Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1.O.[NH2:24][NH2:25].C([O-])([O-])=O.[K+].[K+]>CC1OCCC1>[NH:24]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1)[NH2:25]
Reactant: NN
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1nc(NN)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 85 °C

Procedure:
Compound 2-2 (900 mg, 2.87 mmol), hydrazine hydrate (431 mg, 8.6 mmol) and K2CO3 (1.2 g, 8.6 mmol) were suspended in 2-MeTHF (8 mL) in a vial that was capped and heated at 85° C. for 16 h. After cooling to room temperature, the reaction was filtered and the collected solids were washed with water and ether and dried over suction to give Intermediate 2 as a white solid. MS: m/z=310.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(O[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=O)C>CCOCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(=O)OCCOCOC(C)=O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCOCC
Product: CC(=O)OCCOCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 138 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,6-Dichloropurine 5.5 g and 2-oxa-1,4-butanediol diacetate 513 g were placed in a flask and partially evacuated and then heated to 138° C., initially the mixture was too thick to stir but gradually gave rise to a melt which was stirred, and after 20 minutes was completely melted and the reaction mixture heated for 10 minutes more (total heat time=30 minutes). The mixture was then cooled to room temperature and para-toluenesulphonic acid 150 mg was added, the vacuum reapplied and heating resumed with stirring. After 20 minutes heating vigorous bubbling was noted; the mixture was cooled to room temperature; chloroform was added, and the solution was extracted once with saturated aqueous sodium bicarbonate and once with water. The chloroform phase was dried over anhydrous sodium sulphate and evaporated. The residual oil was dissolved in benzene and applied to a column of 200 g. of silica gel in benzene. Benzene elution removed the acetate by-products. Ether solution gave 2,6-dichloro-9-(2-acetyloxyethoxymethyl)purine (64% yield). Recrystallization from benzene gave lustrous white flakes, m.p. 96°-99° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:12]1[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:13]1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]2.[CH2:47]=[CH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:49]1(/[CH:48]=[CH:47]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([O:11][C@@H:12]2[O:38][C@H:37]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]([O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C@H:13]2[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:5][NH:6]3)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(/C=C/c4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Yield: 64.6 %

Procedure:
A mixture of 4-bromo-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (75 mg), styrene (33 mg), triethylamine (0.073 mL), palladium (II) acetate (2 mg) and tris(2-methylphenyl)phosphine (6 mg) in acetonitrile (2 mL) was heated for reflux under an argon atmosphere overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (50 mg).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([CH3:17])=[CH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>N1C=CC=CC=1>[C:13]([C:12]1[CH:11]=[C:10]([CH3:17])[S:9][C:8]=1[NH:7][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])([O:15][CH3:16])=[O:14]
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)c1cc(C)sc1N
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)sc1NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Cyclopropanecarboxylic acid chloride (10.9 g, 0.105 mol) was added dropwise during 40 min. to a stirred solution of methyl 2-amino-5-methyl3-thiophene-carboxylate (prepared by the method of Gewald, Chemische Berichte, 99, 94, (1966)), (17.1 g, 0.1 mol) in anhydrous pyridine (100 ml) kept at 0° C. The reaction mixture was stirred below 10° C for the next 4 hours, at room temperature overnight, and finally under reflux for 1.5 hours. The excess of pyridine was evaporated under reduced pressure and the residue was dissolved in CHCl3 (200 ml) and extracted in turn with 2N-HCl, H2O, 2N-NaOH and H2O. The dried (Na2SO4) organic solution was evaporated and the residue was recrystallised from EtOH to yield the amide as yellow crystals (11.1 g, 46%), m.p. 121°-123° C.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[O:34][CH:35]([CH2:36][CH3:37])[CH2:38][CH3:39])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OC(CC)CC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CC)Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (190 mg) is dissolved in ethanol (5 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→93:7) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (158 mg). The resulting 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (158 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (237 μl) and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethyl-propoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (149 mg). MS (m/z): 666 [M−Na]−
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)(O)=[O:2].S(Cl)([Cl:26])=O>CN(C)C=O>[Cl:26][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH:5]=1)=[O:2]
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12

