Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:12][C:13]([F:43])([F:42])[C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][N:26]([CH3:41])[C:27](=[O:40])[CH:28](OS(C)(=O)=O)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(N(CC)CC)C>CC(C)=O>[F:12][C:13]([F:42])([F:43])[C:14]1[CH:15]=[C:16]([CH2:24][CH2:25][N:26]([CH3:41])[C:27](=[O:40])[CH:28]([N:8]2[CH2:7][CH2:6][CH:5]([NH:4][C:3]([NH:2][CH3:1])=[O:11])[CH2:10][CH2:9]2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=1
Reactant: CNC(=O)NC1CCNCC1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)NC1CCN(C(C(=O)N(C)CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Yield: 32.8 %

Procedure:
6.8 g of 4-(3-methylureido)-piperidine are refluxed together with 19.2 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide (prepared analogously to the method described in WO 99/62893) and 6.8 ml of triethylamine in 400 ml of acetone for 8 hours. Then the solution is evaporated down, combined with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract is dried, the solvent is eliminated in vacuo and the residue is chromatographed with methylene chloride/methanol 9:1 over silica gel. The fractions found to be uniform by TLC are combined and the solvent is eliminated in vacuo. N-[2-(3,5-bis-tifluormethyl-phenyl)-ethyl]-N-methyl-2-[4-(3-methyl-ureido)-piperidin-1-yl]-2-phenyl-acetamide is crystallised from the residue with ethanolic hydrochloric acid and ether in the form of the hydrochloride, yielding 7.1 g of colourless crystals. 1H-NMR (250 MHz, CD3OD) δppm=7.93-7.33 (8H, m); 5.58; 5.38 (1H, 2s); 4.03-2.59 (5H, m); 3.05 (4H, m); 2.98; 2.90 (3H, 2s); 2.74; 2.70 (3H, 2s); NH in the solvent blind peak 4.89; 2.27-1.52 (4H, m). Most signals are split by amide rotation.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[C:47]1(C=O)[CH2:51][CH2:50][CH2:49][CH:48]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.ClCCl>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][N:10]1[CH2:11][C@@H:12]([CH3:13])[C@@:8]([CH2:7][C:6]([OH:5])=[O:39])([C:23](=[O:24])[NH:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:47]3[CH2:51][CH2:50][CH2:49][CH:48]=3)[CH2:30][CH2:31]2)[CH2:9]1
Reactant: Cc1cccc(Cl)c1CN1C[C@@H](C)[C@@](CC(=O)OC(C)(C)C)(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: O=CC1=CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(Cl)c1CN1C[C@@H](C)[C@@](CC(=O)O)(C(=O)NC2CCN(CC3=CCCC3)CC2)C1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
A mixture of tert-butyl 4-[(3R*,4S*)-3-[(2-tert-butoxy)-2-oxoethyl]-1-[(2-chloro-6-methylphenyl)methyl]-4-methylpyrrolidin-3-amido}piperidine-1-carboxylate obtained in Example 8a (237 mg, 0.42 mmol), trifluoroacetic acid (2.3 ml, 31 mmol) and dichloromethane (dehydrated) (2.3 ml) was stirred at mom temperature for three hours and 30 minutes. The reaction mixture was concentrated, and cyclopent-1-ene-1-carbaldehyde obtained in Example 7a (121 mg, 1.26 mmol), triethylamine (0.176 ml, 1.26 mmol) and tetrahydrofuran (5 ml) were added to the resulting residue, followed by stirring for 35 minutes. Sodium triacetoxyborohydride (267 mg, 1.26 mmol) was added to the reaction mixture, which was stirred at room temperature for 13 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (ODS silica gel, elution solvent: water/methanol) twice to give the title compound (88 mg, yield 42.9%).
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:11][CH2:10][CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1>CO>[ClH:1].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccs2)C1
Agent: Cl
Solvent: CO
Product: NC1CCN(c2nccs2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
Aq. conc. hydrochloric acid (2 ml) was added to a solution of 890 mg (3.3 mmol) of tert.-butyl 1-(thiazol-2-yl)pyrrolidin-3-ylcarbamate in MeOH (20 ml). The reaction solution was stirred at RT for 16 h and then evaporated under a vacuum. 653 mg (3.2 mmol, 97%) of 1-(thiazol-2-yl)pyrrolidin-3-amine hydrochloride were obtained by crystallising the residue from an ethanol/ether mixture.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](C)[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1
Reactant: CN1CC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CC2CNCC2C1

