Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1=[O:8].C([Li])CCC.CCCCCC.[C:20]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1.[Ag]=O>[CH3:23][C:20]([C:24]1[CH:29]=[C:28]([CH2:30][CH:4]2[S:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:8])[CH:27]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:25]=1[OH:35])([CH3:21])[CH3:22]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CN1CCSCC1=O
Agent: O=[Ag]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCSC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
4-methyl-3-thiomorpholinone (1.88 g, 14.3 mmol) dissolved in tetrahydrofuran (72 ml) was cooled to 0° C. and treated with 1.37M n-butyl lithium in hexane (20.9 ml, 28.7 mmol). After five minutes, the cold bath was removed. Ten minutes later a solution of 2,6-di-t-butyl-quinone methide, prepared by adding silver oxide (33.2 g, 143 mmol) to 2,6-di-t-butyl-4-methyl-phenol (BHT) (3.16 g, 14.3 mmol) in tetrahydrofuran (72 ml) stirring for 30 minutes and filtering, was added dropwise over 20 min. The reaction was stirred for three hours, quenched with 1N hydrochloric acid, and evaporated to an aqueous suspension. The crude product was extracted into ethyl acetate, dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel eluting with 8 L of a 0-50% ethyl acetate in hexane gradient yielded desired product (2.0 g, 40%):
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[C:26]([OH:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[O:24][C:23](=[O:34])[CH:22]=1>>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:35])[C:19]=1[NH:20][C:21]1[C:30]2[C:25](=[C:26]([O:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[O:24][C:23](=[O:34])[CH:22]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CCOC(=O)CCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCC(=O)O

Procedure:
The title compound was prepared from ethyl 7-bromoheptanoate and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 42. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.19 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 2.19 (t, 2H), 1.66 (m, 2H), 1.54-1.40 (m, 4H), 1.31 (m, 2H); MS (ESI): 480.9.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]([OH:30])([CH3:29])[CH2:27][OH:28])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:42][C:32]1[CH:37]=[CH:36][C:35]([S:38]([O:28][CH2:27][C:26]([OH:30])([CH3:29])[CH2:25][O:24][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][N:13]([C:8]2[CH:7]=[C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:31])[CH:11]=[CH:10][C:9]=2[CH3:12])[C:22]3=[O:23])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCC(C)(O)CO)cc2c1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(O)COc2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)cc1
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution of N-cyclopropyl-3-[6-(2,3-dihydroxy-2-methylpropoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.2 g) in pyridine (10 ml) was added p-toluenesulfonylchloride (0.18 g) followed by 4-dimethylaminopyridine (cat.) and the mixture heated at 60° C. for 18 hours. The reaction mixture was concentrated under reduced pressure and redissolved in ethyl acetate. The organics were washed with 1N citric acid, brine, dried (magnesium sulfate) and concentrated to give the crude 3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (0.21 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.[CH:29]([S:32](Cl)(=[O:34])=[O:33])([CH3:31])[CH3:30]>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:32]([CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])=[CH:14][CH:13]=2)[N:4]=1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
A mixture of ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine (100 mg, 0.339 mmol), triethylamine (0.07 ml, 0.51 mmol) in DCM (10 ml) was stirred in an ice bath under argon. Then isopropylsulfonyl chloride was added (148 mg in total, 1 mmol) in DCM (1 ml) dropwise with stirring. The reaction mixture was allowed to stir at room temperature for 16 hr. Then the reaction mixture was washed with water (20 ml), separated the organic layer and dried with sodium sulphate. Solvent was removed by rotary evaporation and the sample purified by MDAP to give the title compound as an off white solid (51 mg, 37%).