Procedure:
20 cm3 of sulphinyl chloride and one drop of dimethylformamide are added at a temperature in the region of 20° C. under an argon atmosphere to 1.53 g (5 mmol) of 3-carboxy-5-fluoro-1-(quinol-4-yl)-1H-indole. After stirring at reflux for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 1.8 g of 3-chlorocarbonyl-5-fluoro-1-(quinol-4-yl)-1H-indole in the form of a cream solid which is used directly in the following step.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][C@@H:32]([CH3:35])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: C[C@@H](CO)CCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 46.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-4-hydroxy-3-methyl-butyl)-amide (45 mg) was prepared by following General Procedure F starting 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (80 mg), (R)-4-amino-2-methyl-butan-1-ol (25 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 493.6.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43](C2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:42][CH:41]1[CH2:77][OH:78])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:30])([F:32])[F:31])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:42][CH:41]1[CH2:77][OH:78])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(OC)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C(=O)OC(C)(C)C)C(CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(2R) 2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].S(=O)(=O)(O)O.CC(C)=O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2ccccc2c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1'-bromoethyl)naphthalene, prepared as described above, wtih sodium acetate in acetic acid to afford 2-(1'-acetonyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1'-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].[C:9](=O)([O-])[O-:10].[K+].[K+].C[O-].[Na+]>CO>[CH3:9][O:10][CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(CBr)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C=C(COC)C(=O)OC
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred mixture of methyl 2-(bromomethyl)acrylate (239 μl, 2 mmol) in petroleum ether (3 ml) was added potassium carbonate (276 mg, 2 mmol), followed by sodium methoxide (119 mg, 2.2 mmol) and methanol (450 μl). The resulting mixture was stirred overnight, filtered, concentrated to a residue that was purified by column chromatography eluting with 10% ether in hexanes to provide the title compound (150 mg, 58%). (Reference: J. Med. Chem.; 42; 15; 1999; 2760-2773.)
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=[N:5]1>C(O)(=O)C>[Br:1][CH2:17][C:16]([C:7]1[CH:6]=[N:5][N:4]([CH3:3])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:18]
Reactant: CC(=O)c1cnn(C)c1-c1ccc(C)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(-c2c(C(=O)CBr)cnn2C)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Bromine (97%, 0.104 mL, 1.97 mmol) was added to a solution of 1-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone (420 mg, 1.96 mmol) in glacial acetic acid (10 mL), and the reaction mixture was vigorously stirred for 2 hours at 80° C. After removal of solvent under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration of the filtrate in vacuo provided a residue, which was purified via silica gel chromatography (Gradient: 10% to 30% ethyl acetate in heptane) to afford the product as a colorless oil. Yield: 353 mg, 1.20 mmol, 61%. LCMS m/z 293.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.71 (s, 3H), 3.97 (s, 2H), 7.31 (br AB quartet, JAB=8 Hz, ΔvAB=23 Hz, 4H), 8.05 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1>>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=2)=[CH:15][CH:14]=1)[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Product: CC(=Nc1ccc(C2=NNC(=O)CC2)cc1)c1ccc(O)cc1O
Temperature: 140 °C

Procedure:
A mixture containing 0.91 g (0.006 mol) of 2',4'-dihydroxyacetophenone and 0.95 g (0.005 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one was heated for 4 h at 140° C. in a stream of nitrogen gas. The product was triturated with boiling ethanol and filtered. Yield 0.88 g (54%), m.p. 350° C. (decomp).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([C:11](=[O:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.[BrH:20].C(O)(=O)C.BrBr>C(Cl)(Cl)Cl>[Br:20][CH2:12][C:11]([C:9]1[S:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1)=[O:13]
Reactant: CC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 0 °C