Procedure:
A solution of 2-benzyl-5-methyloctahydropyrrolo[3,4-c]pyrrole (2.4 g) in methanol (60 ml) was mixed with ammonium formate (2.1 g) and palladium on carbon (5%, 0.12 g), and the mixture was refluxed for 8 hours. After cooling, the reaction solution was filtered and concentrated. The crude product could be directly reacted further. The product with the molecular weight of 126.20 (C7H14N2); MS (ESI): 127 (M+H+) was obtained in this way.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:27][NH:26][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: COCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 2-methoxyacetohydrazide 218 (0.141 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 219 (0.27 g, 82%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[N:17]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[N:17]1
Reactant: C#CC1CC1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1)C(F)(F)F
Yield: 7.6 %

Procedure:
The title compound was prepared according to the procedure described in Example 111 using N-(4-chloro-3-(3-(4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)-2,2,2-trifluoroacetamide (Intermediate-146, 0.300 g, 0.568 mmol), ethynylcyclopropane (0.056 g, 0.852 mmol), TBAF (0.444 g, 1.72 mmol), bis(triphenylphosphine)palladium(II) chloride (0.016 g, 0.022 mmol) and DMSO (3.0 mL) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.75 (m, 2H), 0.90 (m, 2H), 1.55 (m, 1H), 4.43 (d, J=6.0 Hz, 2H), 7.38 (d, J=6.6 Hz, 1H), 7.46-7.51 (m, 3H), 7.64 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 10.06 (m, 1H), 12-13 (br s, 1H). MS (m/z): 461.12 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]([C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:31]=[O:32]>CCN(CC)CC>[CH2:1]([CH:8]1[CH:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=2)[CH2:12][CH2:11][N:10]([C:31]([NH:30][C:33]2[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccccc1N=C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NC(=O)N1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2ccccc2)C1
Yield: 57456.6 %

