Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)cc1
Reaction time: 4 h
Yield: 66.1 %

Procedure:
5-(4-Aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.5 g, 2.3 mmol) was dissolved in pyridine (5 mL), methane sulfonyl chloride (0.16 mL, 2.1 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture diluted with ethyl acetate and the mixture was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]methanesulfonamide (0.382 g).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:31]([N:33]([CH2:36][CH2:37]Cl)[CH2:34][CH3:35])[CH3:32].[I-].[Na+]>CN(C=O)C>[CH2:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH2:35][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3)[CH3:32]
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 62.8 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.048 g, 0.159 mmol), potassium carbonate (0.044 g, 0.318 mmol), and DMF (1.0 mL) at 100° C. is added diethylaminoethyl chloride hydrochloride (0.033 g, 0.191 mmol) in aliquots over 1 h. After 5.5 h, an additional 0.011 g of diethylaminoethyl chloride hydrochloride is added, and one hour later, a few crystals of sodium iodide are added. After heating for ten hours, the mixture is allowed to stir at room temperature for the remainder of the night. Additional potassium carbonate (0.022 g) and diethylaminoethyl chloride hydrochloride (0.017 g) are added and the mixture is stirred at 100° C. for 1.5 h. The major portion of the DMF is distilled off and the residue is partitioned between dichloromethane and water. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel (17 mL) using EtOAc/dichloromethane (30/70 to 60/40) to give 0.040 g of N,N-diethyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.CC([O-])=O.[K+].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][CH:33]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C>CCOC(C)=O.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].CC(O)C>[C:7]([C:6]1[C:2]([NH:1][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[CH:34][CH:33]=2)=[N:3][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)[CH:5]=1)(=[O:9])[NH2:8]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(N)=O)c(N)n2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCc1cc(CCC)c(-c2c(C)c(C)c(C)c(C)c2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COC(=O)Cc1ccc(Nc2nn(C3(CC#N)CCN(C(=O)OC(C)(C)C)CC3)cc2C(N)=O)cc1
Temperature: 95 °C

Procedure:
To a microwave vessel was added tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 47-1, 0.30 g, 0.86 mmol), KOAc (127 mg, 1.29 mmol), methyl (4-bromophenyl)acetate (237 mg, 1.03 mmol) and 2-propanol (4.3 mL). The mixture was degassed for 5 minutes by bubbling argon gas. Pd2(dba)3 (39 mg, 0.04 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-1-propylbiphenyl (83 mg, 0.17 mmol) were added, the vial was sealed and heated at 95° C. for 18 hours. The mixture was cooled to ambient temperature, then diluted with EtOAc and washed with H2O. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 50-100% EtOAc/hexanes) to afford the title compound. 1H NMR (600 MHz, Acetone-d6): δ 9.17 (s, 1H), 8.45 (s, 1H), 7.52-7.55 (m, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.14 (brs, 1H), 6.51 (brs, 1H), 3.80-3.90 (m, 2H), 3.60 (s, 3H), 3.53 (s, 2H), 3.15 (s, 2H), 3.00-3.18 (m, 2H), 2.52-2.60 (m, 2H), 2.04-2.12 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:5]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:37][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:31][C:32]=2[CH3:48])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-methyl-2-p-tolyloxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.05 (bs, 1H), 8.02-7.96 (m, 2H), 7.51-7.45 (m, 3H), 7.18 (d, 2H, J=8.4 Hz), 7.05 (d, 2H, J=8.4 Hz), 6.81 and 6.81 (d of Abq, 4H, J=8.0 Hz), 4.22 (t, 2H, J=6.0 Hz), 3.23 and 3.11 (d of Abq, 2H, J=14.0 Hz), 3.06 (t, 2H, J=6.0 Hz), 2.42 (s, 3H), 2.28 (s, 3H), 1.38 (s, 3H). IR (KBr) 3420, 1718, 1712, 1508, 1228 cm−1. HRMS (ES+) m/z exact mass calcd for C29H30NO5 472.2124, found 474.2139.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1.O>CN(C=O)C>[CH2:17]([NH:16][C:11]1=[N:12][C:13](=[O:15])[S:14]/[C:10]/1=[CH:9]\[CH:6]1[CH2:7][CH2:8][N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=2)[CH2:4][CH2:5]1)[C:18]#[CH:19]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (300 mg) in DMF (3 mL) were added potassium carbonate (517 mg) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.15 mL). The reaction mixture was stirred at room temperature for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (64 mg).
Reaction SMILES: [S:1](Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([NH2:17])[C:9]([NH2:16])=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C>ClCCl>[Br:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2=[N:16][S:1][N:17]=[C:8]2[CH:7]=1
Reactant: Nc1cc(Br)c(C(F)(F)F)cc1N
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc2nsnc2cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
Thionyl chloride (373 mg, 3.1 mmol) in dichloromethane (0.8 mL) was added dropwise to a refluxing solution of diamine 18 (500 mg, 2.0 mmol) and triethylamine (794 mg, 7.8 mmol) in dichloromethane (8.0 mL). The mixture was refluxed with stirring for 4 h. The mixture was then cooled to room temperature, quenched with water (20 mL), and extracted with dichloromethane (3×75 mL). The combined extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-25% ethyl acetate in hexane) provided 19 (377 mg, 68%) as a solid: LRESIMS m/z 294.1.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14].O>ClCCl>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[S:2]([Cl:1])(=[O:5])=[O:3])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(S(=O)(=O)Cl)c2c1
Yield: 51 %

