Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([CH:23]([O:52][SiH](C)C)[C:24]1[C:25]([CH:49]([CH3:51])[CH3:50])=[N:26][C:27]([CH:46]([CH3:48])[CH3:47])=[C:28]([CH2:37][O:38][C:39](=[O:45])[C:40]([CH3:44])([CH3:43])[CH2:41][CH3:42])[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)(C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:46]([C:27]1[C:28]([CH2:37][O:38][C:39](=[O:45])[C:40]([CH3:43])([CH3:44])[CH2:41][CH3:42])=[C:29]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:24]([CH2:23][OH:52])=[C:25]([CH:49]([CH3:50])[CH3:51])[N:26]=1)([CH3:48])[CH3:47]
Reactant: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 ml (2.6 mmol) of a 1 molar tetrabutylammonium fluoride solution in tetrahydrofuran are added to 1.3 g (2.6 mmol) of the compound from Example 65 dissolved in 20 ml of absolute tetrahydrofuran and the mixture is stirred for 1 hour at room temperature. Saturated sodium hydrogen carbonate solution is added to the mixture and it is extracted several times using dichloromethane. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9) as eluent).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].[C:22]([Si:26]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]I)=[CH:35][CH:34]=1)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Si:26]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH:14]([CH2:15][CH:16]=[CH2:17])[C:13]([O:19][CH2:20][CH3:21])=[O:18])=[CH:35][CH:34]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(CI)cc1
Reactant: C=CCCC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC(Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (1.1 eq.) in THF (0.12 M) was added, at −78° C., n-butyllithium (1.6 M hexane solution, 1.1 eq.) over a period of 5 min. The resulting mixture was stirred at −78° C. for 15 min and then warmed at RT for 10 min. With the reaction mixture re-cooled to −78° C., ethyl pent-4-enoate (1.1 eq.) was added dropwise as a 1.6 M THF solution. The resulting solution was stirred for 30 min at −78° C. Finally, tert-butyl{2-[4-(iodomethyl)phenoxy]ethoxy}dimethylsilane (1 eq.) was added dropwise as a 1.5 M THF solution. The reaction mixture was allowed to warm slowly to RT over 12 h. After the reaction was carefully quenched with the addition of a sat. aq. NH4Cl solution, the reaction mixture was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 10:1 (v/v) Hex:ether) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([S:9][S:10][CH3:11])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[N:32]1([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH2:47][OH:48])[N:44]=[C:43]([CH2:49][OH:50])[CH:42]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C>[CH3:8][C:2]([S:9][S:10][CH3:11])([CH3:1])[CH2:3][CH2:4][C:5]([N:35]1[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][O:40][C:41]2[CH:46]=[C:45]([CH2:47][OH:48])[N:44]=[C:43]([CH2:49][OH:50])[CH:42]=2)[CH2:33][CH2:34]1)=[O:7]
Reactant: OCc1cc(OCCN2CCNCC2)cc(CO)n1
Reactant: CSSC(C)(C)CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSSC(C)(C)CCC(=O)N1CCN(CCOc2cc(CO)nc(CO)c2)CC1
Reaction time: 15 h
Yield: 39.2 %

Procedure:
344 μL of TEA and then, after stirring for 10 min, 748 mg of 4-methyl-4-(methyldisulphanyl)pentanoic acid, 417 μl of diisopropylcarbodiimide and 69 mg of 1-hydroxybenzotriazole hydrate are added to 600 mg of 4-[2-(piperazin-1-yl)ethoxy]-2,6-bis(hydroxymethyl)pyridine in solution in 12 ml of DMF. After 15 h at AT, the mixture is concentrated under RP, 15 ml of water are added and extraction is carried out 2× with AcOEt. The combined organic phases are dried over MgSO4 and concentrated under RP, and the residue is purified by flash chromatography on silica (Analogix Super Flash SiO2 SF25-80 g) using a gradient from 2 to 10% of MeOH in DCM. 390 mg of 4-(2-[4-(4-methyl-4-(methyldisulphanyl)pentanoyl)piperazin-1-yl]ethoxy)-2,6-bis(hydroxymethyl)pyridine are thus obtained.