Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:14]1[S:15][C:16]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[N:18]=1)[CH3:13].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[C:12]([C:14]1[S:15][C:16]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[N:18]=1)(=[O:11])[CH3:13]
Reactant: CCC(=O)Nc1cc(-c2sc(C(C)O)nc2-c2cccc(C)c2)ccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(-c2sc(C(C)=O)nc2-c2cccc(C)c2)ccn1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
A solution of dimethylsulfoxide (0.30 mL, 4.2 mmol) in dichloromethane (1.0 mL) was added to a solution of oxalyl chloride (0.11 mL, 1.26 mmol) at −78° C. and the resulting mixture was stirred for 15 minutes. A solution of N-[4-[2-(1-hydroxyethyl)-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]propionamide (0.38 g, 1.0 mmol) in dichloromethane (1.5 mL) was added to the mixture and the resulting mixture was stirred for 45 minutes. The reaction mixture was allowed to warm up to −50° C. and triethylamine (0.72 mL, 5.17 mmol) was added dropwise to the mixture. The resulting mixture was stirred for 30 minutes and poured into aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the extracts were washed with aqueous sodium hydrogen carbonate solution and brine. The resulting solution was dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1) to obtain a crude crystal. The obtained crude crystal was recrystallized from isopropyl ether to give a title compound (0.22 g, yield 58%).
Reaction SMILES: FC(F)(F)C(O)=O.N1[CH2:13][CH2:12][C:11](=[C:14]2[CH:28]=[CH:27][CH:26]=[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=3)[CH:15]2C)CC1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37](=[O:45])OC2C=CC=CC=2)[CH:31]=1.[CH:46]([N:49](C(C)C)[CH2:50]C)(C)[CH3:47]>CS(C)=O>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:15]=[C:14]([CH:28]=[CH:27][CH:26]=2)[CH:11]=[C:12]2[CH2:13][CH2:50][N:49]([C:37]([NH:36][C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[O:45])[CH2:46][CH2:47]2)=[N:19][CH:20]=1)#[N:25]
Reactant: CC1C(Oc2ccc(C#N)cn2)=CC=CC1=C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
A solution of 2-(3-piperidin-4-ylidene-methyl-phenoxy)-5-cyanopyridine trifluoroacetate (0.280 g, 0.72 mmol) and phenyl pyridin-3-ylcarbamate (0.154 g, 0.72 mmol) in DMSO (2.0 mL) was treated with diisopropylethylamine (0.170 g, 1.6 mmol) and heated to 60° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% of 1N NH3 in MeOH, in dichloromethane) to afford the title compound (155 mg, 52%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 412.16; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.45 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 6.39 (s, 1H) 7.02-7.04 (m, 2H) 7.12 (d, J=7.60 Hz, 1H) 7.21 (d, J=8.20, Hz, 1H) 7.25-7.27 (m, 1H) 7.39 (t, J=8.01 Hz, 1H) 7.83 (dd, J=5.28 Hz, 2.74 Hz, 2H) 8.10 (d, J=2.86 Hz, 1H) 8.25 (s, 1H) 8.30 (s, 1H) 8.8 (m, 1H) 8.75 (s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])[C:2]#[CH:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.C(Cl)Cl>[C:13]([O:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][C:2]#[CH:3])[CH:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCOc1cccc(CO)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C#CCOc1cccc(COC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 5.0 L flange flask was charged with 3 (706 g, approx. 4.36 mol, 1 eq) and acetic anhydride (99.5%, ex. Fisher, 1300 ml, 1 mol) to give a clear solution. Sulfuric acid (conc. 98%, 150 drops, ˜3 ml, catalytic) was then added very slowly (dropwise) over 30 minutes, with cooling to 0° C. by aid of an ice/water bath to control the exotherm to give a very dark reaction mixture. Maximum internal temperature observed was 45° C. After the addition the reaction mixture was stirred for 30 min, then the reaction mixture was stirred at 99° C. for 3 h. TLC-examination (silica-gel plate, DCM eluent, PMA stain) showed that all the starting material had been consumed. The mixture was cooled to room temperature (r.t.) overnight to give a dark green solution, which was poured onto an ice-water mixture (2.5 L water and 2.5 Kg of ice) with vigorous stirring. The product was extracted with DCM (5.0 L×3), and the combined extracts washed with water (3.0 L×3), dried over Na2SO4, and evaporated to give a black/brown oily residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][NH2:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.O[CH:14]1[O:18][C:17](=O)[CH2:16][CH:15]1[CH2:20][CH2:21][CH3:22]>ClCCCl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:14][CH:15]([CH2:20][CH2:21][CH3:22])[CH2:16][C:17]1=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCCC1CC(=O)OC1O
