Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](=[O:33])[C@H:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C@H:22]([CH2:26][CH:27]=[CH2:28])[C:23]([NH2:25])=[O:24])[C:3]1=[O:34].C1CC=CCC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](=[O:33])[C@H:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C@H:22]([CH2:26][CH2:27][CH3:28])[C:23]([NH2:25])=[O:24])[C:3]1=[O:34]
Reactant: C=CC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCC=CC1
Product: CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C

Procedure:
The product of Example 6 was hydrogenated by dissolution in methanol (0.25M), addition of an equal amount by weight of Pearlman's catalyst [Pd(OH)2/C (20% Wt, Water %≦50)] and 30 eq. of 1,4-cyclohexadiene at room temperature. The solution was heated to reflux for 1 hr, then cooled to room temperature. Removal of volatiles and purification by flash chromatography using 4% methanol in CH2Cl2 gave the title compound. MS (M+H)+=463.3; MS (M+Na)+=485.3.
Reaction SMILES: Cl.Cl.[N:3]1([C:10]2[CH:11]=[C:12]([CH:20]([CH3:22])[CH3:21])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH:20]([C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([N:3]3[CH2:9][CH2:8][CH2:7][N:6]([CH2:24][C:25]4[N:26]=[C:27]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[S:28][CH:29]=4)[CH2:5][CH2:4]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[CH:15]2)([CH3:22])[CH3:21]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CC(C)c1cc(N2CCCNCC2)c2ncccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cc(N2CCCN(Cc3csc(-c4ccccc4)n3)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 49.7 %

Procedure:
A mixture of 8-[1,4]-diazepan-1-yl-6-isopropyl-quinoline dihydrochloride (0.34 g, 1 mmol, 1 equiv), 4-chloromethyl-2-phenyl-thiazole (0.21 g, 1 equiv) and Cs2CO3 (1.63 g, 5 equiv) in 5 mL of DMF was heated to 60° C. for 3 hours and then cooled to room temperature. EtOAc (˜70 mL) was added and the mixture washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 40% EtOAc in hexanes. Silica gel chromatography was repeated using 5% to 10% MeOH in EtOAc to afford the title compound (0.22 g, 50%) as light tan solid. 1H NMR (400 MHz, d6-CD3OD) δ 8.66 (dd, 1H, J=1.8 and 4 Hz), 8.07 (dd. 1H, J=1.5 and 8.4 Hz), 7.91 (m, 1H), 7.90 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.36 (s, 1H), 7.31 (dd, 1H, J=4.0 and 8.0 Hz), 7.16 (d, 1H, J=1.6 Hz), 7.04 (d, 1H, J=1.6 Hz), 3.90 (s, 2H), 3.71 (m, 2H), 3.59 (t, 2H, J=5.6 Hz), 3.11 (m, 2H), 2.92 (m, 3H), 2.10 (m, 2H), 1.31 (d, 6H, J=7.2 Hz). MS (ES) m/z 443.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH2:21])[CH3:20])[CH3:2].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>>[CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2)[CH3:20])[CH3:2]
Reactant: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c([C@H](C)Nc2ncnc3[nH]cnc23)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 31.1 %

