Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Cl:3])Cl.[Li]CCCC.C[B:10]([OH:12])[OH:11].[OH:13][C:14]([C:17]([OH:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1COCC1>[Cl:3][CH:1]([B:10]([OH:12])[OH:11])[CH3:14].[OH:13][C:14]([C:17]([OH:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: ClCCl
Reactant: CB(O)O
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cl)B(O)O
Temperature: -100 °C
Reaction time: 0.75 h

Procedure:
A 250 mL round bottom flask is charged with THF (60 mL) and CH2Cl2 (2.63 mL, 41.0 mmol). The solution was cooled to −100° C. with a liquid nitrogen/methanol/H2O bath. n-BuLi (1.6 N in hexanes, 25.7 mL) was added slowly over the course of 1 h. The resulting solution was stirred for an additional 45 min at −100° C. Pinacol methyl boronate, dissolved in THF (40 mL), was added and the solution was stirred overnight while warming to room temperature. The THF was removed by evaporation and hexanes (100 mL) were added. The resulting precipitate was filtered and the solution concentrated. The residue was distilled at 70° C., 2 mm Hg to yield 2.06 g (30%) of a clear colorless oil. 1H-NMR (CDCl3) δ 3.49 (q, 1H), 1.52 (d, 4H), 1.27 (s, 12H).
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[N:20]#[C:21][NH2:22].C(OCC)(=O)C>O>[NH2:22][C:21]1[N:1]=[C:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:20]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: N#CN
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 8.4 %

Procedure:
A suspension of 1.33 g of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate (5.00 mmol) in 4.20 g of 50% strength aqueous cyanamide solution (50.0 mmol) was heated to reflux. After 17 h, it was cooled to room temperature and treated with ethyl acetate (5 ml) and water (5 ml). The undissolved solid was filtered off. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate (2×5 ml). The combined organic phases were dried over magnesium sulphate and concentrated in vacuo. The crude product (0.97 g) was purified by flash chromatography on silica gel (eluent: methylene chloride). 121.6 mg of methyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate were obtained in the form of a colourless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:11]([C:12](=[O:13])[NH2:24])[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
To a solution of (S)-4-benzyloxy-2-tert butoxycarbonylamino butyric acid (1.16 g, 3.7 mmol) in anhydrous THF (15 mL) at −15° C. was added N-methylmorpholine (0.41 mL, 3.7 mmol) and isobutylchloroformate (0.51 mL, 3.7 mmol) under a nitrogen atmosphere. After 2 minutes, 33% aqueous ammonia (0.34 mL, 5.6 mmol) was added and the resulting mixture stirred at −15° C. for 2 h. The reaction mixture was left to warm to RT and was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The combined organic fractions were washed with aqueous 5% NaHCO3, water, dried (MgSO4) and concentrated in vacuo. The resulting white solid was used without further purification (quant. yield). 1H NMR (CDCl3, 300 MHz): δ 7.41-7.25 (5H, m), 6.38 (1H, br s), 5.75 (1H, br s), 5.38 (1H, br s), 4.55-4.45 (2H, m), 4.30 (1H, br s), 3.75-3.52 (2H, m), 2.10-2.00 (2H, m), 1.42 (9H, s).
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]([CH:25]2[CH2:27][CH2:26]2)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])C1C=CC=CC=1>C(OCC)(=O)C>[NH2:8][C:9]1[CH:10]=[C:11]([CH2:16][CH:17]([CH:25]2[CH2:26][CH2:27]2)[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(NCc2ccccc2)c1)C1CC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(N)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (4.63 mmol) of (+/−)-tert-butyl 3-[3-(benzylamino)-4-chlorophenyl]-2-cyclopropylpropanoate were dissolved in 160 ml of ethyl acetate, the mixture was deoxygenated with argon and 150 mg of palladium on carbon (10%) were added. The reaction mixture was stirred at RT under an atmosphere of hydrogen at atmospheric pressure for 8 h. The mixture was then filtered through celite, the residue was washed with ethyl acetate, the filtrate was concentrated under reduced pressure and the residue was dried under high vacuum. The residue was purified by chromatography on silica gel (mobile phase pure cyclohexane to cyclohexane/ethyl acetate 20:1). This gave 1.41 g of the target product (73.6% of theory).
