Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[CH:6]1([N:12]=[C:13]=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1>[CH:6]1([NH:12][C:13]([N:4]([CH2:3][CH2:2][OH:1])[NH2:5])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NNCCO
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Product: NN(CCO)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxyethylhydrazine (7.15 g, 0.09 moles) in 125 mL tetrahydrofuran was added dropwise with stirring 11.76 g (0.09 moles) cyclohexyl isocyanate in 70 mL tetrahydrofuran. The solution was stirred overnight at room temperature, and the solvent was evaporated to yield quantitatively a pale viscous oil which slowly crystallizes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Br:20]Br>C(O)C>[Br:20][C:15]1[CH:14]=[N:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=3)[N:9]=[CH:10][C:11]=2[C:16]=1[OH:17]
Reactant: BrBr
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(O)c(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (10.00 g, 39.17 mmol, prepared as described in WO 2007/103308) in absolute ethanol (220 mL) was cooled to 0° C., treated dropwise with bromine (2.15 mL, 43.09 mmol) and stirred at 0° C. for 30 minutes. The ice bath was then removed, and the mixture was allowed to warm to room temperature. After 30 minutes, water (150 mL) and concentrated HCl (10 mL) were added to the slurry, and the mixture was stirred at room temperature for 10 minutes. The solid formed was filtered and washed with water (3×20 mL) followed by EtOH (2×20 mL). The solid collected was triturated with CH3CN, filtered, washed with additional CH3CN (2×10 mL), and air dried to provide 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (10.90 g, 83% yield) as a solid. LCMS (APCI+) m/z 333.9 (M+H)+, Retention time=2.33 minutes.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][C:24]2[S:28][CH:27]=[N:26][C:25]=2[CH3:29])[CH:17]=[CH:16][N:15]=1>>[CH3:20][C:19]1[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[N:15][CH:16]=[CH:17][C:18]=1[S:21][CH2:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][C:25]=1[CH3:29]
Reactant: Cc1ncsc1CCSc1ccnc(CCl)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Product: Cc1ncsc1CCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C

Procedure:
Following the procedure described in Example 1, the reaction of 2-mercapto-1H-benzimidazole with 2-chloromethyl-3-methyl-4-[2-(4-methyl-5-thiazolyl)ethylthio]pyridine hydrochloride gives the title compound as a colorless solid of m.p. 150°-152° C. following crystallization from dichloromethane/diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH:3](O)[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1.S(Cl)([Cl:20])=O.C>C1C=CC=CC=1>[CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH:3]([Cl:20])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Agent: C
Solvent: c1ccccc1
Product: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Yield: 69.4 %

Procedure:
A solution of 242.8 g (1.016 moles) of 1,1-dimethyl-2-hydroxy-2-(3,4-methylenedioxyphenyl)nitroethane in 500 ml of benzene was treated with 139 g (84 ml, 1.17 moles) of thionyl chloride, after which the mixture was refluxed for 4 hours, cooled slightly and concentrated to a dark yellow oil which crystallised on cooling and seeding. The resulting solid was broken up and dispersed in 150 ml of 2-propanol after which it was separated, washed twice with cold 2-propanol and dried to give crude 1,1-dimethyl-2-chloro-2-(3,4-methylenedioxyphenyl)nitroethane as a light yellow solid, m.p. 63°-66° C (Yield 230.9 g). A 201.3 g portion of the crude product was treated with "Darco" (Trade Mark) and recrystallised from 402 ml of SDA-30 to give 181.6 g (79.6%) of the pure product as a white solid, m.p. 65°-67° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[OH:25])=[C:20](Cl)[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O)([CH3:37])[CH3:36].C([O-])(O)=O.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[OH:25])=[C:20]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH:35]([CH3:37])[CH3:36])[N:21]=[CH:22][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Cl)ncc21
Reactant: CC(C)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccccc1-c1ncc2c(c1C(O)c1ccc(Cl)cc1)c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 25 °C
Yield: 13 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-6-chloro-5-((4-chlorophenyl) (hydroxy)methyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.19 mmol), 2-isopropyl phenylboronic acid (62.52 mg, 0.38 mmol), NaHCO3 (48 mg, 0.57 mmol), aq. 2M K3PO4 (0.47 ml, 0.94 mmol) in dioxane (1 mL) and water (0.2 mL) was added Pd(dppf)Cl2 (5 mg, 0.0068 mmol). The reaction was degassed with nitrogen (3×), heated at 120° C. (MW) for 1.5 h, cooled to RT then diluted with EA (10 mL) and water (2 mL) and filtered. The filtrate was concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(3-(tert-butyldimethylsilyloxy)propyl)-5-((4-chlorophenyl)(hydroxy)methyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (15 mg, 12.9% yield) as a colorless oil. LCMS: MH+ 608 and TR=2.668 min.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:7][CH:6]=1>C(O)C>[CH3:3][O:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH2:13][OH:14])=[CH:7][CH:6]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Oc2cccc(CO)c2)cc1
Yield: 81.1 %