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.NC1N=CC=CN=1.C[O:33][C:34]1[CH:35]=[C:36]([C:40]2[C:41]3[CH2:54][CH2:53][N:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=4)[C:42]=3[N:43]=[C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[N:45]=2)[CH:37]=[CH:38][CH:39]=1>>[N:46]1([C:44]2[N:45]=[C:40]([C:36]3[CH:35]=[C:34]([OH:33])[CH:39]=[CH:38][CH:37]=3)[C:41]3[CH2:54][CH2:53][N:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=4)[C:42]=3[N:43]=2)[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccccn2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Nc1ncccn1
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccccn2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-aminopyrimidine, 4-(3-methoxy-phenyl)-2-morpholin-4-yl-7-pyridin-2-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([S:10]([CH2:13]CC(OC)=O)(=[O:12])=[O:11])([CH3:9])[CH3:8])=[N:4][CH:3]=1.C[O-].[Na+].CI>C1COCC1.CS(C)=O.O>[Br:1][C:2]1[S:6][C:5]([C:7]([S:10]([CH3:13])(=[O:11])=[O:12])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(=O)CCS(=O)(=O)C(C)(C)c1ncc(Br)s1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CS(C)=O
Product: CC(C)(c1ncc(Br)s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Methyl 3-{[2-(5-promo-1,3-thiazol-2-yl)propan-2-yl]sulfonyl}propanoate (Example 70, Step 4, 500 mg, 1.403 mmol) was taken up in THF (15 mL) at room temperature, and NaOMe (25% in MeOH, 303 mg, 1.403 mmol) was added. After 30 min at room temperature, the suspension was evaporated to dryness, providing a white solid. The solid was taken back up in DMSO (5 mL), and methyl iodide (398 mg, 2.81 mmol) was added. After stirring for 2 h at room temperature, the reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-40% ethyl acetate in hexanes) afforded of 5-bromo-2-[2-(methylsulfonyl)propan-2-yl]-1,3-thiazole (372 mg, 93%) as a colorless solid. MS ESI: [M+H]+ m/z 283.9/285.9.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([O:34]C)=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:32]([OH:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[O:22][CH:23]=[CH:24][N:25]=4)=[CH:18][C:17]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(c1ncco1)=Cc1cc(OC)ccc1-3
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(c1ncco1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 93.5 %

Procedure:
Methyl 13-cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (75.4 mg, 0.16 mMol) was dissolved in 2 mL of THF and potassium trimethylsilanolate (103 mg, 0.80 mMol) added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere for 19 hrs. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase was washed sequentially with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 68 mg (93%) of the title product as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.18-1.33 (1 H, m), 1.36-1.45 (2 H, m), 1.58 (1 H, br. s.), 1.79 (2 H, d, J=10.07 Hz), 1.96 (1 H, br. s.), 2.08 (3 H, br. s.), 2.88 (1 H, t, J=12.05 Hz), 3.94 (3 H, s), 4.44 (1 H, br. s.), 6.00 (1 H, br. s.), 7.04 (1 H, d, J=2.75 Hz), 7.09 (1 H, dd, J=8.70, 2.59 Hz), 7.31 (1 H, s), 7.56 (1 H, d, J=8.85 Hz), 7.65 (1 H, s), 7.68 (1 H, s), 7.82 (1 H, dd, J=8.55, 1.22 Hz), 7.90 (1 H, d, J=8.55 Hz), 8.54 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.83 min, purity 96%. Flow injection Mass Spectrometry: MS m/z 455(MH+), m/z 453(M-H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([O:25]C)=O)=[CH:13][C:12]=2[N:11]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:25])=[CH:13][C:12]=2[N:11]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(F)c(C(F)(F)F)c1)cc1nc(Nc3c(F)cccc3Cl)[nH]c12
Yield: 19.4 %

Procedure:
Under inert atmosphere to a solution of methyl 7-[(2-chloro-6-fluorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylate (Step-3 of Intermediate-56, 0.100 g, 0.297 mmol) in dry toluene was added 4-fluoro-3-trifluoromethyl aniline (0.080 g, 0.446 mmol) and trimethyl aluminium (2.0 M solution in toluene) (0.037 g, 0.516 mmol). The reaction mixture was refluxed for 1 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 0.75-1% DCM: MeOH to afford 0.030 g of the desired product. 1HNMR (DMSO-d6): δ 2.65 (s, 3H), 7.40-7.57 (m, 4H), 7.65 (s, 1H), 8.06 (m, 1H), 8.30 (s, 1H), 9.37 (s, 1H), 10.40 (s, 1H), 11.68 (s, 1H); MS [M+H]+: 522.14.