Reaction SMILES: [C:1]([OH:10])(=O)[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)([Cl:13])=O>C1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCC(CCC)C(=O)Cl
Temperature: 50 °C

Procedure:
To 4.32 g (30 mmol) of valproic acid in an ice bath, thionyl chloride (3.60 g, 30 mmol) was slowly added, with stirring. The neat mixture was allowed to come to room temperature and then heated in a water bath at 50° C. for 30 minutes. 50 M1 portions of dry benzene were twice added and removed under reduced pressure. The resultant product was used in subsequent reactions without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]3([C:18]([F:21])([F:20])[F:19])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[CH:8][C:7]=2[N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)[CH2:3][CH2:2]1.[CH3:28][C:29]([O-])(CC)C.[Na+].ICC>CN(C=O)C>[CH2:28]([N:14]([C:15]1([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:25][C:24]([F:27])([F:26])[CH2:23]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:11]=1)=[O:13])[CH3:29]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCC(C)(C)[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C1(C(F)(F)F)CC1
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)picolinamide (Example 16 a), 15 mg, 38 μmol) and sodium 2-methylbutan-2-olate (5 mg, 46 μmol) in DMF (150 μL) was stirred for 15 minutes at ambient temperature. Iodoethane (9 mg, 7 μL, 58 μmol) was added and stirring was continued for 1 h. The reaction mixture was poured onto ice/sat. aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (2×20 mL), dried over Na2SO4 and brought to dryness. The crude product was purified by preparative TLC (silica gel, 1 mm, heptan/EtOAc 2:1, elution with EtOAc) to give the title compound (12 mg, 75%) as colorless oil; MS (EI): m/e=420.2 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[Cl:11])[NH:4][N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:4]2[C:5]3=[N:6][CH:7]=[N:8][C:9]([Cl:11])=[C:10]3[C:2]([Br:1])=[N:3]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.2 %

Procedure:
3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B) (5.0 g, 21.42 mmol), 1-benzyl-4-piperidinol (8.2 g, 42.83 mmol) and triphenylphosphine (11.23 g, 42.83 mmol)were suspended in 250 ml of tetrahydrofuran. The reaction mixture was cooled in an ice-water bath and diethyl azodicarboxylate (6.8 ml, 42.83 mmol) was added dropwise. 10 minutes later, the reaction mixture was allowed to warm up to room temperature. After stirring for 2 hours, solvent was removed and the residue was taking into ethyl acetate. The organic layer was washed, dried and evaporated. The crude product was passed through Biotage flash column using dichloromethane/ethyl acetate (90:10) as the mobile phase to yield 10.56 g of 1-(1-benzyl-4-piperidinyl)-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine. The product was 61% pure with a HPLC retention time of 12.46 min. (HPLC condition: 5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min., the column size is 3.9×150 mm, 300 A).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CCCCCC.[C:39]1([N:45]=[C:46]=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([NH:45][C:46]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=4)[N:9]=3)[NH:4][CH:3]=2)=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Solvent: CCCCCC
Product: COc1cc(-c2cnc3[nH]cc(C(=O)Nc4ccccc4)c3n2)cc(OC)c1OC
Reaction time: 0.01 h

Procedure:
7-Iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine 0.057 gm, 0.1 mM was placed in an oven dried flask and 1 ml anhydrous THF was added. The flask was chilled in an Acetone-dry ice slurry and evacuated and refilled 3 times with nitrogen. Via syringe 0.065 ml of 2.13M Buli in hexane solution (0.14 mM, 1.4 eq) was added and the now yellow mixture was stirred for 30 seconds then phenylisocyanate, 0.027 ml, 0.25 mM, 2.5 eq.) was added. The mixture was stirred for 30 minutes, removed from the dry ice-acetone bath and immediately quenched with saturated aqueous ammonium chloride. Ethyl acetate was added and insoluble material removed by filtration and discarded. The mixture was separated and the aqueous layer was extracted two times with ethyl acetate. The organic layers were rinsed three times with 0.1M HCl and dried over magnesium sulfate. The solution was concentrated and purified on a silica gel column (ethyl acetate/hexane gradient). The product was recrystallized from acetonitrile and dried at 2 torr in a 60° C. vacuum oven overnight to give 2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid phenylamide. (M+H)+=405.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][OH:25].[Na+].[I-]>CC(C)=O>[OH:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: OCCCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1ccc(OCCO)cc1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