Procedure:
Sodium borohydride (158 mg, 4.18 mmol) was added to a solution of 3-[(4-methoxy)phenoxy]benzaldehyde (573 mg, 2.51 mmol) in ethanol (10 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 25 min. The solvent was distilled off from the reaction mixture, and the residue was diluted with ethyl acetate, washed with water and brine in turn and dried. The solvent was distilled off and the residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=20) to give 3-[(4-methoxy)phenoxy]benzyl alcohol (469 mg, 81%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:32]2([CH3:33])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:24][C:25]([OH:27])=[O:26])[CH3:22])[CH2:12][C@@H:11]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:43][CH2:44][CH:45](O)[CH2:46][CH3:47].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Si:1]([O:8][C@@H:9]1[C@@:32]2([CH3:33])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:24][C:25]([O:27][CH:45]([CH2:46][CH3:47])[CH2:44][CH3:43])=[O:26])[CH3:22])[CH2:12][C@@H:11]([O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(O)CC
Reactant: C[C@H](OCC(=O)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)OC(=O)CO[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 36.5 %

Procedure:
[{1α,3β-Bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20(S)-yl}oxy]acetic acid (91 mg, 0.147 mmol) was treated with 3-pentanol (39 mg, 0.443 mmol), N,N′-dicyclohexylcarbodiimide (61 mg, 0.296 mmol) and 4-(dimethylamino)pyridine (54 mg, 0.443 mmol) in dichloromethane (1.5 ml) in the same manner as shown in Example 17(3) (at room temperature for 15 hours), followed by work up and purification using preparative thin layer chromatography (0.5 mm×3 plates, hexane:ethyl acetate=5:1, developed once) to give the titled compound (37 mg, 37%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][CH:20]\2O)=[CH:12][N:11]=[N:10]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:57]([OH:60])(=[S:59])[CH3:58].[Cl-].[Na+]>CN(C)C=O>[C:57]([S:59][CH:20]1[CH2:19][CH2:18][N:17]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16]/[C:15]/1=[CH:14]\[C:13]1[N:9]([CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:10]=[N:11][CH:12]=1)(=[O:60])[CH3:58]
Reactant: CC(O)=S
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of (E)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (14.34 g) in N,N-dimethylformamide (100 ml) was added N,N-dimethylformamide dineopentyl acetal (14.90 ml). Then thioacetic acid (3.58 ml) was added to the reaction mixture under ice-cooling. The resulting mixture was stirred at room temperature for 30 minutes and then N,N-dimethylformamide dineopentyl acetal (14.90 ml) and additional thioacetic acid (3.58 ml) were supplemented, and the resulting mixture was stirred for one hour. Further N,N-dimethylformamide dineopentyl acetal (14.90 ml) and thioacetic acid (3.58 ml) were added, and the resulting mixture was stirred for 30 minutes. Still further N,N-dimethylformamide dineopentyl acetal (14.90 ml) and thioacetic acid (3.58 ml) were added, and the resulting mixture was stirred for 30 minutes. Then aqueous sodium chloride solution was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was repeatedly purified for three times by silica gel chromatography using ethyl acetate and hexane (1:1 or 2:1) as the eluent to afford the less polar isomer title compound (7.45 g, yield: 47%), as a yellow foam and the more polar isomer 5-((acetylsulfanyl){1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (5.58 g, yield: 35%) as an orange-coloured foam, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]([S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH2:18]1>>[CH3:16][CH:17]1[N:22]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:21][CH2:20][N:19]([S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH2:18]1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 3-methyl-1-(2-naphthylsulphonyl)piperazine to give 3-methyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 32% yield;
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:22][N:23]([CH3:25])[NH2:24]>>[CH3:22][N:23]([CH3:25])[NH:24][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: CN(C)N
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 59 %

