Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][OH:6].Cl[CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1>CN(C)C=O>[F:3][C:4]([F:26])([C:7]([F:24])([F:25])[C:8]([F:22])([F:23])[C:9]([F:20])([F:21])[C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:5][O:6][CH2:28][C:29]1([CH3:33])[CH2:32][O:31][CH2:30]1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(CCl)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dispersion of 50 weight percent sodium hydride (4.0 g, 83 mmol) in mineral oil was washed with hexanes and suspended in 200 milliliters of dimethylformamide. A solution of 30 grams of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan-1-ol (75 mmol) in 50 milliliters of dimethylformamide was added over a period of 3 hours, and the resulting mixture was stirred at room temperature for one hour. Next, a solution of 9.3 grams (77 mmol) of 3-chloromethyl-3-methyloxetane in 20 milliliters of dimethylformamide was added and the resulting mixture was heated at 75° C. for 16 hours. The mixture was cooled to room temperature and slowly poured into 1 liter of ice/water and extracted with two volumes of Freon 113. The combined organic extracts were washed twice with water, once with 2 weight percent aqueous hydrochloric acid and once with brine, dried over magnesium sulfate, filtered, and evaporated to give 32 grams of crude product. The crude product was distilled under reduced pressure to give 26.5 grams (73%) of analytically pure 3-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctoxymethy)-3-methyloxetane (i.e., 15-FOX), an oil with a boiling point of 68 to 70° C./16 mm-Hg. The experimental analyses were: 1H NMR (CDCl3/Freon 113) δ 4.49 and 4.37 (AB, J=5.5 Hz, 4 H), 4.00 (triplet, J=13.2 Hz, 2 H), 3.70 (singlet, 2 H), and 1.32 (singlet, 3 H); 13C NMR δ 21.02, 40.33, 68.77 (triplet, J=146.2 Hz), 78.60, and 79.87 (signals from carbon bearing fluorine are not included due to complex splitting patterns and low peak intensities); 19F NMR δ −81.3 (3 F), −119.9 (2F), −122.6 (2 F), −123.3 (2 F), −123.5 (2 F), −123.9 (2 F) and −126.8 (2 F). The elemental analysis was: Calculated for C13H11F15O2: C, 32.2; H, 2.3; F, 58.9. Found: C, 32.2; H, 2.2; F, 58.3.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C[O:15][C:16](=[O:45])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C3C=CC(C(F)(F)F)=CC=3Br)[CH:27]=2)=[CH:21][C:20]=1[CH3:44]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([O:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:45])=[O:15])=[C:20]([CH3:44])[CH:21]=2)=[C:5]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:4]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccc(C(F)(F)F)cc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 4-trifluoromethylphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 99 mg (62%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H22O4F6 560, found 561 (M+1, 100%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C[O:17][C:18]([NH:20][NH2:21])=[S:19]>C(#N)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]2[CH2:2][S:19][C:18](=[O:17])[NH:20][N:21]=2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(C=Cc1ccc([N+](=O)[O-])cc1)CCl
Reactant: COC(=S)NN
Solvent: CC#N
Product: O=C1NN=C(C=Cc2ccc([N+](=O)[O-])cc2)CS1

Procedure:
A solution containing 11.2 g of 1-chloro-4-(4-nitrophenyl)-2-oxo-3-butene (J. Org. Chem. 28, 2446, 1963) and 6.8 g of hydrazinecarbothioic acid O-methylester in 200 ml of acetonitrile was refluxed for 3 h. The crystals were filtered and washed with acetonitrile and ether. Yield 7.7 g (59%), mp. 231°-240° C.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([OH:8])/[CH:5]=[CH:6]/[I:7].[C:13]1([C:19](Br)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:3][CH:4]([O:8][C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)/[CH:5]=[CH:6]/[I:7]
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(C)(C)CC(O)/C=C/I
Product: CCCC(C)(C)CC(/C=C/I)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 6.0 g. of 5,5-dimethyl-1-iodo-trans-1-octen-3-ol (Example 1000) with 6.9 g. of triphenylmethyl bromide in 30 ml. of pyridine and purification on Florisil, all as described in Example 728 gives the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([CH3:42])=[C:10]([O:15][C:16]2[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[N:25]=3)[CH:17]=2)[C:11]([CH3:14])=[N:12][CH:13]=1)=[O:7].[Cl:44]CCl.[ClH:47]>CO>[ClH:44].[ClH:47].[Br:22][C:21]1[C:16]([O:15][C:10]2[C:11]([CH3:14])=[N:12][CH:13]=[C:8]([C:9]=2[CH3:42])[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:43])=[O:7])=[CH:17][C:18]([NH:23][C:24]2[S:28][N:27]=[C:26]([CH:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)[N:25]=2)=[N:19][CH:20]=1
Reactant: ClCCl
Reactant: Cc1ncc(C(=O)NCCN(C)C)c(C)c1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)ncc1Br
Agent: Cl
Solvent: CO
Product: Cc1ncc(C(=O)NCCN(C)C)c(C)c1Oc1cc(Nc2nc(C3CCNCC3)ns2)ncc1Br
Reaction time: 8 h
Yield: 100 %