Procedure:
A mixture of (S)-1-(1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.203 g, 0.715 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (145 mg, 0.60 mmol) and DIPEA (543 μL, 3.0 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was loaded onto an SCX column to remove the THP group. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The product fractions were collected, concentrated in vacuo and the resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-7% MeOH in DCM) to give 412 as a white solid (75 mg, 25%). LCMS (Method K): RT 2.76 min [M+H]+ 403. 1H NMR (DMSO, 400 MHz): δ 12.83 (1H, br s), 8.68 (1H, d, J=4.8 Hz), 8.12 (2H, d, J=14.3 Hz), 7.95 (1H, br s), 7.91 (1H, td, J=7.7, 1.7 Hz), 7.68-7.62 (2H, m), 7.46 (1H, d, J=7.2, 5.0 Hz), 7.11 (1H, dd, J=10.4, 9.0 Hz), 5.78-5.67 (1H, m), 3.91-3.71 (2H, m), 1.63 (3H, d, J=6.8 Hz), 0.71 (3H, t, J=6.9 Hz)
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[C:19]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]3[CH:45]=[CH:44][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][C:38]=3[C:39]([OH:41])=O)=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.Cl.[NH:58]1[CH2:63][CH2:62][CH:61]([C:64]([O:66][CH3:67])=[O:65])[CH2:60][CH2:59]1>ClCCl.O>[C:19]1([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]3[CH:45]=[CH:44][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][C:38]=3[C:39]([N:58]3[CH2:63][CH2:62][CH:61]([C:64]([O:66][CH3:67])=[O:65])[CH2:60][CH2:59]3)=[O:41])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Reactant: COC(=O)C1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Yield: 96.4 %

Procedure:
75 mg of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC), 27 mg of 1-hydroxy-1H-benzotriazole hydrate (HOBT) and 40 mg of triethylamine, are successively added to a suspension of 100 mg of 2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and 39 mg of methyl piperidine-4-carboxylate hydrochloride in 30 ml of dichloromethane. Water is added to the reaction mixture after 15 hours at room temperature. After phase separation, the aqueous phase is extracted with ethyl acetate. The combined dichloromethane and ethyl acetate phases are washed with saturated brine and dried over anhydrous sodium sulphate. Filtration and concentration result in a crude product which is purified by suction filtration through silica gel with cyclohexane/ethyl acetate 1:1 as mobile phase. 120 mg of product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH:3]=1.[Li+].[OH-].CO.Cl>C1COCC1.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2cc(F)ccc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 8 (246.68 mg, 1.1 mmol) and LiOH (75.9 mg, 3.3 mmol) in THF (9 mL) was added MeOH (1 mL) and H2O (3 mL), stirred at room temperature for 6 h. Then HCl (1 M) was added to the reaction mixture to pH=4, and extracted with EtOAc (3×15 mL), wash with H2O (3×20 mL). The organic extracts were dried with Na2SO4 and concentrated under reduced pressure. Purified by flash chromatography on silica gel, using ethyl acetate/hexane (4:1) as eluent, give 8-acid as white powder; (212.79 mg, 98.6%). 1H-NMR (300 MHz, acetone-d6): δ 8.14 (s, 1H), 8.10-8.05 (m, 1H), 7.80-7.76 (m, 1H), 7.41-7.34 (m, 1H). 13C NMR (300 MHz, acetone-d6): δ 162.52, 159.31, 140.12, 137.78, 130.11, 124.65, 116.10, 110.66.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](F)=[N:10]2)=[O:4].C(NC1C([Cl:39])=NC2C(N=1)=C(C(=O)C)C=CC=2)(C)(C)C>>[Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([Cl:39])=[N:10]2)=[O:4]
Reactant: CC(C)(C)Nc1nc2c(C(=O)CBr)cccc2nc1F
Reactant: CC(=O)c1cccc2nc(Cl)c(NC(C)(C)C)nc12
Product: CC(C)(C)Nc1nc2c(C(=O)CBr)cccc2nc1Cl
Yield: 59 %

Procedure:
This compound (215 mg, 59% yield) as a yellow oil was prepared according to the procedures described for intermediate 343c, using 1-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)ethanone (345a) (285 mg, 1.02 mmol) as the starting material. 1H NMR (400 MHz, CDCl3) δ ppm 1.57 (s, 9H) 4.93 (s, 2H) 5.82 (br. s., 1H) 7.43 (t, J=7.82 Hz, 1H) 7.94 (d, J=7.63 Hz, 2H). MS (ESI, pos. ion) m/z: 356.0/358.0 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Na+].[CH3:11][C:12]1([CH3:24])[CH2:17][CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][C:14]([CH3:23])([CH3:22])[NH:13]1.C([O:29]O)(C)(C)C>[Mo](=O)(=O)=O>[CH2:1]([O:29][N:13]1[C:12]([CH3:24])([CH3:11])[CH2:17][CH:16]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][C:14]1([CH3:23])[CH3:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC
Reactant: CC(C)(C)OO
Reactant: CC(=O)NC1CC(C)(C)NC(C)(C)C1
Agent: O=[Mo](=O)=O
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCON1C(C)(C)CC(NC(C)=O)CC1(C)C
Temperature: 5 °C
Yield: 61 %