Procedure:
As described for example 26d, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) was converted, using N,N-dimethylhydrazine instead of 4-aminotetrahydropyran, to the title compound (65 mg, 59%) which was obtained as a colorless oil. MS: m/e=322.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:38])[CH:23]2[CH2:26][CH:25]([NH:27]C(=O)OCC3C=CC=CC=3)[CH2:24]2)[O:12]1.C(Cl)Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:38])[CH:23]2[CH2:24][CH:25]([NH2:27])[CH2:26]2)[O:12]1
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(N)C1
Temperature: 35 °C
Reaction time: 5 h
Yield: 42.3 %

Procedure:
To a solution of benzyl (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)carbamate (190 mg, 0.17 mmol) and Pd(OH)2 (14 mg, 0.1 mmol) in MeOH (5 mL) was charged with H2. The reaction was stirred at 35° C. for 5 h. The reaction was filtered with Celite and concentrated to dryness. The residue was purified by prep-TLC (DCM:MeOH=10:1) to the desired compound (28 mg, yield 42%). 1HNMR (500 MHz, MeOD): δH 8.29 (s, 1H), 8.21 (s, 1H), 6.19 (d, J=2.0 Hz, 1H), 5.51 (dd, J=6.5 and 2.0 Hz, 1H), 5.00 (dd, J=6.0 and 3.5 Hz, 1H), 4.34 (d, J=8.5 Hz, 1H), 3.14-3.11 (m, 1H), 2.60-2.57 (m, 1H), 2.52-2.48 (m, 2H), 2.34-2.31 (m, 2H), 2.10 (s, 3H), 1.66 (q, J=10.0 Hz, 1H), 1.58 (s, 3H), 1.48 (q, J=10.0 Hz, 1H), 1.37 (s, 3H) ppm; ESI-MS (m/z): 390.2[M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][NH:22][C:21]4=[O:25])[N:12]=3)=[CH:10][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:27]=[CH:26][C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][NH:22][C:21]4=[O:25])[N:12]=3)=[CH:10][C:6]=2[CH:5]=1
Reactant: O=C1NCCN1CCNc1nccc(-c2cc3cc([N+](=O)[O-])ccc3s2)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2sc(-c3ccnc(NCCN4CCNC4=O)n3)cc2c1
Reaction time: 5 h

Procedure:
A mixture of 1-(2-(4-(5-nitrobenzo[b]thiophen-2-yl)pyrimidin-2-ylamino)ethyl)imidazol-idin-2-one (50 mg) and palladium (10% on activated carbon, 10 mg) in ethanol (10 mL) was stirred under hydrogen (1 atm) for 5 h. The mixture was filtered through Celite and washed with methanol/dichloromethane. The solvent was removed in vacuo and the product was purified by flash chromatography eluting with NH3 in methanol (1 M)/DCM (1:20) to give the title compound as a slightly yellow solid (32 mg, 69%). MS (M+H)+ 355.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[CH2:41]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[CH3:42]>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[C:2]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([CH2:41][CH3:42])[CH:44]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Product: CCc1cccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)c1
Yield: 97.7 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid (145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH2:23]([O:30][C:31]1[C:32](Cl)=[N:33][S:34][N:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:23]([O:30][C:31]1[C:32]([O:22][C:3]2[CH:4]=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]3=[O:21])[C:6]([F:8])=[CH:7][C:2]=2[Cl:1])=[N:33][S:34][N:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1nsnc1OCc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3OCc3ccccc3)c(Cl)cc2F)c1=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
To a solution of 0.60 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol and 0.50 g of 4-benzyloxy-3-chloro-1,2,5-thiadiazole in 8 ml of dimethyl sulfoxide, 0.25 g of potassium carbonate was added, and stirred for 30 minutes at 50° C., and for 3 hours at 100° C. The reaction solution was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.27 g of 4-benzyloxy-3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-1,2,5-thiadiazole (purity: 44%)
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:10][C@H:9]2[NH:11][C@H:6]([CH2:7][CH2:8]2)[CH2:5]1.F[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[CH3:3][N:4]1[CH2:10][C@H:9]2[N:11]([C:13]3[CH:18]=[N:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C@H:6]([CH2:7][CH2:8]2)[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: CN1C[C@H]2CC[C@@H](C1)N2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C[C@H]2CC[C@@H](C1)N2c1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of (1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (981 mg, 4.93 mmol), 5-fluoro-2-nitropyridine (100 mg, 4.93 mmol), and triethylamine (4.99 g, 49.3 mmol) in DMSO (8 ml) was heated to 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride, and water. The organic phase was then concentrated and triturated with ether to give desire product as a yellow solid (1 g, 81.8%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.O.[C:51]([C:54]1[CH:61]=[CH:60][C:57]([CH:58]=O)=[CH:56][CH:55]=1)([OH:53])=[O:52]>CO.[Pd]>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:58]([C:57]4[CH:60]=[CH:61][C:54]([C:51]([OH:53])=[O:52])=[CH:55][CH:56]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Agent: [Pd]
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Yield: 80 %

