Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:3][C:2]=1[N:1]=[C:15]=[S:16]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(=O)NC(C)c1ccc(Cl)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(Cl)c(N=C=S)c1

Procedure:
N-[1-(3-Amino-4-chlorophenyl)ethyl]acetamide (90 mg, 0.2 mmol) was added to a mixture of 1,1′-thiocarbonyldi-2-pyridone (69 mg, 0.2 mmol), DMAP (7 mg, 0.05 mmol) and DCM (2 mL) at rt. The mixture was concentrated and used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[H-].[Na+].[CH2:18](I)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C)C=O.O1CCCC1.CCOCC>[CH2:35]([O:1][CH2:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CC(=O)NC(CO)COC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(COC1CCCCO1)NC(C)=O
Reaction time: 24 h
Yield: 34.1 %

Procedure:
A solution of about 10.85 g of N-[1-(hydroxymethyl)-2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]acetamide in about 240 ml of dry dimethylformamide was added dropwise to a suspension of about 3.12 g of about 50% sodium hydride (pre-washed with anhydrous ether). After stirring about one hour a solution of about 22.8 g of octadecyl iodide in about 150 ml of tetrahydrofuran was added, stirring was continued for about 24 hours, then the mixture was diluted with ether and washed with a minimum amount of brine. The organic layer was dried, the solvents evaporated and the crude material purified by chromatography on silica gel, eluting with ethyl acetate:hexane:ethanol (about 1:1:0.2), giving about 8 g of the desired title compound, mp 52°-55° C.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:24]=[CH:23][C:22]2[O:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:25])[C:13]=2[CH:12]=1.[Cl-].[NH4+]>>[F:10][C:11]1[CH:24]=[CH:23][C:22]2[O:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:25])[C:13]=2[CH:12]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccccc2oc2ccc(F)cc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CN1CCC(C2(O)c3ccccc3Oc3ccc(F)cc32)CC1

Procedure:
The Grignard reagent prepared from 0.53 g. (0.0216 m.) of magnesium and 2.9 g. (0.0216 m.) of 4-chloro-N-methylpiperidine is reacted with 2.3 g. (0.0108 m.) of 2-fluoroxanthone as described in Example 3. The reaction mixture is heated for four hours and then decomposed with saturated ammonium chloride solution to yield 2-fluoro-9-(1-methyl-4-piperidyl)-xanthene-9-ol, m.p. 193°-200° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([Si:22](OC)([O:25][CH3:26])[O:23][CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([Si:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([O:25][CH3:26])[O:23][CH3:24])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Reactant: CO[Si](OC)(OC)c1ccccc1
Product: CO[Si](OC)(c1ccccc1)c1ccc(Oc2ccccc2)cc1

Procedure:
Another suitable approach to making the (thio)phenoxyphenyl phenyl silane of the present invention is the sequential formation of a Grignard reagent [a (thio)phenoxyphenyl magnesium halide] followed by introduction of a phenyl trialkoxy silane. A reaction scheme illustrative of this approach follows in which p-phenoxyphenyl bromide is reacted with magnesium metal to form p-phenoxyphenyl magnesium bromide. The p-phenoxyphenyl magnesium bromide intermediate is then reacted with phenyl trimethoxy silane to produce p-phenoxyphenyl phenyl dimethoxy silane. Typically, this Grignard approach is carried out in an anhydrous ether solvent such as tetrahydrofuran (“THF”) or diethyl ether.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[NH:3][C:2]1=[O:12].C[Si](C)(C)N[Si](C)(C)C.S(=O)(=O)(O)O.C[Si](C)(C)OC1N=C(O[Si](C)(C)C)C2CCCCC=2N=1.Br[CH2:48][C:49]1[CH:50]=[C:51]([CH:56]=[CH:57][CH:58]=1)[C:52]([O:54][CH3:55])=[O:53]>C1(C)C=CC=CC=1.CN(C=O)C.CO.O1CCOCC1>[CH3:55][O:54][C:52]([C:51]1[CH:50]=[C:49]([CH:58]=[CH:57][CH:56]=1)[CH2:48][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[NH:3][C:2]1=[O:12])=[O:53]
Reactant: O=c1[nH]c2c(c(=O)[nH]1)CCCC2
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)Oc1nc2c(c(O[Si](C)(C)C)n1)CCCC2
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1