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[C:30]([CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])=[O:21])[S:17][CH:18]=2)=[CH:7][CH:6]=1>[Li+].[OH-]>[CH:32]1([C:30]([C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[NH:22][C:20](=[O:21])[NH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:37])=[O:2])=[CH:10][CH:9]=3)[N:15]=2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COC(=O)Cc1ccc(OCCc2csc(NC(=O)Nc3ccc(C)cc3C(=O)C3CCCC3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)Nc2nc(CCOc3ccc(CC(=O)O)cc3)cs2)c(C(=O)C2CCCC2)c1
Yield: 82.1 %

Procedure:
[4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}ethoxy)-phenyl]acetic acid (25 mg, 86%) was prepared from [4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl)ethoxy)-phenyl]acetic acid methyl ester (0.03 g, 0.06 mmol) and 2.5M LiOH (20 uL) following the general procedure J.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[NH2:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C1COCC1.CC#N.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[NH:29][C:45]([NH:44][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CC[C@H](NC(=O)c1c(N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(NC(=O)Nc2ccccc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 40 °C
Yield: 46.1 %

Procedure:
1.5 g (3.9 mmol) of (S)-N-(α-ethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide (compound of Description 2) were dissolved in 30 ml of dry CH2Cl2, 10 ml of dry THF and 10 ml of dry CH3CN. 0.47 ml (4.3 mmol) of phenylisocyanate dissolved in 10 ml of CH2Cl2 were added and the reaction mixture heated to 40° C. for 4 hours. After cooling of the reaction mixture, the precipitate was collected by filtration and washed with CH2Cl2 to yield 0.9 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Yield: 57 %

Procedure:
The product from Example 1b (1.0 g, 4.30 mmol) was reacted with 12 mL of POCl3 for 4 h following the procedure from Example 1d giving the title compound as a brownish-pink solid (619 mg, 57%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(C(OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[CH2:33]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)(CCCCCCOCc1ccccc1)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 180 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
First, 14.8 g of diethyl 2,2-bis(6-benzyloxyhexyl)malonate, 0.5 g of water, 2.3 g of lithium chloride, and 50 ml of dimethyl sulfoxide were placed in a 100 ml flask. Then, the mixture was stirred at 180° C. for 12 hours. The reaction mixture was poured into water, and an organic layer was extracted with methylene chloride. The methylene chloride layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 9.4 g of ethyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 72.9%). The compound thus obtained had a purity of 97.9% by GC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:31])=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:31][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccc(OC)cc2)[nH]c(=O)c1C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)nc(-c2ccc(OC)cc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 100 °C

Procedure:
To 300 mg of 3,4-diethoxycarbonyl-6-(4-methoxyphenyl)-5-nitro-2(1H)pyridone were added 0.5 ml of phosphorus oxychloride and two drops of DMF. The mixture was heated at 100° C. for 1 hour. After ice water was added, the mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane 1:1).
