Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH3:3][C@@H:4]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6][O:5]1>C(OCC)C.[Cu]I>[CH3:3][C@@H:4]1[CH2:9][C:8](=[O:10])[CH2:7][C@@H:6]([CH3:1])[O:5]1
Reactant: C[C@@H]1CC(=O)C=CO1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: C[C@@H]1CC(=O)C[C@@H](C)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Methyllithium in diethyl ether (1.6M, 218 mL, 349 mmol) was added in ˜10 mL portions over 20 min to a stirred slurry of copper(I) iodide (44.3 g, 233 mmol) in diethyl ether (350 mL) cooled to 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 min and then (R)-2-methyl-2H-pyran-4(3H)-one (13.5 g, 116 mmol) in diethyl ether (150 mL) was added dropwise over 30 min. The cold bath was removed and the reaction mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was slowly added (over ˜5 min) to a stirred solution of sat. NH4Cl (aq) (˜750 mL) and ice. Additional diethyl ether (˜500 mL) and water (˜150 mL) were added and the solution, which contained a grey precipitate, was stirred overnight. The layers were separated and the aqueous layer was extracted with diethyl ether (500 mL) and DCM (500 mL). The combined organic phase was dried (MgSO4), filtered and concentrated (the rotary evaporator bath temperature was held at or below ambient temperature) to an orange oil. The crude oil was purified with a Biotage® Horizon (240 g SiO2, 1-4% diethyl ether in DCM, column was pre-equilibrated with DCM) to yield (2R,6R)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (13.4 g, 86% pure by 1H-NMR) as a light yellow oil. [Note: The material was carefully concentrated and contained 10% w/w DCM by 1H-NMR. 1H-NMR analysis also indicated that the material was contaminated with ˜2.5% TBDMSOH carried over from a previous reaction and 1.6% of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one]. The analytical data of the product complied with the data reported in the literature, and the material was used without additional purification. 1H-NMR (400 MHz, CDCl3) δ 4.41-4.25 (m, 2H), 2.55 (ddd, J=14.1, 4.8, 1.4 Hz, 2H), 2.24 (ddd, J=14.1, 6.5, 1.5 Hz, 2H), 1.28 (d, J=6.5 Hz, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: NC1CCC(CCO)CC1
Agent: Cl
Product: OCC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.102 g, 0.34 mmol) was reacted with 2-(4-aminocyclohexyl)ethanol (0.140 g, 1.0 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.006 g, 4%) as a white solid. MW=407.38. 1H NMR (DMSO-d6, 500 MHz) δ 13.48 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.71-7.51 (m, 3H), 7.09 (s, 1H), 4.34 (br s, 1H), 3.85-3.82 (m, 1H), 3.45 (t, J=6.0 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H), 1.91-1.85 (m, 2H), 1.78-1.73 (m, 2H), 1.46-1.32 (m, 5H), 1.16-1.05 (m, 2H); APCI MS m/z 371 [M+H]+.
Reaction SMILES: [IH:1].O.[CH2:3]1[O:11][CH:4]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[I:1][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:11]
Reactant: I
Reactant: c1ccc(C2CO2)cc1
Solvent: CCO
Solvent: O
Product: OCC(I)c1ccccc1
Temperature: 0 °C

Procedure:
2-iodo-2-phenylethanol was synthesized as described in Golumbic, C. and Cottle, D. L. J. Am. Chem. Soc. 61, 996 (1939). An aqueous HI solution (81.7 grams, 54.7%) and 556 ml of water were added to a 1 L reaction flask equipped with an addition funnel, which was cooled to zero degrees C. Styrene oxide (40 grams) and 50 grams of ethanol were added to the addition funnel. The styrene oxide solution was added dropwise to the flask over a 40-minute period during which a white precipitate was formed. Filtration over a fritted glass funnel followed by drying under vacuum for four hours yielded 69.8 grams of a white solid having a melting point of 62-66° C. The solid was dissolved in 560 ml of ethanol and poured into rapidly stirred water (2.5 L containing 100 ml of 5% NaHSO3). The white precipitate was collected on a fritted glass funnel and dried in a vacuum oven at room temperature for four hours in the presence of P2O5 as a desiccant. The white solid (24 grams) had a melting point of 75.5-76° C. NMR analysis was consistent with the reports in the above-cited literature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH3:14][O:15][CH2:16][C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([C@H:29]3[CH2:31][C@H:30]3[CH2:32][CH2:33]O)[CH2:25][CH2:24]2)=[N:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:33][CH2:32][C@@H:30]2[CH2:31][C@@H:29]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:19]=[CH:18][C:17]([CH2:16][O:15][CH3:14])=[CH:22][N:21]=3)[CH2:24][CH2:25]2)=[CH:7][C:2]=1[F:1]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an RT solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (1.60 g, 5.49 mmol) in 15 ml of anhydrous dichloromethane was added a solution of 2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethanol (2.10 g, 7.22 mmol) in 20 ml anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 4.32 g, 16.5 mmol), and di-tert-butyl azodicarboxylate (2.53 g, 11.0 mmol). The mixture was stirred at RT for 3 hours, filtered through Celite and concentrated. The residue was purified by column chromatography (50 g silica gel) using a gradient eluent of 0-50% ethyl acetate:hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 458.