Procedure:
The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formula I, II or III can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of cyclohexanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclohexanecarboxy late. Reaction of ethyl 2-oxocyclohexanecarboxylate with urea at 175-185° C. produced 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione. Reaction of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazol. Reaction of 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazoline with methyl 3-(bromomethyl)benzoate in DMF , followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H )-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[FH:13]>>[C@H:11]1([F:13])[O:12][C@H:3]([CH2:2][OH:1])[C@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: F
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 98.9 %

Procedure:
In an apparatus and by the procedure according to Example 1, 1 g of D-galactose was reacted with 10 g of hydrogen fluoride, the mixture was left to stand for 1 hour at -30° to -40° C. and the hydrogen fluoride was then stripped out within 15 minutes by blowing in nitrogen. The working-up gave α-D-galactosyl fluoride (about 1 g) which was identified by elemental analysis, thin-layer chromatogram and 19F and 13C nuclear magnetic resonance spectra (cf. J. E. C. Barnett et al., Biochem. J. 105 (1967), page 669). Melting point: 130° (decomposition).
Reaction SMILES: C(OC([N:8]([CH2:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=C(C)C)=O)(C)(C)C.[ClH:18]>>[ClH:18].[ClH:18].[CH3:17][O:16][CH2:15][CH2:14][CH2:13][NH:8][NH2:9]
Reactant: COCCCN(N=C(C)C)C(=O)OC(C)(C)C
Agent: Cl
Product: COCCCNN
Temperature: 80 °C
Yield: 96 %

Procedure:
To a solution of N′-isopropylidene-N-(3-methoxypropyl)-hydrazinecarboxylic acid tert-butyl ester (6.49 g, 26.6 mmol) in tetrahydroufuran (50 mL) was added 2.0N hydrochloric acid (27 mL). The solution was heated to reflux (˜80° C.) in a preheated oil bath for 3 h. The solution was cooled to room temperature and concentrated in vacuo to remove the tetrahydrofuran. To the aqueous layer was added toluene (200 mL) and the water was removed via concentrating in vacuo (this was repeated 2 additional times) providing (3-methoxypropyl)-hydrazine dihydrochloric acid (4.65 g, 96%) as a light yellow sticky solid, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([O:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](/[CH3:16])\[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)CC/C(C)=C\CC/C(C)=C\COC(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.5 g (0.0021 mol) of (6Z,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one dissolved in 5 ml of methylene chloride and 1.3 ml of pyridine is treated with 1 ml of acetic anhydride. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is taken up three times in toluene and freed from solvent each time on a rotary evaporator. The residue is chromatographed on silica gel with ether-hexane 1:5. There is obtained (2Z,6Z)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienyl acetate which has the following bands in the IR spectrum: 1742 cm-1, 1671 cm-1, 1634 cm-1, 1442 cm-1, 1367 cm-1, 951 cm-1.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([NH:2][CH:3]([CH:8]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)C(N)C(C(=O)OC)c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.6 %