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C.C(OCC)C>[CH2:13]([O:20][C:13]([CH:14]1[CH2:19][C:11](=[CH2:12])[CH2:15]1)=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1CC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.2 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (1.59 g, 9.81 mmol) in ethyl acetate (5 ml) was added in portions to a solution of the product of Preparation 12 (1 g, 8.9 mmol) in ethyl acetate (5 ml). Gentle effervescence was observed. The mixture was stirred at room temperature for about 1.5 hours, benzyl alcohol (1.11 ml, 10.7 mmol) added and stirring continued overnight. The solution was diluted with diethyl ether (20 ml), washed with water (2×10 ml), dried over magnesium sulphate and evaporated in vacuo to a colourless liquid which was purified by filtering through 10 g SiO2, eluting with dichloromethane, to give the title compound as a colourless oil (1.246 g, 69%).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:16][C:17]([O:19]C)=[O:18])[C:9]=2[O:8][CH:7]=1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:29]([S:36](Cl)(=[O:38])=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>Cl>[CH2:29]([S:36]([NH:4][CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:9]=2[O:8][CH:7]=1)(=[O:38])=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)COc1cccc2c(CNC(C)=O)coc12
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)COc1cccc2c(CNS(=O)(=O)Cc3ccccc3)coc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
To 1N hydrochloric acid (10 ml), methyl (3-acetylaminomethylbenzofuran-7-yloxy)acetate (145 mg) was added and the obtained mixture was heated to reflux for 5 hours. To the reaction mixture, 2N aqueous sodium hydroxide solution (5 ml) was added to neutralize the mixture, and potassium carbonate (1.46 g) and benzylsulfonyl chloride (1.48 g) were added to the mixture, followed by stirring the resultant at 80° C. for one day and night. To the resulting mixture, 1N hydrochloric acid was added to neutralize the mixture and the resultant was extracted with ethyl acetate (3×20 ml). The organic layers were washed with saturated brine and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained solids were purified by recrystallization (ethyl acetate/n-hexane) to obtain the desired compound (85 mg, yield: 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:16])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Product: FC(F)(F)c1cc(CCl)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
(4-Chloro-3-(trifluoromethyl)phenyl)methanol (5.1 g, 24.22 mmol) was added in small portions to thionyl chloride (20 mL, 275 mmol). The reaction mixture was stirred at 50° C. for 18 h and heated under reflux for 23 h. The mixture was concentrated and dried under high vacuum to give the title compound as a colorless liquid (5.41 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.58 (s, 2H), 7.50-7.51 (m, 2H), 7.71 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:8][CH:4]1[CH2:5][C:6](=[O:7])[N:2]([CH3:1])[CH:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)#[N:27]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2c2ccccc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1C(=O)CC(CC#N)C1c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 42 g. of 1-methyl-2-phenyl-3-tosyloxymethyl-pyrrolidin-5-one in 72.5 ml. of dimethylsulfoxide was slowly added 5.7 g of sodium cyanide at 45° C. The reaction was stirred for 3 hours at 100° C. and then set at ambient temperature for 18 hours. After decanting into 1500 ml. of ice water, the product was extracted with 2:1 chloroform-ether, dried (Na2SO4) filtered, and concentrated in vacuo to provide 19.0 g. of light yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.C(N(C(C)C)C(C)C)C.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)[N:3]=2)[CH2:17][CH2:16]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCN(c2ccccc2)CC1
Temperature: 100 °C
Yield: 59.3 %

Procedure:
A mixture of 70 mg (0.27 mmol) of 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile and 0.047 ml (0.27 mmol) of N-ethyl-diisopropylamine in 5 ml of dioxane was treated with 49 mg (0.3 mg) of 1-phenyl-piperazine. The solution was heated to 100° C. during 18 hours, thereafter, for the working-up, evaporated under reduced pressure. For purification, the residue obtained was chromatographed by preparative HPLC on RP18-silica gel using a gradient of a mixture of acetonitrile and water (plus 0.1% of formic acid) as the eluent to give 60 mg (0.16 mmol, 58% of theory) of the 2-cyclopropylamino-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as a white powder after lyophilization; MS: [M+H]+=380.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:15]2([CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[S:14][CH:13]([CH:22]([N:30]2C(=O)C3=CC=CC=C3C2=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>O1CCOCC1.C1(CO)C=CC=CC=1>[NH2:30][CH:22]([CH:13]1[NH:12][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:15]2([CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[S:14]1)[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: CN1CCC2(CC1)SC(C(C(=O)OC(C)(C)C)N1C(=O)c3ccccc3C1=O)NC2C(=O)OCc1ccccc1