Procedure:
A two-phase mixture of 260 grams (2.02 mol) of 70% aqueous tert-butyl hydroperoxide, 350 ml of n-octane, and 50 grams of sodium chloride is vigorously stirred. The organic phase is separated, dried over anhydrous magnesium sulfate and filtered. The filtrate is diluted with n-octane to a volume of 580 ml. To a mixture of 100.0 grams (0.504 mol) of N-(2,2,6,6-tetramethylpiperidin-4-yl)acetamide, 1.8 gram of molybdenum trioxide, and 100 ml of n-octane preheated to 120° C. is added 300 ml of tert-butyl hydroperoxide solution over a 15-minute period. The mixture quickly turns red and water is collected in a Dean-Stark trap. The remaining tert-butyl hydroperoxide solution (280 ml) is added to-the refluxing reaction mixture over a period of 2.5 hours. The reaction mixture is heated at reflux for three hours after the addition is complete, then treated with 50.1 grams (0.50 mol) of 90% tert-butyl hydroperoxide and heated at reflux for 2.5 hours to discharge the red color of the N-oxyl intermediate. Solids are removed by filtration, and the filtrate is cooled to 5° C. and stirred with a solution of 40 grams of sodium sulfite in 400 ml of water to decompose unreacted hydroperoxide. The organic layer is dried over anhydrous magnesium sulfate and concentrated to an oil. Purification by flash chromatography (1:1 heptane:ethyl acetate) affords 100.2 grams (61% yield) of the title compound as a waxy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[N:19]3[C:15]([S:16]C=C3)=[N:14][CH:13]=2)=O)=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[C:28](=O)(O)[O-].[Na+].C([O:36][CH2:37][CH3:38])(=O)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[S:16][C:15]3=[N:14][CH:13]=[C:38]([CH:37]=[O:36])[N:19]3[C:12]=2[CH3:28])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(/C=C/c1ccc(Br)cc1)c1cnc2sccn12
Reactant: CCOC(C)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(CCc2ccc(Br)cc2)sc2ncc(C=O)n12

Procedure:
A solution of 2-(4-Bromophenyl)-E-ethenylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-9) (1.04 g) in toluene (160 mL) was treated with a solution prepared by dissolving Na2S2O4 (14.4 g) in water (220 mL), adding sodium bicarbonate (15.6 g) and Aliquot®336 (0.41 mL). The vigorously stirred suspension was heated at 100° for 85 hours, diluted with ethyl acetate and partitioned. The extract was washed with saline solutions, dried and evaporated to a viscous residue. The residue was chromatographed on silica gel and product was eluted with 4:1 hexane:ethyl acetate to provide 2-(4-Bromophenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-10) (0.220 g). An aliquot was crystallized from isopropanol to yield pure 2-(4-Bromophenylethyl)-3-methylimidazo[2,1-b]thiazol-5-yl methanone (Formula B-10), m.p, 113-115°.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:25])[CH2:12][N:13]2[C:17](=[O:18])[C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[S:14]2(=[O:24])=[O:23])[CH:6]=1>CN(C=O)C>[CH3:4][C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH2:12][NH:13][S:14]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]([O:2][CH3:1])=[O:18])(=[O:24])=[O:23])=[O:25])[CH:6]=1
Reactant: C[O-]
Reactant: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1S(=O)(=O)NCC(=O)Nc1cc(C)on1
Yield: 74.4 %

