Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.CC(C)=O.[CH3:11][NH:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:13])[C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: CNC
Reactant: C=C1CC(=O)O1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)C

Procedure:
A solution of 9 ml (0.05 mmol) of diketene-acetone adduct in 20 ml of toluene was treated with gaseous dimethylamine at room temperature until the reaction was complete. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→10%) yielding 7.0 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].[CH3:15][C:16]1([CH3:24])[CH2:20][O:19][CH2:18][N:17]1[C:21](Cl)=[O:22].O>O1CCCC1.CN(C)C=O>[CH3:15][C:16]1([CH3:24])[CH2:20][O:19][CH2:18][N:17]1[C:21]([N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:22]
Reactant: CC1(C)COCN1C(=O)Cl
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COCN1C(=O)n1nnc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
A solution of 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (3 g, 18.39 mmol) in a mixture of tetrahydrofuran (90 mL) and dimethylformamide (50 mL) was added dropwise to a stirred suspension of sodium hydride (1.839 g, 46 mmol) in tetrahydrofuran (30 mL) at 0° C. The suspension was allowed to stir at room temperature for 30 minutes before adding dropwise, at 0° C., a solution of 4,4-dimethyloxazolidine-3-carbonyl chloride (3.16 g, 19.31 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to stir at room temperature for 4 h. Water was added at 0° C. and the solvent was evaporated. A mixture of dichloromethane/isopropanol (7:3) was added and the organic layer was separated. The aqueous layer was re-extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and evaporated. The orange residue was recrystallised from isopropanol to give a beige solid (840 mg) that was used in the next step without further purification.
Reaction SMILES: [Li+].[Cl-].[I:3][C:4]1[N:5]=[C:6]([C@@H:10]2[CH2:14][C@H:13]([CH3:15])[CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:7][C:8]=1I.C[Mg]Cl.C([Mg]Cl)(C)C.[NH4+].[Cl-]>C1COCC1.O>[I:3][C:4]1[N:5]=[C:6]([C@@H:10]2[CH2:14][C@H:13]([CH3:15])[CH2:12][N:11]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[NH:7][CH:8]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)[Mg]Cl
Agent: C[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1C[C@@H](c2nc(I)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.7 %

Procedure:
A solution of LiCl in THF (3.9 mL of a 0.5 M solution, 1.99 mmol) is added to tert-butyl (2S,4S)-2-(4,5-diiodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (1 g, 1.99 mmol). After stirring for 5 minutes at rt the reaction mixture is cooled down to −20° C. and a solution of methyl magnesium chloride in THF (946.7 μL of 2.1 M, 1.99 mmol) is added dropwise. After stirring for 20 minutes at −20° C., a solution of isopropyl magnesium chloride in THF (3.2 mL of 1.24 M, 3.97 mmol) is added dropwise. The reaction mixture is slowly warmed up to rt and stirred for 2 hours. The reaction mixture is cooled down to 0° C. and a saturated aqueous NH4Cl solution is slowly added followed by water. This mixture is then extracted with EtOAc (3×20 mL), and the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue is purified by flash column chromatography on silica gel (0 to 25% EtOAC/Hexane) to afford tert-butyl (2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (636 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH:36]3[CH2:39][CH2:38][CH2:37]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH:36]3[CH2:39][CH2:38][CH2:37]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNC4CCC4)c23)ccc1OCc1ccccn1
Reactant: O=C(O)CO
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCC1
Yield: 22 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(cyclobutylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 17, preparation of starting materials) to give the title compound in 22% yield; NMR spectrum (DMSO-d6) 1.49-1.65 (m, 2H), 2.08-2.27 (m, 4H), 3.97 (s, 2H), 4.12 (d, 2H), 4.20-4.29 (m, 1H), 4.32-4.43 (m, 3H), 5.31 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 7.33-7.40 (m, 2H), 7.57-7.63 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.92 (m, 1H), 8.02 (s, 1H), 8.47 (s, 1H), 8.60 (d, 1H), 9.92 (s, 1H); Mass spectrum MH+ 534.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][C@@H:21]([CH2:26][O:27][CH2:28][CH3:29])[C:22](OC)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.O>[Si:13]([O:20][C@@H:21]([CH2:26][O:27][CH2:28][CH3:29])[C:22]([NH:12][C:9]1[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1cnc(N)cn1
Reactant: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of trimethylaluminium (2M in hexane, 5.51 mL, 11.02 mmol) was added dropwise to a stirred solution of 5-methylpyrazin-2-amine (CAS no. 5521-58-4) (1.20 g, 11.0 mmol) in toluene (20 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. The resulting solution was stirred for 15 minutes. A solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-ethoxypropanoate (Intermediate G3) (2.63 g, 10.0 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was allowed to warm to ambient temperature and then heated to reflux for 3 hours. 20% Sodium potassium tartrate solution (50 mL) then water (25 mL) were added and the mixture extracted with ethyl acetate (25 mL). The aqueous was re-extracted with ethyl acetate (25 mL). The organic phases were combined, washed with water (5 mL) and brine (20 mL), dried (MgSO4) and evaporated The residue was purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in isohexane to give (2S)-2-(tert-butyl-dimethylsilyl)oxy-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (1.45 g, 42%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:19]([Br:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br>CN(C)C=O.CCOCC.O>[BrH:26].[C:20]1([CH2:19][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(Cc3ccccc3)c3ccccc23)CC1
Reaction time: 1 h
Yield: 44.6 %