Procedure:
The title compound was prepared from 1,3-bis(cyclohexylmethyl)-5,6-aminouracil by the method of J. Perutmattam, Syn. Commun. 1989, 19:3367-3370. 1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was freshly prepared by shaking a mixture of 6-amino-1,3-bis(cyclohexylmethyl)-5-nitrosouracil (from step (c) example 1, 2.00 g, 5.74 mmol) in methanol (250 mL)-water (25 mL) with 10% palladium on carbon (0.20 g) under hydrogen (40 psi) on a Parr shaker for 2 h. The catalyst was filtered off (Celite) and the colorless filtrate was concentrated to 50 mL. 4-Carboxybenzaldehyde (Aldrich, 860 mg, 5.73 mmol) was added to this solution of 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil. The resulting yellow mixture was concentrated and the residual yellow solid dried by evaporation of several portions of absolute ethanol. The yellow powder (Schiff base) was then stirred in dimethoxyethane (80 mL) with iodine (1.6 g, 6.30 mequiv) at 60° C. (oil bath) for 24 h. A saturated aqueous solution of sodium thiosulfate (~15 mL) was added to the warm reaction mixture until complete decolorization of iodine resulted. The pale yellow precipitate was filtered off, washed with water, and dried at 0.5 Torr to give 4-[1,3 bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid as a pale yellow powder (2.13 g, 80%), m.p. >300° C.; 1 H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].CC1C=CC(S(O[CH2:17][CH:18]2[CH2:22][S:21][C:20]3([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]3)[O:19]2)(=O)=O)=CC=1>CC(C)=O>[C:1]([S:3][CH2:17][CH:18]1[CH2:22][S:21][C:20]2([CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)[O:19]1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)CC1CCC2(C1)OC(COS(=O)(=O)c1ccc(C)cc1)CS2
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC2(C1)OC(CSC(C)=O)CS2

Procedure:
A stirred slurry of potassium thioacetate (1.14 g, 10 mmol) in a solution of the tosylate of Example P (4.15 g, 10 mmol) in acetone (30 ml) is refluxed under nitrogen for 5 hrs. The reaction mixture is filtered and the filtrate is concentrated on a rotary evaporator. The residue is dissolved in ethyl acetate, washed with water and dried over sodium sulfate. The drying agent is filtered, the solvent is removed using the rotary evaporator and the residue is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the titled compound.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O>Br>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Agent: Br
Product: CC(C)(C)CC[C@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
(2S,4S)-Methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (341 mg, 1.1 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 20 mL) and the mixture was stirred at room temperature for 24 h. The solvent was evaporated and the compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 15 minutes with a flow of 100 mL/min. 5-((2S,4S)-2-(3,3-Dimethylbutyl)piperidin-4-yl)-isoxazol-3(2H)-one (235 mg, 85%) was isolated. 1H NMR (600 MHz, cd3od) δ 0.90 (s, 9H), 1.22-1.34 (m, 2H), 1.43-1.78 (m, 4H), 2.10 (d, 1H), 2.22 (d, 1H), 2.85-2.94 (m, 1H), 2.98-3.07 (m, 2H), 3.40 (d, 1H), 5.46 (s, 1H). HRMS Calculated for [C14H24N2O2+H]+: 253.1916. Found: 253.1898