Procedure:
To a solution of 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone (1.0 eq) dissolved in a mixture of CHCl3, 33% wt HBr and acetic acid (1:1:1) at −0° C. was added a solution of Br2 in CHCl3 (1.05 eq). Reaction mixture was stirred at −0° C. until completed, then extracted in dichloromethane with saturated bicarbonate solution one time. The organic layer is dried, filtered and concentrated to yield the crude intermediate. This intermediate is purified by flash chromatography to yield 2-bromo-1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1>CO.C(COC)OC.CO>[CH3:1][O:2][C:5]1[N:9]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])[C:8](=[O:19])[N:7]([CH3:20])[N:6]=1
Reactant: C[O-]
Reactant: COC(=O)c1sccc1-n1c(Cl)nn(C)c1=O
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1sccc1-n1c(OC)nn(C)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (16.5 mL of a 30% solution in methanol) was added to a solution of the title compound of Step C (7.9 g) in anhydrous dimethoxyethane/methanol (85 mL/35 mL). The resulting yellow solution was heated to 50° C. for 2 h under N2 and then left to stir overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methylene chloride. The resulting mixture was washed with water and then with saturated aqueous NaCl. The aqueous layer was filtered through Celite® and the filtrate was extracted three times with methylene chloride. The combined methylene chloride layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give 5.4 g of an off-white solid. The crude product was purified by flash chromatography (20-100% ethyl acetate/hexane as eluent) to afford 3.9 g of the title compound of Step D as a white solid. 1H NMR (CDCl3): δ 7.58 (d,1H), 7.12 (d,1H), 3.93 (s,3H), 3.83 (s,3H), 3.44(s,3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O.CC(C)=O>[C:1]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
17.3 ml (20.90 g, 149 mmol) of benzoyl chloride (Aldrich, purity 99%) are added dropwise over a period of 30 minutes with vigorous stirring to an ice-cooled solution of 20.00 g (145 mmol) of 4-hydroxybenzoic acid (Aldrich, purity 99%) and 12.00 g (300 mmol) of sodium hydroxide in 300 ml of distilled water and 30 ml of acetone. After a further 30 minutes, the mixture is acidified using concentrated hydrochloric acid and diluted with 750 ml of distilled water. The resultant white precipitate is filtered off and recrystallized from methanol/ethanol/ethyl acetate (450 ml+225 ml+300 ml).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@@H:20]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][C@H:22]([C:33](OC)=[O:34])[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:41].[Na+]>CO.C1COCC1>[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:8]([C:17]([N:19]([CH2:37][CH:38]([CH3:39])[CH3:40])[C@H:20]2[CH2:21][C@@H:22]([C:33]([N:6]3[CH2:7][CH2:8][O:41][CH2:1][CH2:5]3)=[O:34])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:25]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(2-tert-butyl-4-hexylpyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (219 mg) was dissolved in methanol (3 ml) and THF (2 ml), 1M aqueous sodium hydroxide solution (2 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the aqueous layer of the mixture was adjusted to pH 5-6 with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue, morpholine (41 μl), 1H-benzotriazol-1-ol (30 mg) and triethylamine (140 μl) were dissolved in 1,2-dichloroethane (4 ml), WSC.HCl (115 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous is magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-80:20) was concentrated under reduced pressure to give the object product (88 mg).
Reaction SMILES: [CH:1]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>>[CH:14]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])[CH2:7][CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CCNCC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN1CCN([Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 194.0 g (0.8 mol) of 1-triisopropylsilylpiperazine (Synthesis Example 2) and heated at 70° C. Once the internal temperature became steady, 75.8 g (0.88 mol) of methyl acrylate was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 250.0 g of a fraction having a boiling point of 163-164° C./0.4 kPa was collected.
Reaction SMILES: [C:1](O)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].C1COCC1.O.C([O-])(O)=O.[Na+]>O>[CH2:20]([OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:23]
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCCCCCO

Procedure:
Icosane-1,20-diol was synthesized according to Yoon et al., J. Org. Chem. 1973, 38(16), 2786-2792. Briefly, under N2 atmosphere to 25 g eicosanedioic acid 100 ml THF was added. Then 474.5 ml of borane/THF complex was added dropwise over 1.5 hours. The mixture was refluxed over night before 200 ml THF/H2O 1:1 were added dropwise. Under further stirring 100 g NaHCO3 dissolved in 250 ml H2O was added and two hours later 1000 ml H2O was added to the mixture and the precipitate was removed by filtration. At the next day and the day after next a white precipitate was removed by filtration from the mixture, dried and recrystallized from acetic acid ethyl ester. The product was characterized by thin layer chromatography and 1H-NMR.