Reactant: NCc1c(F)cc2ccccn12
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC1CC(=O)N(Cc2c(F)cc3ccccn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 1-(2-fluoroindolizin-3-yl)methanamine x263 (0.38 g, 2.3 mmol) and 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.33 g, 2.3 mmol) in DCE (12 ml) is kept at room temperature for 2 h, then STAB (0.74 g, 3.5 mmol) is added, and the mixture is stirred overnight. The reaction mixture is kept under stirring at 50° C. for 2 h, cooled to room temperature, and diluted with dichloromethane (10 ml). The mixture is washed with a 20% K2CO3 solution (2×15 ml), and the aqueous layer is washed with brine (25 ml), dried over anhydrous Na2SO4 and evaporated. The residue (0.60 g) is purified by chromatography on silica gel (gradient: chloroform to chloroform/methanol 50/1) to isolate a product of approximately 80% purity (0.162 g). This product is purified by chromatography on silicagel (hexane/ethyl acetate 5/2) to afford pure 1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one 264 (0.126 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
1.1 g of Z-Val-Gly-Ala-Pro-NH2 are dissolved in 50 ml of 80 % strength methanol and the solution is hydrogenated in the presence of 0.3 g of palladium on charcoal (10 % Pd). When the hydrogen uptake has ended the catalyst is filtered off, the solution evaporated and the residue dried in a high vacuum at 35° C. bath temperature. Hereupon the tetrapeptide H-Val-Gly-Ala-Pro-NH 2 is obtained as a colourless substance, Rf-Value = 0.20 (silica gel plates, system chloroform-methanol = 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[O:8][Si](C)(C)C)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:8])[CH3:2]
Reactant: CCOC(=O)CCC(O[Si](C)(C)C)c1ccccc1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 20 h
Yield: 93.3 %

Procedure:
To a solution of 4-(2-nitro-phenyl)-4-trimethlysilanyloxy-butyric acid ethyl ester (530 mg, 1.6 mmol) in dry DCM (5 mL) under Argon was added PCC (pyridinium chlorochromate) (878 mg, 4.1 mmol) and the resulting mixture stirred vigorously for 20 h. Then silica gel (5 g) was added and the mixture filtered. The filtrate was then evaporated and the residue purified by chromatography on silica gel, eluting with ethyl acetate: hexane (3:1) to afford the title compound (375 mg, 92%) as a colorless liquid; m/z 252 (MH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]([OH:14])=O)=[O:5])[CH3:2].C([N:17]([CH:21]([CH3:23])C)[CH:18](C)C)C.N1CCC1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]([N:17]1[CH2:18][CH2:23][CH2:21]1)=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)O)cnn1C
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
To a cooled solution of 5-(ethoxycarbonyl)-1-methyl-1H-pyrazole-4-carboxylic acid (1.5 g, 7.57 mmole), N-ethyldiisopropylamine (3.97 ml, 22.7 mmole) and azetidine (1.02 ml, 15.1 mmole) in ethyl acetate (30 ml) is added at 0° C. propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 11.4 ml, 18.9 mole). The ice-bath is removed and the light yellow solution is stirred for 3 hr at room temperature. The light yellow solution is adjusted to pH 9 with sat. aqueous sodium carbonate solution, the aqueous layer is separated and extracted twice with ethyl acetate. The combined organic layer is washed with water and brine, dried with magnesium sulfate and the solvent is removed in vacuo affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.09 g, 60.7%) as a light brown viscous oil. MS: m/z=238.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].C(N(CC)CC)C.C([SiH](CC)CC)C>C(Cl)Cl.