Procedure:
To a stirred suspension of 0.86 g of sodium hydride (50% oil dispension) in 50 ml of dimethylformamide under nitrogen, was added, dropwise, 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 15 ml of hot dimethylformamide. After stirring one hr. at ambient temperature, 2.6 g of benzyl bromide in 5 ml of dimethylformamide was added. The reaction mixture was stirred at ambient temperature for 15 hrs and then poured into water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine and dried over anhydrous magnesium sulfate. The ethyl acetate was evaporated in vacuo to yield an oil. The oil was dissolved in ether and gaseous hydrogen bromide was passed through the solution to yield an oily material. The oily material was triturated with boiling ethyl acetate. The solid was collected and recrystallized from absolute ethanol to yield 2.4 g (44.3%) of product, mp 218°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(NC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To an ice-cold solution of p-anisidine (25 g, 203.0 mmol) in DCM (300.0 mL) was added triethyl amine (90.0 mL, 609.0 mmol) dropwise and the reaction mixture was stirred at the same temperature for 15 min. Acetyl chloride (23.0 mL, 304.50 mmol) was then added and the reaction mixture was continued to stir at room temperature for 1 h. After the completion of the reaction (TLC monitoring), water (500 mL) was added and extracted with DCM (2×300 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (30.0 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ 1.99 (s, 3H), 3.70 (s, 3H), 6.86 (d, J=8.80 Hz, 2H), 7.48 (d, J=8.80 Hz, 2H) and 9.77 (br s, 1H).
Reaction SMILES: C(OC([NH:6][C:7]([NH2:9])=S)=O)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.Cl.NO.CCN(C(C)C)C(C)C>C(O)C.CO>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:6]=[C:7]([NH2:9])[N:18]=2)[CH:17]=1
Reactant: CCOC(=O)NC(N)=S
Reactant: COc1ccc(N)nc1
Agent: Cl
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCO
Product: COc1ccc2nc(N)nn2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To 5-methoxypyridin-2-amine ethoxycarbonyl thiourea (10.21 g, 40 mmol) in ethanol (57 mL) and methanol (57 mL) was added hydroxylamine hydrochloride (14 g, 200 mmol) and Hunig's Base (21 mL, 120 mmol). The mixture was stirred at room temperature for 2 hours, and then heated at 60° C. for 4 hours. The reaction was cooled to room temperature and filtered to remove solids. It was concentrated in vacuo and then suspended in chloroform. The solids were filtered off to yield 6-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine (6.05 g, 33.2 mmol, 83% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.30 (1 H, d, J=1.83 Hz), 7.24-7.32 (1 H, m), 7.16-7.23 (1 H, m), 5.82 (2 H, br. s.), 3.78 (3 H, s). MS (LC/MS) R.T.=0.53; [M+H]+=165.2.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:20]1([C:2]2[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=3)[N:6]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1oc(-n2cnc3ccccc32)nc1-c1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of methyl 3-[2-chloro-4-(3-chlorophenyl)-5-oxazolyl]propionate (2.31 g), 1H-benzoimidazole (1.82 g), potassium carbonate (3.19 g) and N,N-dimethylformamide (12 mL) was stirred at 120° C. for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-(1H-benzoimidazol-1-yl)-4-(3-chlorophenyl)-5-oxazolyl]propionate (1.85 g, 63%) was obtained as a solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=2)=[C:8]([F:23])[CH:7]=1)[NH2:2].[OH:25]/[CH:26]=[C:27](\[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)/[C:28](OC)=O.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:23][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][O:3][C:1]2[NH:2][CH:28]=[C:27]([CH2:32][C:33]3[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=3)[C:26](=[O:25])[N:24]=2)[CH:11]=[CH:10][C:9]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]=1
Reactant: COC(=O)/C(=C/O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cccc(C(F)(F)F)n4)c(F)c3)nc2=O)cn1
Temperature: 160 °C
Yield: 21.7 %