To a solution of 4-hydroxybenzophenone (6.0 g, 29.7 mmol) in acetone (50 mL) were added K2CO3 (12.3 g, 89.0 mmol) and 2-chloroethanol (4.0 mL, 59.3 mmol), followed by addition of NaI (4.50 g, 29.7 mmol). The reaction mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. The white solid was filtered off and washed with acetone (100 mL). The filtrate was concentrated to a brown oil residue with some white solid. EtOAc (200 mL) was added, the white solid was filtered off and then washed with 50 mL of EtOAc. The filtrate was washed with 1 N NaOH, water, brine and dried over Na2SO4. Concentration afforded a pale yellow oil which was further purified by chromatography on a silica gel column eluted with a gradient from hexanes to 60% EtOAc:hexanes to give 5 as a white solid (1.52 g, 21%). 1H NMR (400 MHz, CDCl3): δ 4.00-4.05 (m, 2H), 4.15-4.20 (m, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.45-7.50 (m, 2H), 7.55-7.60 (m, 1H), 7.75 (d, J=7.1 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>C(N(CC)CC)C>[CH2:12]([N:14]([CH2:15][CH3:16])[C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: CCNCC
Reactant: O=C(Cl)Cc1ccc(I)cc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
4-Iodobenzeneacetyl chloride (10.62 g) was added portionwise to diethylamine (3.0 g) in triethylamine (40 ml) and washed in with MC (5 ml) at 0° under nitrogen and the suspension was stirred at room temperature for 2 h. ER (150 ml) was added, the mixture was filtered and the filtrate was concentrated to give a residue (7.94 g) which was purified by FCC eluting with ER-H (2:1) to give the title compound as a yellow oil (4.72 g). T.l.c. (ER) Rf 0.31.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([F:14])[F:13])[N:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([F:14])[F:13])[N:3]=2)=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: N#Cc1ccc(Cl)nc1OCC(F)F
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OCC(F)F
Temperature: 110 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloro-2-(2,2-difluoro-ethoxy)-nicotinonitrile (5.01 g, 22.9 mmol), 2-bromo-5-hydroxy-benzaldehyde (3.84 g, 19.1 mmol) and K2CO3 (5.3 g, 38 mmol) in dimethylformamide (30 mL) was heated to 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with H2O (800 mL) and extracted with ethyl acetate (4×800 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (20% ethyl acetate/hexanes) to give the title compound as a white solid (6.62 g, 90%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[C:10]([C:15]([O:17]CC)=[O:16])=[CH:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:20])[C:10]([C:15]([OH:17])=[O:16])=[CH:11][N:12]([CH3:14])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(C)cc(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.1 g, 4 mmol) and NaOH (1.6 g, 40 mmol) in water (25 mL) was stirred at RT overnight. The mixture was washed with EtOAc (2×) and the aqueous layer was acidified to pH=1-2 with conc. HCl. The resulting precipitate was collected by filtration and dried under vacuum to afford 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (810 mg, 81.9% yield). 1H-NMR (400 MHz, CDCl3): δ 15.76 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 7.58 (m, 3H), 7.14 (t, J=8.8 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[I:16][CH2:17][C:18]([OH:20])=[O:19].[CH:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:35][C:34]=2O)=[CH:27][C:26]=1[O:46][CH3:47])([CH3:23])[CH3:22]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[I:16][CH2:17][C:18]([O:20][C:29]1[CH:30]=[C:25]([O:24][CH:21]([CH3:22])[CH3:23])[C:26]([O:46][CH3:47])=[CH:27][C:28]=1[C:31]#[C:32][C:33]1[CH:34]=[CH:35][C:36]([O:41][CH:42]([CH3:44])[CH3:43])=[C:37]([O:39][CH3:40])[CH:38]=1)=[O:19]
Reactant: O=C(O)CI
Reactant: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2O)ccc1OC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C#Cc2cc(OC)c(OC(C)C)cc2OC(=O)CI)ccc1OC(C)C
Temperature: 18 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