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][NH:20][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of benzyl (3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}4-ethoxypyrrolidine-1-carboxylate (8.60 g, 15.8 mmole) in CH2Cl2 (0.1M, 158 ml) under N2 was added Palladium chloride (279 mg, 1.58 mmole) and triethyl amine (3.29 ml, 1.5 eq.). Triethylsilane (3.78 ml, 1.5 eq.) was added dropwise over 15 min. After one hour an additional 8.74 ml of triethylsilane was added dropwise. After 2 additional hours, the reaction mixture was filtered through celite. Trifluoroacetic acid (8 ml) was added and the reaction mixture was stirred for 30 min. Quenched to pH 10 with 2N NaOH and extracted 3×300 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Vacuum chromatography was run on a 1 L frit funnel with 5–15% MeOH/CH2Cl2 with 0.5% NH4OH to give 5.95 g (92%) of an oil. 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.33–7.26, 5.38, 4.54, 4.07, 3.68, 3.52, 3.22, 2.95, 2.71, 2.46, 1.29, 1.15; HRMS (FAB) calcd for C20H26Cl2N4O+H 409.1562. found 409.1567. Anal. Calcd for C20H26Cl2N4O: C, 58.68; H, 6.40; N, 13.69. Found: C, 58.42; H, 6.43; N, 13.50.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.Cl.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]1.C(N(CC)CC)C.N1C=CC=NC=1.Cl>C(O)C>[NH2:16][C:4]1[N:3]=[C:2]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]2)[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:6][N:5]=1
Reactant: CC(C)N(C=Nc1ncc(Oc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: c1cncnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ncc(Oc2ccc(Cl)cc2)c(N[C@H]2CC[C@H](O)CC2)n1
Reaction time: 56 h

Procedure:
4-Chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine (3.68 g, 0.01 mole) and trans-4-aminocyclohexanol hydrochloride (5.31 g, 0.035 mole) were combined in absolute ethanol (25 mL). Triethylamine (7.08 g, 0.07 mole) was added, and the mixture was refluxed with stirring for 56 hours when thin layer chromatography confirmed the absence of the starting pyrimidine. The mixture was cooled slightly, concentrated hydrochloric acid (5 mL) was added and reflux was resumed for an additional 2 hours. The mixture was spin evaporated in vacuo. The oily residue was dissolved in water (200 mL) and extracted with dichloromethane (2×200 mL). The aqueous phase was basified with 2 M sodium hydroxide to pH 9, and the gummy residue that precipitated was dissolved in dichloromethane (100 mL). The aqueous phase was back washed with dichloromethane (100 mL), and the combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered and spin evaporated in vacuo to a foam. This material was dissolved in ethyl acetate and chromatographed on Silica Gel 60 (E. M. Science, 230-440 mesh) (8 g; 2×7 cm column bed) using ethyl acetate as eluent. The first 100 mL of eluent was collected and spin evaporated in vacuo to give 2.30 g (69% yield) of 2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine as a white powder, mp 154-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nn3c(-c4cnc(N)nc4)c(C)nc3s2)cc1OC
Yield: 31.9 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.041 g, 0.102 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.056 g, 0.255 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.007 g, 0.0102 mmol, 0.1 eq) and potassium carbonate (0.07 g, 0.51 mmol, 5 eq) in water (0.3 mL) and dioxane (2.2 mL) was subjected to MW irradiation (120° C., 35 min, 200 W). The solvents were evaporated, and the residue obtained was purified by silica gel chromatography (0-3% MeOH in DCM) and preparative HPLC (RP-C18, ACN/water) to give the desired product (0.012 g). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=4.08 min, [M+H]+ m/z 369.1
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[SH:34])([CH2:26][CH3:27])[CH3:25].N1CCCCC1>ClCCl>[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8])([CH2:26][CH3:27])[CH3:25]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: CCC(C)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCC(C)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.1 mmol of 2-sec-butylbenzenethiol, and 2.1 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 67°-68° C.). 1H NMR (DMSO-d6) δ0.82 (q, 3H), 1.09 (t, 3H), 1.46-1.61 (m, 2H), 2.26 (m, 2H), 2.35 (m, 1H), 2.62 (m, 1H), 2.98 (m, 1H), 3.47 (q, 2H), 5.90 (t, 1H), 6.56 (t, 1H), 6.94 (t, 1H), 7.07-7.18 (m, 4H), 7.25 (m, 2H), 7.45 (m, 5H).