Procedure:
To 60 ml DMF is added 13.5 grams (0.25 mole) of sodium methoxide. To this slurry at 15° C. is added a solution of 20 grams (0.062 mole) of 2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide dissolved in 70 ml DMF. The reaction mixture is stirred at 25°-30° C. for a half hour whereupon it is acidified and extracted with chloroform. These extracts are washed with sodium bicarbonate and water, dried (Na2SO4) and concentrated to an oil which is triturated with petroleum ether to give 16.3 grams (75%) of methyl 2-{[({[(5-methyl-3-isoxazolyl)amino]carbonyl}methyl)amino]sulfonyl}benzoate, mp 153°-156° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([PH:20](=[O:22])[OH:21])[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][CH:24]([CH3:33])[CH2:25][C:26](=[CH2:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(OCC)(=O)C.O>C(#N)C>[OH:22][P:20]([CH2:32][CH:26]([CH2:25][CH:24]([CH3:23])[CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH:8]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21]
Reactant: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Reactant: C=C(CC(C)C)C(=O)OCC
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 81.3 %

Procedure:
To a solution of 1 g (3.13 mmol) of [2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinic acid synthesized in 1.4., 2.2 g (14.10 mmol) of ethyl 4-methyl-2-methylenepentanoate and 0.52 ml of N,O-bis(trimethylsilyl)acetamide in 0.27 ml of acetonitrile is stirred at a temperature in the region of 20° C. for 24 hours. 60 ml of a 1/1 ethyl acetate/water mixture are added. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under vacuum. The product is purified by recrystallization from a mixture of ethyl acetate and hexane. 1.21 g of product are recovered (yield=81.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cnccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1N

Procedure:
A mixture of 3-amino-isonicotinic acid (613 mg, 4.44 mmol), methanol (15 mL) and thionyl chloride (0.7 mL, 8.88 mmol) was stirred at reflux for 3 days. The volatiles were removed under reduced pressure and the residue stirred with diethylether (20 mL) and saturated solution of sodium hydrogenocarbonate (40 mL). The phases were separated and the aqueous phase extracted with diethylether (2×20 mL). The combined organic phases were dried over sodium sulfate and evaporated to dryness affording 400 mg of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH2:1]([CH:3]([CH:6]1[CH2:7][C:8](=[O:13])[CH:9]([C:24](=[O:25])[NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C:10](=[O:12])[CH2:11]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)C1CC(=O)CC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: CCC(CC)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(C)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-(1-ethylpropyl)-1,3-cyclohexanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ETHYLPROPYL)-2-(N-p-TOLUENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 111.5°-112.5° C. (corr.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]([CH3:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16]I.[OH-].[K+].O>C(COC)OC>[Cl:1][C:2]1[C:3]([CH:12]([CH3:16])[C:13](=[O:14])[CH3:15])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CI
Reactant: CC(=O)Cc1ncc(C(F)(F)F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(=O)C(C)c1ncc(C(F)(F)F)cc1Cl
Yield: 9.9 %