Procedure:
A mixture of 2-(3-fluoro-4-{[6-(trifluoromethyl)-2-pyridinyl]oxy}phenyl)ethyl imidocarbamate (44 mg, 0.089 mmol), methyl (2E)-3-hydroxy-2-{[2-(methyloxy)-5-pyrimidinyl]methyl}-2-propenoate (30.1 mg, 0.134 mmol), and K2CO3 (37.1 mg, 0.268 mmol) in NMP (15 mL) was heated with a microwave reactor at 160° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (10 mg, 21.63% yield). LCMS: rt=3.13 min, [M+H]=518
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=[O:17])[C:12](=[O:19])[N:11]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:13]2[C:12](=[O:19])[N:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]([CH3:9])[C:14]=2[CH3:15])=[O:17])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 46 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
To a mixture of 4-aminophenol (1.09 g, 10 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.37 g, 10.2 mmol) in DCM (30 mL) was added EDCI (2.3 g, 12 mmol) and HOAT (0.27 g, 2 mmol). The mixture was stirred at 46° C. for 4 hours, then cooled to rt and diluted with EtOAc (10 mL) and water (10 mL). The mixture was stirred at rt for 1 hour, then filtered to give the title compound as a white solid (1.7 g, 52.5%).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:8][C:9]2[CH:10]=[C:11]([CH:17]3[CH2:21][NH:20][C:19](=[O:22])[CH2:18]3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4]1.C1OCCOCCOCCOCCOC1.[F:38][C:39]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[F:38][C:39]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][N:20]1[CH2:21][CH:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7]3)[CH:10]=2)[CH2:18][C:19]1=[O:22]
Reactant: Fc1cccc(CBr)c1F
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(=O)N(Cc3cccc(F)c3F)C2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.7 %

Procedure:
Sodium hydride (20 mg, 0.5 mmol) was added, under an atmosphere of nitrogen at room temperature, to a mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (110 mg, 0.4 mmol) and 110 μL of 15-crown-5 in 2 mL of N,N-dimethylformamide. After 3 hours, the mixture was cooled to 0° C. and 2,3-difluorobenzyl bromide (166 mg, 0.8 mmol) in 2 mL of tetrahydrofuran was added. The resulting mixture was allowed to stir at room temperature for 6 hours. 100 mL of ethyl acetate was added, followed by the addition of 100 mL of ice cold water. After standard aqueous work up, the crude product was purified by flash column chromatography (ethyl acetate/hexane 2:1) to afford 112 mg (70%) of 1-(2,3-difluorobenzyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.18-6.98 (m, 3H), 6.79 (d, J=8.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.68 (s, 1H) 4.71-4.69 (m, 1H), 4.60 (s, 2H), 3.81 (s, 3H), 3.68 (t, J=9.0 Hz, 1H), 3.66-3.54 (m, 1H), 3.29 (dd, J=9.6, 7.2 Hz, 1H), 2.84 (dd, J=16.8, 9.0 Hz, 1H), 2.57 (dd, J=16.8, 8.4 Hz, 1H), 2.00-1.75 (b, 6H), 1.70-1.52 (b, 2H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]3[CH:24]=[C:25]([NH2:38])[C:26]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][C:28]=3[O:29][CH3:30])[N:16]=2)=[CH:7]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][C:26]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[C:25]([NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH:24]=3)[N:16]=2)=[CH:7]1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
Acryloyl chloride (0.025 mL, 0.30 mmol) was added dropwise to N′-[4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 12, 135 mg, 0.30 mmol) and DIPEA (0.090 mL, 0.33 mmol) in CH2Cl2 (10 mL) and DMF (2 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 2 h. then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and extracted with CH2Cl2 (40 mL). The resulting organic solution was washed with sat. Na2CO3 (20 mL) and then sat. brine (20 mL). The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-5% 7M methanolic ammonia in CH2Cl2 gave crude product. Further purification by preparative HPLC (Waters SunFire column, 5μ it silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN, followed by HPLC (Waters XBridge Prep C18 OBD column, 5μ it silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 1% NH3) and CH3CN, gave the title compound (23 mg, 15%) as a white solid; 1H NMR: 2.26 (3H, s), 2.37 (3H, s), 2.48-2.57 (4H, m), 2.87 (4H, t), 3.84 (3H, s), 5.70 (1H, d), 6.18 (1H, dd), 6.59 (1H, dd), 6.87 (1H, s), 7.05 (1H, dd), 7.15 (1H, t), 7.44 (1H, d), 7.83 (1H, s), 7.98 (1H, d), 8.22 (1H, s), 8.34 (1H, d), 8.49 (1H, s), 8.97 (1H, s), 11.68 (1H, s); m/z: ES+ MH+ 498.60.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]([NH2:35])=[O:34])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][C:33]([NH:35][C:1]3[C:11]4[CH:10]=[CH:9][C:8]5[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=5[CH2:6][C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:34])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: NC(=O)CCCN1CCN(c2ccc(F)cc2)CC1
Reactant: OC1c2ccccc2C=Cc2ccccc21
Solvent: CC(=O)O
Product: O=C(CCCN1CCN(c2ccc(F)cc2)CC1)Nc1cccc2c1C=Cc1ccccc1C2
Temperature: 70 °C
Reaction time: 20 h
Yield: 57.1 %

