N-(2-iodophenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4-nitrobenzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue is dissolved in ethyl acetate-di-chloromethane (5:1) and the solution washed with 1N HCl, saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethyl ether and hexane to give 1.10 g of product as a white solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]([NH2:31])=[NH:30].[OH-].[Na+]>C(O)(C)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[NH:28][C:29]1[N:31]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)[CH:4]=[CH:3][N:30]=1
Reactant: CN(C)/C=C/C(=O)c1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
(2E)-3-(Dimethylamino)-1-pyrimidin-5-ylprop-2-en-1-one (1 g, 5.6 mmol) and N-(2-methyl-5-nitrophenyl)guanidine nitrate (1.44 g, 5.6 mmol) (Z. Szakacs et al., J. Med. Chem. 2005, 48, 249) were suspended in 20 mL of isopropanol. Sodium hydroxide (0.28 g, 7 mmol) was then added. The mixture solution was stirred overnight and cooled to room temperature. The solid was collected by filtration and rinsed with isopropanol and diethyl ether. The filtrate was concentrated under reduced pressure and the residue was dissolved in 15 mL of isopropanol. The solution obtained was refluxed overnight and cooled to room temperature. The solid was collected by filtration and rinsed with isopropanol and diethyl ether. The pooled solid was rinsed with water and diethyl ether, and dried in vacuum to obtain 1.2 g (70% yield) of the title compound. MS (M+1)=309.10.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:6]1[O:7][C:8](=[O:21])[C:9]2[C:14]([C:15]=1[C:16]1[CH:17]=[N:18][NH:19][CH:20]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:5].[Cl:22][C:23]1[C:24]2[S:31][CH:30]=[CH:29][C:25]=2[N:26]=[CH:27][N:28]=1>CC(O)(C)C>[ClH:22].[NH:18]1[CH:17]=[C:16]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:21])[O:7][C:6]=2[CH:4]([NH:3][C:23]2[C:24]3[S:31][CH:30]=[CH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH3:5])[CH:20]=[N:19]1
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1cn[nH]c1
Reactant: Clc1ncnc2ccsc12
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(Nc1ncnc2ccsc12)c1oc(=O)c2ccccc2c1-c1cn[nH]c1
Yield: 29.8 %

Procedure:
3-(1-aminoethyl)-4-(1H-pyrazol-4-yl)-1H-isochromen-1-one dihydrochloride (Intermediate E4, 62 mg, 0.189 mmol), 4-chlorothieno[3,2-d]pyrimidine (45.1 mg, 0.264 mmol), TEA (0.092 ml, 0.661 mmol) were reacted in t-BuOH (1.1 ml) at 85° C. for 2 hrs and 90° C. for 4 hrs. The reaction was quenched by the addition of 1M HClaqueous (2 ml) and purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give the title compound (24 mg, 29.8%) as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29]Br)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][CH2:29][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CCC(CCCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(CN2CCC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.8 using 3-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-propyl-bromide (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([CH3:5])=O.[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10]>C(Cl)(Cl)Cl>[CH3:5][C:3]1([CH:2]([Cl:6])[Cl:1])[S:11][CH2:7][CH2:8][CH2:9][S:10]1
Reactant: CC(=O)C(Cl)Cl
Reactant: SCCCS
Solvent: ClC(Cl)Cl
Product: CC1(C(Cl)Cl)SCCCS1
Temperature: 0 °C
Yield: 80 %

Procedure:
In a three-necked flask equipped with a magnetic stirrer and having a nitrogen blanket at the inlet and outlet, are added 13.97 grams (0.11 mole) of 1,1-dichloroacetone, 10.8 grams (0.10 mole) of 1,3-propanedithiol and 50 milliliters of chloroform. The reaction mixture is cooled to 0° C. A slow steam of hydrogen chloride gas is then bubbled through the solution for approximately five minutes. Upon the reaction mixture reaching saturation, the mixture is allowed to set at room temperature for approximately thirty minutes. The solvent is then evaporated and a crude 2-methyl-2-dichloromethyl-1,3-dithiane derivative is expected in a yield of approximately 80–90%.
Reaction SMILES: C[Si]([O:5][C:6](=[O:11])/[CH:7]=[CH:8]/[CH2:9]Br)(C)C.[CH3:12][NH:13][CH3:14]>O1CCCC1>[CH3:12][N:13]([CH3:14])[CH2:9]/[CH:8]=[CH:7]/[C:6]([OH:5])=[O:11]
Reactant: CNC
Reactant: C[Si](C)(C)OC(=O)/C=C/CBr
Solvent: C1CCOC1
Product: CN(C)C/C=C/C(=O)O

Procedure:
The preparation of 4-(dimethylamino)-2-butenoyl chloride (hydrochloride) (I) is described in Scheme II wherein but-2-enoic acid 7 is reacted with chlorotrimethylsilane in pyridine to afford trimethylsilylcrotonate 8 which is brominated with a brominating agent preferably N-bromosuccinimide under free radical conditions in the presence of light and peroxide in methylene chloride, acetonitrile, 1,2-dichloroethane, carbon tetrachloride or ethyl acetate to give trimethylsilyl-4-bromocrotonate 9. Reaction of trimethylsilyl-4-bromocrotonate 9 with dimethylamine in tetrahydrofuran at about 0–5° C. affords 4-dimethylaminocrotonic acid 10 isolated as the hydrochloride salt. Alternatively, 4-dimethylaminocrotonic acid 10 can be prepared by reaction of methyl or ethyl 4-bromocrotonate 11 with dimethylamine at 0 to 10° C. in tetrahydrofuran to give methyl or ethyl 4-dimethylaminocrotonate 12 which is hydrolyzed with aqueous base which includes sodium hydroxide in methanol as a cosolvent at about 40–45° C. to give 4-dimethylaminocrotonic acid 10 which is isolated to 4-dimethylaminocrotonic acid (hydrochloride) 10 with a solution of hydrogen chloride in isopropyl alcohol, and then chlorinated with a chlorinating agent preferably, but not limited to, oxalyl chloride in methylene chloride, tetrahydrofuran (THF) or acetonitrile in the presence of a catalytic amount of N,N-dimethylformamide to afford 4-(dimethylamino)-2-butenoyl chloride hydrochloride 2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (2 g, 11.4 mmol) was reacted with 4-chloro-benzaldehyde (1.91 g, 13.6 mmol) (1.53 g, 13.6 mmol) (Aldrich) and piperidine (1.34 mL, 13.6 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (Yield: 3.3 g, 100%).