Reaction SMILES: [NH2:1][O:2][S:3]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])(=[O:5])=[O:4].[C:15]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[S:3]([O-:5])(=[O:4])=[O:2].[NH2:1][N+:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: c1ccc(COc2ccncc2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (4.05 g, 18.8 mmol) in DCM (60 mL) was cooled to 0° C. 4-[(Phenylmethyl)oxy]pyridine (2.91 g, 15.7 mmol) in DCM (2 mL) was added dropwise. Following complete addition, the mixture was stirred at rt for 45 min. The reaction mixture was evaporated under reduced pressure to give crude white foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.N1C(C)=CC=CC=1C.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C1COCC1>[F:26][C:25]([F:28])([F:27])[S:22]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:21])=[O:23])=[CH:7][CH:8]=2)[CH:3]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccc2ccc(OS(=O)(=O)C(F)(F)F)cc2c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A mixture of 2,7-dihydroxynaphthalene (3.00 g, 18.73 mmol), DMAP (0.42 g, 3.75 mmol) and 2,6-lutidine (4.41 g, 41.18 mmol) was suspended in anhydrous DCM (30 ml) and anhydrous THF (30 ml) in the presence of molecular sieves under an Ar2 atmosphere at −78° C. Tf2O (11.10 g, 39.33 mmol) was added dropwise to this stirred mixture over 15 minutes and the reaction was stirred at −78° C. for 2 hours, then for 5 hours at 0° C. After that time, the reaction was carefully neutralised with saturated aqueous NaHCO3 solution (70 ml), extracted with DMC (6×120 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The orange oil thus obtained was purified by flash column chromatography (petroleum ether:EtOAc, 95:5) to give compound 1 as a white solid (4.94 g, 62%); Rf 0.27 [5% EtOAc in petroleum ether]; mp 60-62° C.; δH (CDCl3, 400 MHz) 7.92 (2H, d, J=9.2 Hz, 2×ArH), 7.73 (2H, d, J=2.4 Hz, 2×ArH), 7.40 (2H, dd, J1=8.8 Hz, J2=2.4 Hz, 2×ArH); δC (CDCl3, 100 MHz) 148.26 (2×Ar—C), 133.62 (Ar—C), 131.27 (Ar—C), 130.80 (2×Ar—CH), 121.13 (2×Ar—CH), 119.48 (2×Ar—CH), 118.77 (2×CF3); HRMS m/z calc. C12H6F6O2S2Na [M+Na]+446.9408. found [M+Na]+446.9424; anal.CHN calcd. C12H6F6O2S2 C, 34.0%; H, 1.4%. found C, 34.2%; H, 1.2%. Spectroscopic data are in accordance with those reported in literature (Yao et al., 1998).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][N:7]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CCNC1CCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A solution of 1.9 g (0.011 mole) of 3-cyclobutylaminopropanoic acid ethyl ester in 7 mL of acetonitrile was added dropwise to a mixture of 1.74 g (0.09 mole) of 2,4-dichloro-5-nitro-pyrimidine and 2.07 g (0.021 mole) of potassium bicarbonate and 20 mL of acetonitrile at ambient temperature over 45 mins. The mixture was stirred for 2.5 hours, then diluted with 45 mL of ethyl acetate. The mixture was filtered, concentrated under reduced pressure and the residue purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) to give 1.7 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-propanoic acid ethyl ester (IV-23).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].F[C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:13]#[N:14].O>CN1CCCC1=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:10]2[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[C:12]([CH:11]=2)[C:13]#[N:14])[CH:6]=1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2cc(C#N)cc(C(F)(F)F)c2)cn1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
A solution of 4-methyl-1H-imidazole (1.98 g, 24.11 mmol) in N-methylpyrrolidinone (NMP) (18 mL) is added to a solution of sodium hydride (0.82 g, 60%, 20.5 mmol) in NMP (18 mL) at 20-25° C. under an atmosphere of nitrogen. The mixture is stirred for 1 hour, before a solution of 3-fluoro-5-trifluoromethyl benzonitrile (XXI) (3.2 g, 16.4 mmol) in NMP (8 mL) is added. The reaction mixture is stirred for 2 hours at 20-25° C. and then water (120 mL) is added within 20 minutes and the resulting suspension is stirred for 16 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=O)[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[S:39])[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=S
Yield: 50 %

Procedure:
5-Benzyloxy-6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-3-methyl-3H-pyrimidin-4-one was treated with 0.62 equiv of Lawesson's reagent at 80-85° C. in toluene for 5-7 h. TLC showed one major product formation with some substrate still present. Chromatography (eluted with 70%-90% EtOAc/hexane) gave ˜50% yield of the title compound.