Procedure:
The compound (0.15 g) obtained in Example 404 and ethyl 2-isocyanatobenzoate (0.076 mg) were reacted and treated in the same manner as in the method described in Example 6 excluding Et3N to obtain the title compound as pale yellow oil (0.139 g, 64%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13](=[NH:17])[O:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.OP([O-])(O)=O.[Na+].O.O.O.O.O.O.O.OP([O-])([O-])=O.[Na+].[Na+].[N:39]#[C:40]N>C(#N)C.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:13](=[N:17][C:40]#[N:39])[O:14][CH2:15][CH3:16])[CH2:10][CH2:11][CH2:12]2)=[CH:7][CH:8]=1
Reactant: CCOC(=N)C1(c2ccc(Cl)cc2)CCC1
Reactant: N#CN
Agent: Cl
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: CCOC(=NC#N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 3A (2.5 g, 9.1 mmol) in acetonitrile (7 mL) was added a solution of sodium phosphate monobasic monohydrate (5.0 g, 36.5 mmol), sodium phosphate dibasic heptahydrate (4.9 g, 18.2 mmol), and cyanamide (0.8 g, 18.2 mmol) in water (70.0 mL). The reaction mixture was stirred at room temperature for 72 hours, and then the mixture was extracted with methylene chloride (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the titled compound. MS (ESI+) m/z 263 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:20])=[C:7]([C:14]#[C:15][Si](C)(C)C)[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OC)(C)(C)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:20])=[C:7]([C:14]#[CH:15])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1c(N)c(C#C[Si](C)(C)C)cc2cn[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C#Cc1cc2cn[nH]c2c(C(=O)OC)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of 500 mg (1.74 mmol) of 6-amino-5-trimethylsilanylethynyl-1H-indazole-7-carboxylic acid methyl ester in 17 mL of anhydrous tetrahydrofuran under an atmosphere of argon is added 2.6 mL (2.6 mmol) of a 1 M solution tetrabutylamonium fluoride in tetrahydrofuran. The reaction mixture is stirred at ambient temperature for 2 hours. Water and tert-butylmethylether are added and the two phases are separated. The aqueous layer is extracted with tert-butylmethylether. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is suspended in hexanes. Filtration affords 210 mg (56%) of the product as a yellowish solid; LC/MS:216/217 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[N:20](COCC[Si](C)(C)C)[N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC(N)(C)C1)=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH3:38])([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:37])[C:19](=[O:36])[NH:20][N:21]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1C(=O)NN=C2COc3ccc(NC4(C)CCN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 80 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
A mixture of 3-methyl-3-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared using a similar procedure as detailed in Example #162, Step C from 3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 1.1 g, 2.016 mmol) in a solution of TBAF in THF (1 M, 20 mL, 20 mmoL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to ambient temperature and diluted with water (25 mL). The aqueous solution was extracted with EtOAc (3×25 mL) and the combined organic phase was washed with brine (10 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum) to give 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 54%). LC/MS (Table 1, Method 2) Rt=0.890 min; MS m/z: 438 [M+Na]+.
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.[CH:38]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39]1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:42](=[O:43])[CH2:41][CH:38]2[CH2:40][CH2:39]2)[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: O=C(O)CC1CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)CC2CC2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 12 h
Yield: 45.5 %

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (0.500 g, 1.31 mmol) in CH2Cl2 (20 mL) was added 4-(dimethylamino)pyridine (0.478 g, 3.91 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.300 g, 1.57 mmol), and 2-cyclopropylacetic acid (0.146 mL, 1.57 mmol). The reaction was stirred for 12 h. Additional CH2Cl2 (80 mL) was added and the organic layer was washed once with saturated aqueous NaHCO3 (10 mL). The organic layer was then dried (MgSO4) and concentrated in vacuo. Flash chromatography of the crude material on silica gel (3:2 EtOAc:hexanes) afforded (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(2-cyclopropylacetamido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.256 g, 56% yield).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCCOc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Cyclohexyl{3-methyl-5-[3-(methylsulfanyl)propoxy]-1-benzofuran-2-yl}methanone (3.1 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (50 mL) and methanol (10 mL), and sodium borohydride (90%, 0.73 g) was added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (5 mL) and 1N hydrochloric acid (25 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.0 g, 95%) as a pale-yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](O)=O.[NH2:9][C:10]1[C:11](=[O:24])[N:12]([CH2:21][CH2:22][CH3:23])[C:13](=[O:20])[N:14]([CH2:17][CH2:18][CH3:19])[C:15]=1[NH2:16].Cl.[OH-].[Na+]>O>[CH2:21]([N:12]1[C:11](=[O:24])[C:10]2[NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:16][C:15]=2[N:14]([CH2:17][CH2:18][CH3:19])[C:13]1=[O:20])[CH2:22][CH3:23]
Reactant: O=C(O)c1ccco1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccco3)nc2n(CCC)c1=O
Reaction time: 2 h