Agent: NN
Solvent: C1COCCO1
Solvent: O
Solvent: OCc1ccccc1
Product: CN1CCC2(CC1)SC(C(N)C(=O)OC(C)(C)C)NC2C(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 113.2 g (0.2 mole) of tert-butyl 4-benzyloxycarbonyl-8-methyl-alpha-phthalimido-1-thia-3,8-diazaspiro[4.5]decane-2-acetate (obtained in 3.1) in 730 ml of dioxan are added 13.4 g of hydrazine hydrate. After 24 hours, a further 6 g of hydrazine hydrate are added, followed by filtration after 24 hours. The mixture is evaporated and the residue is dissolved in 1 liter of benzene, then filtered after 24 hours and the new residue obtained by evaporation is passed through a column of silica gel (60 Merck), using a 91 v/v benzene-methanol mixture as eluent. In this way, a solution of tert-butyl alpha-amino-4-benzyloxycarbonyl-8-methyl-1-thia-3,8-diazaspiro[4.5]decane-2-acetate is obtained, which is subjected as much to step 5.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11]N1C(=O)CCC1=O.O.C(OCC)(=O)C>O1CCCC1.CO>[Br:11][C:5]1[NH:1][C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:3][CH:4]=1
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Br)[nH]1
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
Commercially available ethyl 1H-pyrrole-2-carboxylate (5.10 g, 30.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (120 mL) and methanol (60 mL), and cooled to 0° C. N-Bromosuccinimide (6.52 g, 30.7 mmol) was added, and stirring was carried out at room temperature for 18 hours under nitrogen atmosphere. Water (150 mL) and ethyl acetate (200 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (3.20 g, yield 40%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][NH2:12].CO.[I-].[Na+]>C(O)C>[CH3:11][NH:12][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: CN
Reactant: OCCOCCOCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNCCOCCOCCO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-[2-(2-Chloro-ethoxy)-ethoxy]-ethanol (2.00 mL, 13.8 mmol) was dissolved in ethanol (14.0 mL). A solution of methylamine in methanol (40%, 14.0 mL, 138 mmol) and sodium iodide (103 mg, 0.67 mmol) were added, and the mixture was stirred at 60° C. for 18 hours and then stirred at 75° C. for seven hours in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give 2-[2-(2-methylamino-ethoxy)-ethoxy]-ethanol as a crude product.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][CH2:18][C:17]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:24]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][CH2:18][C:17]=3[CH:23]=2)=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=C1Nc2ccc(OCCCCSc3ccccc3)cc2CO1
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccccc3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-(4-phenylmercapto-butoxy)-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>C1COCC1.C(Cl)Cl>[I:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:36])=[CH:33][CH:32]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(I)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (12.1 g, 62.9 mmol), 1-hydroxybenzotriazole hydrate (9.63 g, 62.9 mmol), and morpholine (9.13 g, 105 mmol) was added to a solution of 4-iodobenzoic acid (13 g, 52.4 mmol) in a mixture of THF (250 mL) and methylene chloride (50 mL). After stirred at 25° C. for 20 hr, the solvent was removed and flash silica gel chromatography (step gradient elution with methylene chloride containing 0 to 3% MeOH) afforded (4-iodophenyl)(morpholino)-methanone (15.1 g). MS (ESI) m/z 317.9 (M+H). 1H NMR (CDCl3) δ ppm 7.76 (2H, d, J=8.24 Hz), 7.14 (2H, d, J=8.24 Hz), 3.23-4.00 (8H, m).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[K+].Cl>CO.O>[OH:1][C@@H:2]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCC(O)CC[C@H]1CC[C@@H](O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)CC[C@H]1CC[C@@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of ethyl 9β,15-dihydroxyprostanoate in 32 ml. of methanol-water (1:1), containing 890 mg. of potassium hydroxide is kept at ambient temperature for 18 hours. The solution is acidified with dilute hydrochloric acid and extracted several times with ether. The ether phase is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.63 g. of an oil; nmr 3H singlet δ 5.53 (hydroxyl and carboxyl protons), 1H singlet 4.23 (9β-carbinolic proton, 30%), 1H singlet 3.90 (9α-carbinolic proton, 70%), 1H singlet 3.65 (15-carbinolic proton), and 3H distorted triplet 0.90 (terminal methyl).