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](O)=[O:14])=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:31])[C@H:26]1[O:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([N:8]1[C:12]([C:13]([NH:31][CH2:25][C@@H:26]2[CH2:27][CH2:28][CH2:29][O:30]2)=[O:14])=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@@H]1CCCO1
Reactant: O=C(O)c1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@@H]1CCCO1)c1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of Example 149C (51 mg, 0.16 mmol) dissolved in dimethylformamide (0.5 mL) was added, followed by the addition of (S)-(+)-tetrahydrofurfurylamine (18.2 mg, 0.18 mmol) dissolved in dimethylformamide (0.9 mL). A solution of HATU (68 mg, 0.18 mmol) dissolved in dimethylformamide (0.5 mL) was added followed by a solution of diisopropylethylamine (0.087 mL, 0.5 mmol) dissolved in dimethylformamide (0.5 mL). The mixture was shaken at 50° C. overnight. The reaction was filtered through a Si-Carbonate cartridge (6 mL-1 g) supplied by Silicycle Chemical Division, and the filtrate was transferred to 20 mL vials. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/methanol and purified by reverse phase HPLC (Agilent, 5%-100% TFA/water gradient, 8 minute run). 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.35-1.54 (m, 1H) 1.64-1.96 (m, 3H) 3.17-3.26 (m, 1H) 3.32-3.38 (m, 1H) 3.50-3.77 (m, 2H) 3.81-4.00 (m, 1H) 5.58-5.74 (m, 2H) 7.21-7.41 (m, 5H) 7.54-7.66 (m, 1H) 7.68-7.84 (m, 1H) 8.01-8.19 (m, 2H). MS (ESI−) m/z 401 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([OH:13])=[O:12].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Chlorobenzoic acid (2 g, 12.7 mmol) was added with stirring at 25° C. to a nitrating mixture (20 mL) prepared from 1:1 HNO3 (70%) and H2SO4 (98%). It was stirred for 1 h. and poured into ice water. The title compound obtained was filtered and dried.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]1([C:16]2[CH:17]=[N:18][NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:10]1([C:16]2[CH:17]=[N:18][N:19]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCBr
Reactant: c1ccc(-c2cn[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
The mixture of ethyl 4-bromobutyrate (0.400 g, 2.05 mmole), 4-phenyl-1H-pyrazole (0.296 g, 2.05 mmole) and K2CO3 (0.567 g, 4.10 mmole) in DMF (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×). The combined organic phases were washed with water and then brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative to afford the desired product (73 mg, 52%) as colorless oil. LCMS calculated for C15H19N2O2 (M+H): 259. found: 259.1.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:12]
Reactant: CCN
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CCNc1ccc(C(=O)O)cn1
Temperature: 170 °C
Yield: 84 %

Procedure:
6-Chloronicotinic acid (100 g, 0.63 mol) was treated with ethylamine (70% in water, 500 ml). The reaction was sealed in an autoclave and heated to 170° C. for 6 hours. The reaction mixture was evaporated, partially neutralised with concentrated HCl and the pH adjusted to pH5 with glacial acetic acid. The solid product was filtered off and dried in vacuo for 18 hours to give 6-(ethylamino)nicotinic acid (87.8 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9]2)[CH:7]=1.B(F)(F)F.CCOCC.[CH3:20][C:21]([CH3:23])=[O:22]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[CH2:10][O:9][C:21]([CH3:23])([CH3:20])[O:22]2)[CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1cncc(C2CO2)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: CC1(C)OCC(c2cncc(Br)c2)O1
Reaction time: 14 h
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-5-(oxiran-2-yl)pyridine (1.00 g, 5.00 mmol) in acetone (25 mL) was added BF3.OEt2 (0.950 mL, 7.50 mmol) dropwise at ambient temperature and the reaction mixture was stirred for 14 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to obtain 3-bromo-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridine (0.700 g, 54.2%) as a pale yellow liquid. LCMS (Condition 8): retention time 2.17 min, [M+2]=260.0. 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 3 H), 1.55 (s, 3 H), 3.72 (dd, J=7.6 Hz, J=8.4 Hz, 1 H), 4.36 (dd, J=6.4 Hz, J=8.4 Hz, 1 H), 5.08 (dd, J=6.4 Hz, J=7.6 Hz, 1 H), 7.85-7.86 (m, 1 H), 8.49 (d, J=1.6 Hz, 1 H), 8.62 (d, J=2.0 Hz, 1 H).