Procedure:
The starting 1,3-dipropyl-8-(2-furanyl)xanthine is prepared as follows: 1.8 g (17 mmol) 2-furoic acid is added to a solution of 3.7 g, 5,6-diamino-1,3-dipropyluracil (17 mmol) (J. Am. Chem. Soc. (1954) 76 2798) in 50 ml water. The pH is adjusted to 5, then 3.2 g (17 mmol) ethyl-3-(3-dimethylamino) propylcarbodiimide is added. The pH is maintained between 5 and 6 using 1 N HCl. After 2 hours the pH stabilizes, and the solution is taken to pH 13 using 50% aqueous NaOH. The resulting mixture is refluxed for 30 minutes, activated carbon added, and filtered hot through celite. The filtrate is then extracted (3×100 ml CH2Cl2), dried (MgSO4), and concentrated to yield 1.7 g yellow solid. This is recrystallized from methanol to give the 1,3-dipropyl-8-(2-tetrahydrofuranyl)xanthine as white needles, mp 246°- 248° C. Analysis as C15H18N4O3 (302.3); Calculated: C, 59.59; H, 6.00; N, 18.53. Found: C, 58,86; H, 6.53; N, 19.45.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:21]([O:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=2)=[N:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:41]3[CH:40]=[CH:39][C:38]([C:35]4[N:36]=[CH:37][C:32]([O:31][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:33][N:34]=4)=[CH:43][CH:42]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCCCCCCCCCOc1cnc(-c2ccc(-c3ccc4c(c3)CC(CCCCCCCC)C4)cc2)nc1
Temperature: 0 °C
Yield: 82.1 %

Procedure:
0.30 g (1.09 mM) of 2-octylindan-5-boronic acid, 0.37 g (0.95 mM) of 5-decyloxy-2-(4-bromophenyl)pyrimidine, 1.8 ml of ethanol, 2.5 ml of benzene, 1.5 ml of 2M-sodium carbonate aqueous solution and 0.05 g of tetrakis (triphenylphosphine) palladium (O) were mixed and heat-refluxed for 4 hours under stirring. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration under reduced pressure and dissolved in toluene, followed by drying with anhydrous sodium sulfate. Then, the sodium sulfate was removed from the mixture and the resultant mixture was evaporated to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized two times from a mixture solvent (toluene/acetone) to obtain 0.42 g of 2-octyl-5-[4-(5-decyloxypyrimidine-2-yl)phenyl]indan (Yield: 82.1%). ##STR279##
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.N1C=CC=CC=1.[OH:31][NH2:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=[N:32][OH:31])[CH2:18][CH2:17]1
Reactant: NO
Reactant: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)Cn1c(CN2CCC(=NO)CC2)cc2cnc(C#N)nc21
Reaction time: 24 h
Yield: 97.9 %

Procedure:
To a solution of 100 mg (0.30 mmoles) of 7-(2,2-dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 0.047 ml (0.75 mmoles) of pyridine in 5 ml of CH2Cl2, 52 mg (0.75 mmoles) of hydroxyl amine is added at ambient temperature. After being stirred for 24 hours, the reaction mixture is quenched with H2O and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 100 mg of desired 7-(2,2-dimethyl-propyl)-6-(4-hydroxyimino-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 98% yield.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Cl[C:20]1[CH:29]=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=2)[N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:29]=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:26]=2)[N:21]=1)[CH3:2]
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc2nc(Cl)cnc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCSc1ccccc1-c1cnc2cc(C(F)(F)F)ccc2n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
A mixture of 0.52 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.46 g of 2-chloro-6-trifluoromethylquinoxaline, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl, 0.84 g of tripotassium phosphate and 6 ml of 1,4-dioxane was stirred at 70° C. for 2 hours. 0.30 g of tripotassium phosphate was added to the cooled reaction mixture, and the mixture was stirred under heat-reflux for 3 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.28 g of 2-(2-ethylsulfanylphenyl)-6-trifluoromethylquinoxaline (Compound of Present Invention 1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:10][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=2[CH3:22])(=[O:19])=[O:20])[S:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1csc(N)n1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Yield: 22 %

Procedure:
The title compound was prepared from 4-butyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 52 mg (22% yield): HRMS Calcd (found) for C14H17ClN2O2S2 m/z 344.0420 (334.0414).