Procedure:
tert-Butyl 4-(5-(4-(5-((2-(dimethylamino)ethyl)carbamoyl)-2,4-dimethylpyridin-3-yloxy)-5-bromopyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.025 g, 0.037 mmol) was dissolved in a mixture of methanol:dichloromethane (1 mL each). HCl (4N in dioxane, 0.5 mL, 2.0 mmol) was added. The reaction stirred overnight. The solution was concentrated to give 5-(5-bromo-2-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)pyridin-4-yloxy)-N-(2-(dimethylamino)ethyl)-4,6-dimethylnicotin-amide dihydrochloride (0.028 g, 100% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.87-1.93 (m, 2H), 2.06-2.14 (m, 2H), 2.22 (s, 3H), 2.34 (s, 3H), 2.83 (s, 3H), 2.84 (s, 3H), 2.96-3.08 (m, 2H), 3.23-3.32 (m, 4H), 3.44-2.52 (m, 1H), 3.62-3.73 (m, 2H), 6.37 (s, 1H), 8.64 (s, 1H), 8.67 (s, 1H), 8.70 (s, 1H), 9.0 (s, 1H), 9.03 (t, 1H), 10.50 (s, 1H), 11.88 (s, 1H).
Reaction SMILES: Cl.Cl.C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)[OH:25])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:6].O.[OH-].[Li+].Cl>CO.O>[Cl:32][C:30]1[CH:31]=[C:26]([C@@H:24]([OH:25])[CH2:23][NH:22][CH2:21][CH2:20][NH:19][C:15]2[CH:14]=[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=3)[CH:18]=[CH:17][CH:16]=2)[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: COC(=O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cc(Cl)cc(Cl)c3)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2cccc(NCCNC[C@H](O)c3cc(Cl)cc(Cl)c3)c2)c1
Reaction time: 24 h
Yield: 16.9 %

Procedure:
A crude sample of (R)-3′-[[2-[[2-(3,5-dichlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester dihydrochloride (from Example 8, 557 mg), was treated with lithium hydroxide monohydrate (220 mg) in 3:1 methanol/water (28 mL) and stirred for 1 day. Additional lithium hydroxide monohydrate (22 mg) was added and the mixture was stirred overnight. The mixture was treated with 0.5 N aq. HCl until approximately pH6, and the resulting solid (400 mg) was collected by suction filtration. Silica gel chromatography (eluting with 6:2:0.1 chloroform/methanol/ammonium hydroxide) gave a solid that was triturated with hexanes. This material was treated with 1 N aqueous HCl, and the solid was washed by stirring with ethyl acetate. The solid was dried in vacuo to give the title compound (78.6 mg).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1.Cl[C:10]([O:12][CH3:13])=[O:11]>N1C=CC=CC=1>[C:10]([CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cl
Reactant: O=C1OCC(CO)O1
Solvent: c1ccncc1
Product: COC(=O)CC1COC(=O)O1
Yield: 30.3 %