Reaction SMILES: [CH:1]12[CH2:39][CH:4]([CH:5]([NH:7][C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]([C@@H:20]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=5)[CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:16](=[O:38])[CH:15]=4)[CH:11]=[CH:10][N:9]=3)[CH2:6]1)[CH2:3][O:2]2.C([O-])([O-])=O.[Na+].[Na+]>Cl.CO>[CH:1]12[CH2:39][CH:4]([CH:5]([NH:7][C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][N:17]([C@@H:20]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([F:37])[CH:31]=5)[CH2:21][OH:22])[C:16](=[O:38])[CH:15]=4)[CH:11]=[CH:10][N:9]=3)[CH2:6]1)[CH2:3][O:2]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CC4CC3CO4)n2)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1cc(-c2ccnc(NC3CC4CC3CO4)n2)ccn1[C@H](CO)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
The crude 4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)pyridin-2(1H)-one was dissolved in a solution of HCl in methanol (5 mL, 1M). After being stirred at room temperature for 2 hours, the reaction mixture was then adjusted to pH around 8 by saturated Na2CO3. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford 4-(2-(2-oxabicyclo[2.2.1]heptan-5-ylamino)pyrimidin-4-yl)-1-((S)-1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)pyridin-2(1H)-one (23 mg, 29% yield). 1H NMR (500 MHz, CD3OD) δ 8.42 (d, J=5.0 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.51 (t, J=16 Hz, 1H), 7.35□7.33 (m, 1H), 7.29 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.14 (d, J=5.5 Hz, 1H), 7.08-7.06 (m, 1H), 6.15-6.13 (m, 1H), 4.40 (s, 1H), 4.32-4.28 (m, 1H), 4.22-4.19 (m, 1H), 4.09-4.07 (m, 1H), 3.71-3.69 (m, 1H), 3.61 (d, J=7.0 Hz, 1H), 2.69 (s, 1H), 2.19 (t, J=12.0 Hz, 1H), 1.86 (d, J=10.5 Hz, 1H), 1.66 (d, J=10.0 Hz, 1H), 1.58 (d, J=14.0 Hz, 1H); LCMS (ESI) m/z: 571.3 [M+H]+.
Reaction SMILES: [BH4-].[Na+].CO.[N+:5]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:9]=1[CH:10]=[O:11])([O-:7])=[O:6]>[OH-].[Na+]>[N+:5]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:9]=1[CH2:10][OH:11])([O-:7])=[O:6]
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
11.0 g of sodium borohydride were dissolved in 160 ml of 0.2N sodium hydroxide at room temperature. The resulting solution was dropwise added to a methanol solution comprising 100 g of 2,6-dinitrobenzaldehyde. This was stirred for 30 minutes at room temperature. Afterwards, methanol was removed therefrom by distillation, and the residue was extracted several times each with diethyl ether. The ether extracts were dried with anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure, using a rotary evaporator, and the residue was recrystallized three times each from chloroform/carbon tetrachloride, to obtain 90.2 g of 2,6-dinitrobenzyl alcohol. 20 g of this 2,6-dinitrobenzyl alcohol and 23.7 g of p-toluenesulfonyl chloride were dissolved in 150 ml of acetone to prepare a solution. An acetone solution comprising 2.25 ml of dicyclohexylamine was dropwise added to the solution and stirred at 25° C. for 24 hours. Afterwards, the reaction mixture was treated and recrystallized in the same manner as in the treatment of the above-mentioned 2,6-dinitrobenzyl alcohol, and 22.3 g of 2,6-dinitrobenzyltosylate (photo acid generator a) having the following formula were obtained. ##STR18##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:4]=1[CH:21]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=1)O.C(O)(C(F)(F)F)=[O:34].C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl.O>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([CH:21]2[C:4]3[C:5](=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH:11]([OH:34])[CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C=Cc2cc(OC)cc(OC)c2C(O)c2cc(OC)cc(OC)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C2C(O)c3cc(OC)cc(OC)c3C2c2cc(OC)cc(OC)c2)cc1
Temperature: -20 °C
Reaction time: 5 h
Yield: 75.3 %

Procedure:
To a solution of aldol adduct 11 (0.150 g, 0.344 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at −78° C. was added in a single portion a solution of TFA (0.027 mL, 0.344 mmol, 1.0 equiv) in CH2Cl2 (0.2 mL). The resultant dark purple reaction mixture was then warmed slowly to −20° C. over the course of 30 min and stirred for 5 h at −20° C. Upon completion, the reaction mixture was quenched sequentially with solid K2CO3 (0.475 g, 3.44 mmol, 10 equiv) and MeOH (10 mL), warmed to 25° C., and stirred for 15 min at 25° C. The reaction contents were then poured into water (15 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried (MgSO4), and concentrated. The resultant brown oil was purified by flash column chromatography (silica gel, EtOAc/hexanes, 2:1) to give alcohol 15 (0.113 g, 75% yield) as an amorphous white solid. 