Procedure:
6.00 g of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetone (Int-11) (27 mMol) (synthesis according to P10 and comm av.) and 5.75 g of methyl iodide (40.5 mMol) were diluted in 120 mL of dimethoxyethane. 3.03 g of potassium hydroxide were added portionwise at room temperature. After cooling, 100 mL of water were added to the reaction mixture which was extracted twice with 150 mL of ethyl acetate. The organic phase was washed twice with 100 mL of water, dried over magnesium sulfate and concentrated. After purification on silica, 0.67 g (39%) of desired product 3-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]butan-2-one (Int-12) were obtained, [M+1]=252.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].I[CH2:44][C:45]1([CH3:49])[CH2:48][O:47][CH2:46]1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:44][C:45]3([CH3:49])[CH2:48][O:47][CH2:46]3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CC1(CI)COC1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC1(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)COC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+).
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:19]([C:22]1[CH:23]=[C:24]([C@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>C(Cl)Cl.CN(C=O)C>[N+:19]([C:22]1[CH:23]=[C:24]([C@H:28]([NH:30][C:1](=[O:18])[O:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: C[C@@H](N)c1cccc([N+](=O)[O-])c1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (4.95 g, 19.9 mmol) and TEA (10 mL) in DCM (50 mL) was added a solution of (R)-1-(3-nitrophenyl)ethanamine (3 g, 18 mmol) in DMF (10 mL). The mixture was stirred 2 h and quenched with water (50 mL). The organic layer was separated and dried (MgSO4) before concentrating in vacuo. The residue was purified by flash chromatography (0-35% EtoAc/Hexane) to afford 64A (5 g, 93%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J=6.59 Hz, 3 H) 4.87-4.98 (m, 1 H) 5.00-5.15 (m, 2 H) 7.34 (s, 5 H) 7.49 (t, J=7.69 Hz, 1 H) 7.64 (d, J=7.03 Hz, 1 H) 8.11 (d, J=7.91 Hz, 1 H) 8.17 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][NH2:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:6][CH:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O.Cl>CCOCC.CCO>[F:1][C:2]1[C:3]([NH:18]/[N:19]=[CH:25]/[C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:6][CH:7]=1
Reactant: O=Cc1cccs1
Reactant: COc1cccc(COc2ncc(F)c(NN)n2)c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc(COc2ncc(F)c(N/N=C/c3cccs3)n2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
A 20 mL vial was charged with 5-fluoro-4-hydrazinyl-2-(3-methoxybenzyloxy)-pyrimidine (74.7 mg, 0.283 mmol), EtOH (2 mL), thiophene-2-carbaldehyde (26 μL, 0.284 mmol) and 1 M HCl in Et2O (14 μL, 0.014 mmol) and heated at 50° C. on shaker. After 90 minutes, the reaction was cooled to room temperature concentrated on high vacuum to provide the title compound (77.8 mg, 77%) as a yellow solid: mp 136-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.46 (bs, 1H), 8.50 (bs, 1H), 8.16 (d, J=3.6 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.12 (dd, J=3.8, 4.8 Hz, 1H), 7.04 (m, 2H), 6.88 (dd, J=2.4, 8.3 Hz, 1H), 5.27 (s, 2H), 3.73 (s, 3H); MS (ESI) m/z 359.2 (M+H)+, 357.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Cl)[CH3:2].[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[N:22]=[C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:24])=[CH:18][CH:17]=2)[S:21][CH:7]=1)[CH3:2]
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(Nc2ccc(C(F)(F)F)cc2)n1

Procedure:
4-Chloro-3-oxo-butyric acid ethyl ester was added to a suspension of (4-trifluoromethyl-phenyl)-thiourea (3 grams), obtained in step (ii), in ethanol (20 mL) and refluxed for about 12 hrs. The reaction mixture was cooled and the solid obtained was filtered and dried to give the pure product (4.1 grams).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=O)[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-].[Na+].[NH2:24][NH:25][C:26]([NH2:28])=[S:27].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=[N:24][NH:25][C:26]([NH2:28])=[S:27])[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(-c2nc(C)c(C(C)=NNC(N)=S)s2)cc(OC)c1OC
Yield: 65 %

Procedure:
2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole prepared in Example 1 (1.0 g corresponding to its 0.0033 mol) was dissolved in 30 ml of ethanol, and to the solution, 8.6 ml of an aqueous 2% solution of sodium hydroxide (0.0045 mol) and 0.4 g (0.0044 mol) of thiosemicarbazide were added, and the mixture was heated for 3 hours under a reflux condenser. After cooling the reaction mixture, it was introduced into 300 ml of iced water, and the precipitate which separated was collected by filtration. After washing the precipitate with water, it was recrystallized from ethanol to obtain the object consisting of yellow needle-like crystals amounting to 0.82 g at a yield of 65%, which decomposed at 209° to 212° C.