Procedure:
To 73 g of 4-hydroxymethyl-1,3-dioxolan-2-one was added 63.3 g of pyridine with stirring and 75.6 g of methyl chloroformate was added at 0° C. for 1 hr, then the reaction mixture stirred at room temperature for 16 hrs. The reaction solution was passed through a glass filter to remove pyridine HCl salts, and then extracted with methylene chloride and distilled water. Recrystallization was carried out in toluene to obtain 30 g of 4-carbomethoxymethyl-1,3-dioxolan-2-one as a final product.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:41])=[O:40])=[CH:16][N:15]=1)[CH3:12].[CH2:50]([O:52]CCO)[CH3:51]>>[CH2:50]([O:52][CH2:12][CH2:11][O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:38])[C:23]3[C:24](=[C:26]([CH2:36][CH3:37])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:39]([N:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]2)(=[O:40])=[O:41])=[CH:16][N:15]=1)[CH3:51]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Reactant: CCOCCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCOCCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A stirred mixture of potassium bis(trimethylsilyl)amide (434 mg, 2.2 mmol) and 2-ethoxyethanol (2 ml) was heated at 90° C. for 30 minutes, then allowed to cool. A solution of the title compound of Example 1 (153 mg, 0.27 mmol) in 2-ethoxyethanol (2 ml) was added and the reaction mixture stirred at 110° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual brown oil purified by column chromatography on silica gel, using dichloromethane: methanol (95:5) as eluant, to furnish the title compound (110 mg, 68%) as a yellow foam. δ (CDCl3): 1.04 (3H,t), 1.31 (6H,m), 2.41 (2H,q), 2.54 (4H,m), 3.04 (2H,q), 3.14 (4H,m), 3.72 (2H,q), 3.90 (2H,t), 4.78 (2H,t), 5.67 (2H,s), 7.10 (1H,d), 7.22 (1H,m), 7.63 (1H,m), 8.57 (1H,d), 8.62 (1H,s), 8.99 (1H,s), 10.78 (1H,s). LRMS: m/z 597 (M+1)+.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=1[O:17][CH2:18][CH3:19])[C:3](OCC)=[O:4].[NH2:20][C:21]([NH2:23])=[S:22].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:18]([O:17][C:9]1[CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=[CH:13][C:8]=1[CH:2]1[S:22][C:21](=[NH:20])[NH:23][C:3]1=[O:4])[CH3:19]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)c1ccc(OCC)cc1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C2SC(=N)NC2=O)c(OCC)c1
Yield: 71.5 %

Procedure:
730 mg of ethyl α-chloro-α-(2,4-diethoxyphenyl)acetate and 380 mg of thiourea, in 7 ml of ethanol, are stirred under reflux for 1 hour. After cooling, the solution is poured in 30 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and distilled to remove the ethyl acetate, whereby 510 mg (74.5%) of 5-(2,4-diethoxyphenyl)-2-iminothiazolidin-4-one is obtained, m.p. 179°-181° C. (hemihydrate).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]#[N:26])=[CH:5][C:4]=2[N:3]=1.[OH-:27].[Na+].OO>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([NH2:26])=[O:27])=[CH:5][C:4]=2[N:3]=1
Reactant: [OH-]
Reactant: COCc1nc2c(N)nc3cc(CCC#N)ccc3c2n1CC(C)(C)O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COCc1nc2c(N)nc3cc(CCC(N)=O)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanenitrile (430 mg, 1.30 mmol) in methanol (75 mL) was heated to 50° C. in an oil bath. Aqueous 10% sodium hydroxide (0.33 mmol) and 30% aqueous hydrogen peroxide (516 mg, 4.55 mmol) were added and the reaction was stirred for 18 hours. The mixture was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was slurried in water (70 mL). The aqueous mixture was washed with chloroform (35 mL), concentrated to a wet solid, slurried in methanol (100 mL) and filtered. The filtrate was absorbed onto silica (1 tbsp) and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient; 0-20% CMA over 1400 mL, followed by 20-25% CMA over 1200 mL). The material was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-9% gradient of methanol in dichloromethane) to provide 102 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanamide as a white solid, mp 228-230° C.
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([OH:24])(=[S:23])[CH3:22]>C(OCC)C>[C:21]([S:23][CH:15]([CH2:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:16]([OH:18])=[O:17])(=[O:24])[CH3:22]
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(O)=S
Solvent: CCOCC
Product: CC(=O)SC(CC(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Reaction time: 5 h