15: Rf=0.41 (silica gel, EtOAc/hexanes, 1:1); IR (film) νmax 2935, 1597, 1512, 1463, 1304, 1248, 1203, 1151, 1060, 829; 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 6.65 (d, J=2.1 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 6.27 (t, J=2.3 Hz, 1H), 6.17 (d, J=2.4 Hz, 2H), 5.13 (app t, J=5.7 Hz, 1H), 4.19 (d, J=6.9 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.68 (s, 3H), 3.59 (s, 3H), 3.18 (d, J=6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 161.7, 160.4, 158.5, 157.1, 146.9, 146.3, 134.0, 128.7, 122.9, 113.9, 105.5, 99.7, 99.4, 99.3, 98.0, 82.5, 66.1, 55.6, 55.3, 55.2, 54.7; HRMS (MALDI-FTMS) calculated for C26H21O6+ [M+] 436.1886. found 436.1870.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32][O:33][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:9][C@H:10]1[C@H:14]([F:15])[C@H:13]([N:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:18][C:17]2=[O:31])[O:12][C@@H:11]1[CH2:32][OH:33])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c(=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
To a solution of compound 2 (0.64 g, 0.92 mmol) in 10.0 mL of anhydrous THF was added TBAF (1.20 mL, 1.0 M in THF) at 0° C. The resulting solution was stirred for 6 h at rt. The solvent was removed under reduced pressure and the residue was purified on silica gel column chromatography (Hexane:EtOAc=4:1 to 1:1 v/v) to give compound 3 (0.39 g, 0.85 mmol) in 93% yield. 1H NMR (CD3OD, 400 MHz) δ 8.58 (d, J=7.6, 1H), 8.00 (m, 4H), 7.63 (m, 3H), 7.51 (m, 4H), 6.16 (dd, J=17.6, 1.6, 1H), 5.55 (dd, J=4.4, 1.6, 0.5H), 5.47 (m, 1H), 5.42 (dd, J=4.4, 1.6, 0.5H), 4.51 (m, 1H), 4.06 (dd, J=12.8, 2.4, 1H), 3.86 (dd, J=12.8, 3.2, 1H); MS calcd for C23H20FN3O6 m/z 454.1 (M+H)+, found 454.2.
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:19][CH3:20])=[N:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28]Cl)[CH:22]=2)[C:10]1=[O:30].[K].[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:19][CH3:20])=[N:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:28][CH:27]=[C:23]([CH2:24][CH2:25][N:36]3[C:35](=[O:37])[C:34]4=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]4[C:32]3=[O:42])[CH:22]=2)[C:10]1=[O:30]
Reactant: CSc1ncc2c(n1)N(c1cccc(CCCl)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N(c1cccc(CCN3C(=O)c4ccccc4C3=O)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A solution of 0.5 g (1.1 mmol) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-(3-(2-chloroethyl)phenyl)pyrimido[4,5-d]pyrimidin-2(1H)-one in 30 ml of dimethylformamide was treated with 0.2 g (1.1 mmol) of phthalimide potassium salt and the mixture was heated at 80° C. for 2 hours. The cooled mixture was evaporated and partitioned between 40 ml of dichloromethane and 40 ml of water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel using diethyl ether/hexane (1:1) for the elution. Product-containing fractions were combined and evaporated to give 0.43 g (70%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =590].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].C(O)C>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:31])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N2CCN(c3ccc(N)cn3)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cn3)CC2)cc1

Procedure:
To a mixture of the product of part (ii) (1.2 g, 4.2 mmole) and triethylamine (0.5 g, 5 mmole) in methylene chloride (20 ml) was added, dropwise, phenyl chloroformate (0.8 g, 5.1 mmole) and the resulting mixture was stirred at room temperature for 20 hours. The reaction was quenched by the addition of water, the aqueous phase separated and re-extracted with methylene chloride. The combined organic extracts were washed with aqueous sodium bicarbonate solution then water, dried over magnesium sulphate and concentrated under reduced pressure to provide a solid. Trituration of this solid material with ethanol yielded the desired product, m.p. 197°-198° (1.4 g, 83%), which was used without further purification.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:22])=[C:19]([CH:21]=1)[NH2:20]>CC(C)=O.ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:22])=[C:19]([NH:20][C:11]([NH2:12])=[S:10])[CH:21]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NC(N)=S

Procedure:
8.9 ml of benzoyl chloride are added to a solution of 5.9 g of ammonium thiocyanate in 130 ml of anhydrous acetone. The reaction mixture is heated under reflux for 15 minutes and then after cooling, 10 g of 5-chloro-2-methylaniline are added. The reaction mixture is heated under reflux for 2 hours and the acetone is removed by distillation under vacuum. The residue obtained is taken up in dichloromethane. The mixture is washed with water, dried over sodium sulphate and evaporated under vacuum. The expected product is obtained in the form of an oil with a quantitative yield.