Reaction SMILES: [Br:1]Br.[CH2:3]([CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>[Fe]>[Br:1][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: CN1CCCC1Cc1ccccc1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Product: CN1CCCC1Cc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
Add 11.4 moles of bromine at room temperature to 2 g of 2-benzyl-1-methylpyrrolidine and 50 mg of iron powder. Allow the resulting mixture to stand for 2 hours before rendering it alkaline 1 N sodium hydroxide solution. Extract the base with diethyl ether. Distil the ether extract to obtain the title compound as almost-colorless liquid of b.p. 72° at 0.001 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)=[O:31]
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: COc1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)Nc1nc2c(OC)ccc(-c3ccccc3)c2s1

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (200 mg, 0.67 mmol) in THF (10 m) was added DMAP (10 mg, 0.08 mmol), triethylamine (163 □l, 1.17 mmol) and 2-methoxybenzoyl chloride (136 □l, 1 mmol) in THF (2 ml). The mixture was then heated to reflux for 2 h, after cooling, it was partitioned between 1:1 AcOEt/THF (70 ml) and 5% NaHCO3 solution( 40 ml). The organic phase was washed with saturated NaCl solution (50 ml), dried with Na2SO4, filtered and the solvent removed under reduced presure. The residue was suspended in ether (10 ml), filtered, washed with ether then dried under vacuum (0.05 mmHg, 60° C.), to afford the title compound was a white solid (260 mg, 85% yield), MS: m/e=390.0 (M+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([C:10]2[O:14][C:13]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[N:12][CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2cnco2)cc(OC)c1Br
Product: COc1cc(-c2cnc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl) ethanone was prepared from 5-(4-bromo-3,5-dimethoxyphenyl)oxazole and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Recrystallization from EtOAc gave the product as a yellow solid (0.308 g, 56% yield). MS: m/z 517.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:12]([SH:15])[CH:13]=[CH2:14]>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:15][CH2:12][CH:13]=[CH2:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: C=CCS
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCO
Product: C=CCSc1ccc([N+](=O)[O-])c(N)c1
Yield: 53.9 %

Procedure:
To a solution of 7 g of 2-nitro-5-chloroaniline in 200 ml of absolute ethanol there is added 4.2 g of allyl mercaptan and 2.5 g of Na-methoxide. Then the mixture is refluxed for three hours, the solvent is evaporated and the residue is chromatographed on neutral alumina (Activity IV). Elution with ether-petroleum ether yields 4.6 g of 2-nitro-5(2-propenylthio)aniline.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][N:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 423.11 g/mol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:43])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]5[N:38]([CH3:40])[CH3:39])[N:23]=[C:22](Cl)[N:21]=3)[CH:17]=2)[N:12]=[C:11]([CH3:42])[CH:10]=1.[CH3:44][N:45]([CH3:50])[CH2:46][CH2:47][CH2:48][NH2:49]>CN(C=O)C>[CH3:7][N:8]([CH3:43])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:34](=[CH:35][CH:36]=4)[N:33]=[C:32]([CH3:37])[CH:31]=[C:30]5[N:38]([CH3:40])[CH3:39])[N:23]=[C:22]([NH:49][CH2:48][CH2:47][CH2:46][N:45]([CH3:50])[CH3:44])[N:21]=3)[CH:17]=2)[N:12]=[C:11]([CH3:42])[CH:10]=1
Reactant: Cc1cc(N(C)C)c2cc(Nc3nc(Cl)nc(Nc4ccc5nc(C)cc(N(C)C)c5c4)n3)ccc2n1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N(C)C)c2cc(Nc3nc(NCCCN(C)C)nc(Nc4ccc5nc(C)cc(N(C)C)c5c4)n3)ccc2n1
Temperature: 100 °C

Procedure:
0.5 g (0.0036 mol) of potassium carbonate, 1 g (0.00189 mol) of 2,4-bis(4-dimethylamino-2-methylquinolin-6-yl)amino-6-chloro-[1,3,5]triazine prepared according to patent W0001561 and 1 ml (0.0078 mol) of N,N-dimethyl-1,3-propanediamine are successively loaded into a 250 ml round-bottomed flask containing 50 ml of DMF, with stirring, and then the mixture is heated for 15 hours at 100° C. The reaction medium is concentrated and taken up in 100 ml of water. The precipitate formed is filtered, washed with 2×50 ml of 0.1N NaOH and then dried. There are thus obtained 1.2 g of N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-N″-(3-dimethylaminopropyl)-[1,3,5]triazine, which is purified by flash chromatography on 30 g of silica (35-70 μm), eluting with a mixture (85/10/5) of dichloromethane, methanol and triethylamine. There is thus obtained, after drying under vacuum at 40° C., 0.45 g (41%) of 2,4-bis(4-dimethylamino-2-methylquinolin-6-yl)amino-6-(3-dimethylaminopropyl)-amino-[1,3,5]triazine, in the form of a yellow powder whose characteristics are the following:
Reaction SMILES: [CH2:1]([C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:41]=[N:42][C:43]([NH:46][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:44][CH:45]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CS(=O)c1ncc2cc(Cc3ccccc3)c(=O)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Cc5ccccc5)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Yield: 19.9 %

Procedure:
6-Benzyl-8-cyclopentyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.64 g, 1.74 mmol) and 4(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.87 g, 2.96 mmol) in toluene (10 ml) were heated to 95° C. for 28 hours. The reaction mixture was allowed to cool then chromatographed on silica gel using a gradient of 20 to 50% ethyl acetate in hexane. The product-containing fractions were evaporated and the residue was triturated with acetonitrile to give a solid. This solid was collected by filtration and dried in vacuo to provide 4-[6-(6-benzyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.201 g, 19.8%). MS (APCI) M++1: Calc'd, 582.31, Found, 582.3.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](O)=O.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Cl:7][CH2:8][C:9]([C:14]1[S:6][C:3]([NH:2][CH3:1])=[N:4][N:5]=1)([CH3:13])[CH3:10]
Reactant: CNC(=S)NN
Reactant: CC(C)(CCl)C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(C(C)(C)CCl)s1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
An 87.2 g. portion of 4-methylthiosemicarbazide and 113.2 g. of 3-chloro-2,2-dimethylpropionic acid were suspended in 300 ml. of dioxane. The mixture was heated to 90°C. and 139.5 g. of phosphorus oxychloride was added dropwise while holding the temperature constant. After the addition was complete, the reaction mixture was stirred at 90°C. for three hours. The mixture was then allowed to cool and stand overnight at room temperature.
Reaction SMILES: [C:1]([CH2:9][N:10]1[C:15]2[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][C:14]=2[C:13](=[O:26])[N:12]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=[C:11]12)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].N1C=CC=CC=1>C(O)C>[CH:19]1([N:17]2[CH2:18][C:14]3[C:13](=[O:26])[N:12]4[N:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:29]=[C:11]4[N:10]([CH2:9][C:1](=[N:37][OH:38])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:15]=3[C:16]2=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NO
Reactant: O=C(Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2c(c(=O)n3nc(-c4ccccc4)cc3n2CC(=NO)c2ccccc2)CN1C1CCCCC1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 4-(benzoylmethyl)-6-cyclohexyl-6,7-dihydro-2-phenyl-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione (see Example 4), (1.00 g.; 2.15 mmoles) and hydroxylamine hydrochloride (225 mg.; 3.23 mmole), in 4.5 ml of absolute ethanol and 1.5 of pyridine was heated to reflux, becoming homogenous. The solution deposited a precipitate with time, so another 2 ml. of ethanol was added to aid stirring. After a total of eight hours at reflux, the mixture was cooled and diluted with 15 ml. of ethanol. The mixture was suction filtered through a medium glass frit and the collected solid was washed with ethanol and dried in vacuo. The crude solid was suspended in boiling 95% ethanol (400 ml.), and chloroform was added until dissolution was achieved (70 ml.). About 50 ml. of the resulting solvent mixture was then boiled off before cooling to room temperature. This procedure afforded 624 mg. (60% yield) of the titled compound, m.p. >280° C. The NMR spectral analysis of a sample of this material indicated that a 1:1 mixture of the titled oxime isomers had been obtained. 1H NMR (DMSO d6, δ) (mixture of oxime isomers) 12.14 (s, 1H, OH), 11.12 (s, 1H, OH), 8.01 [d, 2H, J=7 Hz, 2-phenyl-H (ortho)], 7.89 (d, 2H, J=7 Hz, oxime-phenyl-H (ortho)], 7.2-7.7 (m, 17H, phenyl-H and pyrazole-H of one isomer), 6.76 (s, 1H, pyrazole-H), 6.12 (bs, 2H, (C(NOH)CH2), 5.72 (bs, 2H, C(NOH)CH2), 4.41 (s, 2H, NCH2), 4.30 (s, 2H, NCH2), 4.0 (m, 2H, cyclohexyl CH of both isomers), 1.1-1.9 (m, 20H, cyclohexyl CH2 of both isomers).