Procedure:
2.68 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of diethyl ether, then 0.8 ml of thioacetic acid was added, and the mixture was stirred for 5 hours. After the diethyl ether was distilled off under reduced pressure, the residue was purified first by silica gel chromatography, eluted with a mixture of hexane and dichloromethane, then by recrystallization from a mixture of hexane and dichloromethane to give 2.96 g of 2-acetylthio-3-(4-phenoxybenzoyl)propionic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:5][CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)N=C(c2ccccc2)NC1c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a solution of methyl 4-methyl-2-phenyl-6-(3-nitrophenyl)-1,6-dihydro-5-pyrimidinecarboxylate (475 g) in chloroform (5 l) was added activated manganese dioxide (1.9 kg) and the mixture was refluxed for two hours with stirring vigorously. After allowing to cool to room temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo and the residual precipitate was recrystallized from diisopropyl ether (500 ml). The crystal was filtered off, washed with diisopropyl ether and dried in vacuo to give methyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (320 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:12][N:13](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH:3]=1)[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: COc1ccc(CO)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COc1ccc(CO)cc1C#N
Temperature: 80 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a solution of (3-bromo-4-methoxy-phenyl)-methanol (1 g, 4.607 mmol) in dimethylformamide (10 mL) at room temperature was added zinc cyanide (324.5 mg, 2.764 mmol). The reaction mixture was degassed by passing argon through for 30 min before tetrakis(triphenylphosphine)palladium (319 mg, 0.276 mmol) was added. The reaction mixture was heated at 80° C. for 12 h and stirred at room temperature for 2 d. It was diluted with diethyl ether (50 mL) and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded 5-hydroxymethyl-2-methoxy-benzonitrile (385 mg, 51%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:12])=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH:13](Br)[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.CCOC(C)=O>[N:16]([CH:13]([C:3]1[N:4]=[C:5]2[S:11][CH:10]=[C:9]([CH3:12])[N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:14])=[N+:17]=[N-:18]
Reactant: Cc1csc2nc(C(C)Br)c(Br)c(=O)n12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 6-bromo-7-(1-bromoethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (11.1 g, 31.5 mmol) and sodium azide (6.15 g, 94.6 mmol) in dimethyl formamide (DMF) (100 mL) was stirred at room temperature for 2 h. After diluting with EtOAc, the mixture was washed with water, brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexane, to provide the product (8.68 g, 87.6%). LCMS calculated for C9H9BrN5OS (M+H)+: m/z=314.0. Found: 313.9. 1H NMR (DMSO-d6, 300 MHz) δ 7.15 (1H, s), 4.83 (1H, q, J=6.6 Hz), 2.69 (3H, s), 1.48 (3H, d, J=6.6 Hz) ppm.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](Cl)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[NH:1]([C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:22])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: N[C@@H](CS)C(=O)O
Product: CCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)O

Procedure:
20 g (0.1652 mol) of Cys are reacted with 36.6 g (0.1487 mol) of myristoyl chloride analogously to Stage 6.1 to form tetradecanoyl-Cys: m.p.=63°-65°, Rf =0.13 (CH2Cl2 :acetone=8:2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[N:9]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:17][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)nc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
piperazine (1.38 g) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (3.0 g, prepared according to J. Heterocyclic Chem. 1994, 31, 73) and diisopropylethylamine (3.0 ml) in dichloromethane (100 ml) at 0° C. under N2. The resulting solution was stirred at room temperature for 2 hours then poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:methanol 8:2) to afford 1-(6-Chloro-3-nitro-pyridin-2-yl)-piperazine (2.99 g) as a red solid. M.p. 50-53° C.; MS (ES+) 243/245 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([N:17]3[CH:21]=[C:20](I)[N:19]=[CH:18]3)[N:8]=2)=[CH:4][CH:3]=1.[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:20]2[N:19]=[CH:18][N:17]([C:9]3[N:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=3)[CH:21]=2)[CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(Cl)s4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(5-chloro-thiophen-2-yl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example B.1) (0.46 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.28 g, 1.1 mmol) according to the general procedure III. Obtained as a light yellow solid (0.3 g) which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]2[CH3:25])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:16][CH2:17][CH:18]2[CH:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH:19]2[CH3:25])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC1CCCC(C)C1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of tert-butyl 5-chloro-4-((2,6-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate (0.21 g, 0.58 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 0° C. for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography (0 to 30% gradient ethyl acetate in hexanes) to afford the title compound (0.071 g, 38%): MS (ES−) m/z 315.2, 313.2 (M−1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[CH2:20]Br>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH:7][CH2:20][C:19]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=1[Cl:17])[CH3:3]
Reactant: CCOC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A mixture of 18.24 g of D-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the resulting mixture was heated to 80° C. The solution obtained was added dropwise at this temperature to a solution of 15 g of 2-chloro-6-nitrobenzyl bromide in 60 ml of ethanol. The mixture was stirred at 80° C. overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried over sodium sulphate and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 16 g (93% of theory) of N-(2-chloro-6-nitrobenzyl)-D-alanine ethyl ester; nD25 =1.5247; [α]D =-6.9° (c=1% in ethanol).