Procedure:
To a solution of 5 g (18.5 mmol) of 2-amino-3-phenyl-succinic acid, dimethyl ester hydrochloride in CH2Cl2 (100 mL) was added 7.7 mL (56 mmol) of TEA followed by 6.2 g (22.1 mmol) of trityl chloride. The reaction was stirred at rt for 2 days and then concentrated in vacuo. Et2O was added to the crude residue and the mixture was filtered through a pad of silica gel and concentrated in vacuo to give a colorless oil. The residue was purified by flash column chromatography on silica gel eluted with 3:1 hexanes:Et2O to yield 6 g of 2-(N-tritylamino)-3-phenyl-succinic acid, dimethyl ester as a white solid. The product was a 1.3:1 mixture of diastereomers as judged by 1H-NMR analysis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH:15](=[N:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCN=Cc1ccccc1)(OCC)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
(Imine-TEOS) To a 2000 mL 3-neck round bottom flask placed in an ice water bath and equipped with a stirbar was added 70 g of 5 Å molecular sieves. The flask was then equipped with a reflux condenser and the remaining necks were sealed with rubber septa. The reaction flask was evacuated and backfilled with dry nitrogen three times. After the final backfill cycle, 200.1 g (903.9 mmol) of 3-aminopropyltriethoxysilane was added to the flask, along with 300 mL of anhydrous toluene. With rapid stirring, 95.9 g (903.9 mmol) of benzaldehyde was added dropwise via cannula over 30 minutes. The contents were allowed to stir at room temperature under nitrogen overnight. After an overnight stir, the contents were filtered. An additional 50 mL of anhydrous toluene was added to facilitate the filtration. The filtrate was filtered a second time and collected. The collected filtrate was concentrated via rotary evaporation to yield a pale gold oil (274.9 g, 98%). This solid was isolated in >98% purity, as characterized by 1H NMR spectroscopy and was not purified further. 1H NMR (CDCl3, 400 MHz): 0.68 (m, 2H); 1.22 (m, 9H); 1.85 (m, 2H); 3.61 (m, 2H); 2.82 (m, 6H); 7.40 (m, 3H); 7.72 (m, 2H); 8.27 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[Br:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1>CC(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH2:8][CH2:9][CH3:10])[CH:13]=1
Reactant: CCCI
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCSc1cccc(Br)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Reflux a suspension of potassium carbonate (22.4 g), 1-iodopropane (10.3 mL) and 3-bromothiophenol (8.4 mL) in acetone (375 mL) for 5 hours. Cool to room temperature, filter through diatomaceous earth, and concentrate. Dissolve the residue in hexanes, filter through a silica gel plug, and concentrate to give 1-bromo-3-propylsulfanylbenzene (18 g, 95%) as an oil (GC-MS: m/z=231). Add this material (12 g) to a solution of n-butyllithium (57 mmol) in THF (50 mL) at −78° C. Stir for 45 min, add 110 N,N-dimethylformamide (8.1 mL) and warm to room temperature. Stir for 15 min, pour into water (175 mL), and extract into diethyl ether (3×200 mL). Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography) to give the title compound (7.3 g, 92%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.O>C(O)C>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Sc2ccccc2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cccc(Sc2ccccc2)c1
Yield: 98 %

Procedure:
2-(3-Phenylsulfanyl-benzyl)-isoindole-1,3-dione described in Preparation Example 94 (123 mg, 0.356 mmol) was dissolved in ethanol (3 mL), hydrazine monohydrate (518 μl, 10.7 mmol) was added at 0° C., and the solution was stirred under reflux for 2 hours. Water was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (ethyl acetate), and the title compound (75 mg, 0.35 mmol, 98%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:16][CH2:17][N:18]([CH:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2CC1Br
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Product: O=C1c2ccccc2CC1N1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (12) synthesized in Example 5 and 2-bromo-1-indanone to produce the above.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]>C(O)C>[NH2:16][C:4]1[N:3]=[C:2]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]=1
Reactant: NCCOCCO
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccccc2)c(Cl)n1)C(C)C
Solvent: CCO
Product: Nc1ncc(C#Cc2ccccc2)c(NCCOCCO)n1
Yield: 37.3 %