Procedure:
A mixture of 200 mg of 5H-dibenzo[a,d]cyclohepten-5-ol, 300 mg of 4-[4-(4-fluorophenyl)-1-piperazinyl]butyramide and 8 ml of acetic acid is stirred at 70° C. for 20 hours. The acetic acid is distilled off under reduced pressure and 100 ml of chloroform is added to the residue. The solution is washed successively with 10% aqueous potassium carbonate solution, water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate, and the chrloroform is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (100:3) to give 250 mg of the title compound. m.p. 233°-235° C. (recrystallized from chloroform-n-hexane);
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O>CO>[C:4]1([CH:1]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To a solution of an acetophenone in methanol (10 mL/mmol) was added an aldehyde (1.5 equiv) followed by an aqueous solution of KOH (50%, 1 mL/mmol of acetophenone). The mixture was heated at 70° C. for 4-6 hours and monitored by TLC. Water (20 mL) was then added, the methanol was evaporated, and the solution was extracted with CH2Cl2. The organic layer was dried and evaporated to dryness, then purified by recrystallization with methanol-water to afford the desired chalcone.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(C(CCCCl)=NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-methylbutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 10.15 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 8.65 g (64%) of the tide compound as an off-white solid, mp133-135° C.
Reaction SMILES: [CH:1]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[N+:2]([O-:4])=[O:3].ClC(Cl)C.C[Si](C)(C)[O:17][CH2:18][CH2:19][O:20][CH2:21]I.ICOCI>CN(C)C=O.ClCCCl.C(Cl)Cl>[OH:17][CH2:18][CH2:19][O:20][CH2:21][C:1]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[N+:2]([O-:4])=[O:3]
Reactant: C[Si](C)(C)OCCOCI
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Agent: ICOCI
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C

Procedure:
As illustrated by example 3, a dry solution of nitroform in a suitable inert organic solvent such as methylene chloride, 1,1-dichloroethane, 1,2-dichloroethane, 1,1,2-dichloroethane, etc., is added slowly to the iodomethyl 2-(trimethylsilyloxy)ethyl ether solution while the temperature of the solution is maintained in the range of from -50° C. to -80° C., and preferably from -70° C. to -80° C. Next, dry dimethylformamide is added to ionize the nitroform so that it will react with the iodomethyl ether. The solution is then allowed to warm slowly to a temperature of from about -5° C. to about +5° C. where it is kept until the reaction is completed. Pouring into ice water and then extraction into an organic solvent (e.g., methylene chloride) yields a crude 2,2,2-trinitroethyl 2-hydroxyethyl ether mixture.