DCC (1.60 g, 7.75 mmol) was added to a solution of 2-iodoacetic acid (1.44 g, 7.74 mmol), 2-[(4-isopropoxy-3-methoxy-phenyl)ethynyl]-5-isopropoxy-4-methoxyphenol (2.6 g, 7.03 mmol)and DMAP (43 mg, 0.35 mmol) in CH2Cl2 (30 mL) and the solution thereby obtained was stirred at 18° C. for 3 h. The resulting suspension was filtered (CH2Cl2 rinse) and the filtrate concentrated under reduced pressure. The residue was suspended in ether (30 mL) at 0° C. with rapid stirring then filtered [rinsing with Et2O (20 mL) pre-cooled at 0° C.] giving the title compound (3.67 g, 97%) as a cream solid mp 127-8° C. IR (KBr disc, cm−1) 2969, 2930, 2833, 1755, 1611, 1575, 1516, 1467, 1416, 1402, 1385, 1365, 1320, 1252, 1236, 1212, 1135, 1108. 1H NMR (300 MHz, CDCl3) δ 7.08 (dd, J=1.8, 8.4 Hz, 1H), 7.04 (d, J=2.1 Hz, 1H), 7.01 (s, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.65 (s, 1H), 4.53 (septet, J=6.0 Hz, 2 Hz), 3.95 (s, 2H), 3.85 (s, 6H), 1.38 (d, J=6.0 Hz, 6H), 1.37 (d, J=6.0 Hz, 6H). 13C NMR+APT (75.5 MHz, CDCl3) δ 167.3 (C), 150.0 (C), 148.4 (C), 148.3 (C), 148.2 (C), 145.1 (C), 125.2 (CH), 115.6 (C), 115.3 (CH), 115.2 (CH), 115.0 (CH), 108.8 (CH), 93.6 (C), 82.7 (C), 72.0 (CH), 71.6 (CH), 56.5 (CH3), 56.3 (CH3), 22.3 (CH3), 22.0 (CH3), −6.2 (CH2). MS (70 eV) m/z (%): 538 (80, M+·), 496 (10, M+·-CH2CHCH3), 370 (10, M+·-CH2ICO), 328 (34), 286 (100); HRMS calcd for C24H27O6I 538.0852. Found 538.0854.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]([CH:24]=O)=[CH:14]1)(=[O:12])=[O:11].CO.[CH3:28][NH2:29].[BH4-].[Na+].[ClH:32].C(=O)([O-])O.[Na+]>CO>[ClH:32].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]([CH2:24][NH:29][CH3:28])=[CH:14]1)(=[O:12])=[O:11]
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cc3ccccc3s2)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cc3ccccc3s2)c1
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1-(1-Benzothien-2-ylsulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (180 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (190 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (56 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=3:7→0:1), and dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 126 mg, 61%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][CH:19]([O:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH2:22][NH2:23])[CH3:17].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:25]([O:24][CH:19]([O:18][CH2:16][CH3:17])[CH2:20][CH2:21][CH2:22][NH:23][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)=[O:14])[CH3:26]
Reactant: CCOC(CCCN)OCC
Reactant: O=C(Cl)N1CCC(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CCCNC(=O)N1CCC(c2ccccc2)CC1)OCC
Reaction time: 8 h

Procedure:
A solution of 895 mg (4 mmol) of 4-phenylpiperidine-1-carbonylchloride in 4 mL dichloromethane is added to 0.69 mL (4 mmol) 4,4-diethoxybutylamine and 1.68 mL (12 mmol) of triethylamine dissolved in 20 mL of dichloromethane. The mixture is stirred overnight. 20 mL of saturated sodium carbonate solution is added. The organic phase is separated, dried with sodium sulfate and the solvent evaporated.
Reaction SMILES: C([O-])C.[Na+].[CH3:5][CH2:6][C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10][CH3:11].[I-].[K+].[CH2:16]([N:23]1[C:27]([CH2:28]Cl)=[CH:26][N:25]=[CH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N1C(CCl)=CN=C1)C1C=CC=CC=1>C(O)C>[CH2:16]([N:23]1[C:27]([CH2:28][CH:8]([C:7](=[O:13])[CH2:6][CH3:5])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:26][N:25]=[CH:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCC(=O)CC(=O)CC
Reactant: ClCc1cncn1Cc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [I-]
Solvent: CCO
Product: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.75 ml (10 mmol; ˜21% solution in ethanol) sodium ethanolate in 40 ml dry ethanol were added 1.30 mg (10 mmol) 3,5-heptanedione and stirred at 50° C. for 30 min. Then a tip of spatula of potassium iodide was added followed by a solution of 1-benzyl-5-chloromethyl-1H-imidazole (prepared from 2.27 g (9.4 mmol) 1-benzyl-5-chloromethyl-1H-imidazole hydrochloride in 10 ml ethanol and 3.5 ml (9.4 mmol; ˜21% solution in ethanol). The mixture was heated to 50° C. for further 5 min and then immediately cooled to ambient temperature and concentrated under reduced pressure at max. 30° C. Purification by flash-chromatography on silica gel with heptane/ethyl acetate 1:1 as eluent provided 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione as light yellow waxy solid: MS (ISP): 299.2 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH3:25][N:26]([CH3:37])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:26]([CH3:37])[CH3:25])=[CH:36][CH:35]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CN(C)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
A mixture of 200 mg (0.52 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 140 mg (0.8 mmol) of 4-[2-(dimethylamino)ethoxy]aniline was heated at 160° C. for 2 hours and then cooled. The residue was chromatographed on silica gel using firstly dichloromethane/methanol/acetic acid/water (240:24:3:2) and then dichloromethane/methanol/acetic acid/water (90:18:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 35 mg (23%) of 3-(2,6-dichlorophenyl)-7-[4-[2-(dimethylamino)ethoxy]anilino]-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 173-174° C.