Procedure:
A mixture of 1.5 g of 4-chloro-2-diisopropylaminomethyleneamino-5-phenylethynylpyrimidine, 20 mL of ethanol and 1.83 g of 2-(2-aminoethoxy)ethanol was refluxed for 18 hours. The tea colored solution was evaporated in vacuo and the residue partitioned between water and dichloromethane. The aqueous layer was washed twice more with dichloromethane and the combined organic extracts washed with water. The organic solution was dried over sodium sulfate, filtered and evaporated in vacuo. The yellow residue obtained was triturated with ether and filtered to give 0.49 g of a yellow solid, 2-amino-4-[2-(2-hydroxyethoxy)ethylamino]-5-phenylethynylpyrimidine. m.p. 128–129° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[OH:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]([CH3:21])=[CH:18][CH2:19]O>ClCCl>[CH3:16][C:17]1([CH3:21])[CH2:18][CH2:19][C:6]2[C:7](=[C:8]([CH3:9])[C:2]([CH3:1])=[C:3]([OH:4])[C:5]=2[CH3:11])[O:10]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(C)=CCO
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
257 g (1.69 mol) of 2,3,6-trimethylhydroquinone were introduced into a suspension of 248 g (1.86 mol) of anhydrous aluminum chloride in 850 ml of dry dichloromethane at 5° C. After stirring for 30 min, 160 g (1.86 mol) of 3-methyl-2-buten-1-ol were added dropwise at 5°-10° C. The mixture was stirred at room temperature overnight and then poured into ice-water, the precipitate was filtered off, the filtrate was extracted with dichloromethane, and the organic phase was washed with water to neutrality, dried over magnesium sulfate and evaporated. Distillation of the residue provided a main fraction of 153.3 g of the title compound at 140° C. and 0.4 mbar, and this was recrystallized from heptane with a melting point of 85°-88° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH:39][NH2:40])=[S:38])[CH2:29][CH2:28][CH2:27][CH2:26]1>CO>[CH:25]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:37]([NH:39]/[N:40]=[CH:19]/[C:18]2[CH:21]=[CH:22][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=4)[N:11]=3)=[CH:16][CH:17]=2)=[S:38])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: NNC(=S)Nc1ccccc1C1CCCC1
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CO
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(/C=N/NC(=S)Nc4ccccc4C4CCCC4)cc3)n2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (0.58 g, 1.7 mmol) and N-(2-cyclopentylphenyl)hydrazinecarbothioamide (0.41 g, 1.7 mmol) in a 100 mL roundbottom flask equipped with a magnetic stir bar and reflux condenser was added methanol (17 mL), and the reaction was heated to 50° C. and stirred overnight. The reaction was cooled to room temperature and the resulting solid was filtered, washed with methanol and dried under vacuum (25 in Hg) at 55° C. to give the title compound (795 mg, 1.44 mmol, 83% yield) as a yellow solid: mp 213-216° C.; 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 9.11 (s, 1H), 8.60 (s, 1H), 8.26 (d, J=8.4 Hz, 2H), 7.91 (s, 1H), 7.86-7.71 (m, 5H), 7.40 (dd, J=8.8, 6.4 Hz, 3H), 7.35-7.27 (m, 2H), 3.22 (t, J=8.0 Hz, 1H), 2.13 (d, J=2.5 Hz, 2H), 1.90-1.59 (m, 6H); ESIMS m/z 551 ([M+H]+).
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[CH3:11][C:12]1[S:13][CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O>[CH:9]([C:14]1[S:13][C:12]([CH3:11])=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=1)=[O:10]
Reactant: Cc1sccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1sc(C=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.166 mol (15 mL) of POCl3 was added at 0° C. to a 0.5 mol (39 mL) of DMF. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and treated with 2-methyl-3-phenylthiophene (29 g, 0.166 mol). The resulting reaction mixture was allowed to reach room temperature and after 12 h stirring at the same temperature was heated at 80° C. for 2 days. Then it was poured into a mixture of ice and water and added of sodium acetate. The precipitate so obtained was filtered, washed with water and subsequently with hexane. The yellow powder was dried in vacuo.
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O.[C:26]([O:30][C:31](=[O:102])[CH2:32][CH2:33][C@H:34]([C:65](=[O:101])[NH:66][C@@H:67]([C:89](=[O:100])[NH:90][C:91]1([CH:94]([OH:99])[CH2:95][C:96](O)=[O:97])[CH2:93][CH2:92]1)[CH2:68][S:69][C:70]([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[NH:35][C:36](=[O:64])[CH2:37][C@H:38]([OH:63])/[CH:39]=[CH:40]/[CH2:41][CH2:42][S:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:26]([O:30][C:31](=[O:102])[CH2:32][CH2:33][C@H:34]1[NH:35][C:36](=[O:64])[CH2:37][C@@H:38](/[CH:39]=[CH:40]/[CH2:41][CH2:42][S:43][C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:63][C:96](=[O:97])[CH2:95][CH:94]([OH:99])[C:91]2([CH2:92][CH2:93]2)[NH:90][C:89](=[O:100])[C@@H:67]([CH2:68][S:69][C:70]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)[NH:66][C:65]1=[O:101])([CH3:28])([CH3:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NC1(C(O)CC(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H]1NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CC(O)C2(CC2)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC1=O
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of MNBA (303.7 mg, 0.882 mmol) and DMAP (215.6 mg, 1.76 mmol) in CH2Cl2 (135 mL) was added dropwise a solution of the acid 8 (787 mg, 0.731 mmol) in CH2Cl2 (550 mL) over 3 h, and the mixture was then stirred for 16 h; the mixture was subsequently concentrated in vacuo to furnish a brown solid. Purification by column chromatography on silica (eluant 0:1-1:99-2:98-3:97 MeOH/CH2Cl2) gave 9 (430.2 mg, 0.407 mmol, 56%) as a white solid. The diastereoisomers were separable by flash column chromatography, though were used as a mixture for the subsequent reaction.