Procedure:
A solution of chlorosulfonic acid (3 mL, 45 mmol) and Na2SO4 (700 mg, 4.9 mmol) in dichloromethane (30 mL) was treated dropwise with a solution of 5-nitroindole (800 mg, 4.9 mmol) in dichloromethane (20 mL) over 1 hour, stirred for another 30 minures, and decanted to provide a thick brown oil. The oil was slowly treated with water (20 mnL), stirred for 10 minutes, filtered, and dried in a vacuum oven to provide 651 mg of the desired product.
Reaction SMILES: N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(OC)(OC)(OC)C.[CH:27]([N:30](CC)[CH:31](C)C)(C)[CH3:28].Cl.CN>C(#N)C>[NH2:16][C:15]1[N:30]([CH3:31])[C:27]([CH3:28])=[N:13][C:14]=1[C:17]#[N:18]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CC(N)C#N
Agent: CN
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: Cc1nc(C#N)c(N)n1C
Temperature: 25 °C
Yield: 55.5 %

Procedure:
Dry ammonia was bubbled through a stirred solution of aminomalononitrile p-toluenesulfonate (30.0 g, 119 mmol) in anhydrous acetonitrile (800 mL). The reaction warmed slightly, and precipitate formed. The precipitate was removed by filtration, and the filtrate was concentrated to a volume of about 600 mL. Trimethyl orthoacetate (14.3 g, 119 mmol) was added, and the resulting solution was heated at reflux for 30 minutes and then allowed to cool to room temperature. N,N-Diisopropylethylamine (15.36 g, 119 mmol) and methylamine hydrochloride (8.03 g, 119 mmol) were sequentially added, and the resulting dark red solution was heated at reflux and then cooled to 0° C. Brown crystals formed and were isolated by filtration to provide 9 g of 5-amino-1,2-dimethyl-1H-imidazole-4-carbonitrile. The filtrate was concentrated under reduced pressure, and the resulting oil was triturated with 20% w/w aqueous sodium hydroxide to provide a yellow solid that was isolated by filtration provide 2 g of 5-amino-1,2-dimethyl-1H-imidazole-4-carbonitrile. The total yield of 5-amino-1,2-dimethyl-1H-imidazole-4-carbonitrile was 68%.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CO>C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:20][C:19]2[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: Brc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The method of Taguchi and Westheimer1 was modified as follows: benzophenone (455 g, 2.50 mol) and 4-bromoaniline (473 g, 2.75 mol) were dissolved in toluene (1.2 L) under argon in a 5 L flask containing activated molecular sieves (5 Å, 1.25 kg). The flask was fitted with a reflux condenser, rubber septum, and pressure outlet. The mixture was heated to gentle reflux and shaken occasionally; an intense yellow color soon developed. After 18 h, heating was discontinued and the solution was cooled to rt. The solution was decanted from the molecular sieves, and the sieves were washed with Et2O until the filtrate was colorless. The combined organic solutions were concentrated in vacuo to give an orange oil. MeOH (ca. 80 mL) and a seed crystal of 1 were added. The product was allowed to crystallize at 0° C. and the precipitate was collected by filtration. The mother liquor was further concentrated, and a second crop of crystals was collected from MeOH. Recrystallization of the combined material from MeOH afforded yellow crystals (760 g, 90%). 1: mp 82-83° C.; 1H NMR (300 Mz, CDCl3) δ 7.75 (dd, J=6.9, 1.6 Hz, 2H), 7.52-7.39 (m, 3H), 7.32-7.23 (m, 5H), 7.11 (dd, J=8.5, 2.0 Hz, 2H), 6.61 (dt, J=8.5, 2.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 168.7, 150.4, 139.5, 136.1, 131.6, 131.0, 129.5, 128.8, 128.3, 128.2, 122.8, 116.3, 103.6;IR(CDCl3) 3058, 3024, 1615, 1478 cm−1; Anal. Calcd for C19H14BrN: C, 67.87; H, 4.20. Found: C, 68.08; H, 4.28.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[C:5]([OH:8])=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:38]=[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][C:29]=3[C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:22][CH:21]=1>CC(O)C.O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[C:9]([C:4]1[N:3]=[C:2]([C:36]3[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:28]4[O:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)=[C:30]([C:31]([NH:33][CH3:34])=[O:32])[C:29]=4[CH:35]=3)[CH:7]=[N:6][C:5]=1[OH:8])[NH:10]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Oc1ncc(Br)nc1-c1cc2c(F)cccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc(O)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a degassed solution of 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyrazin-2-ol (prepared using similar method described in Example 1, 1.23 g, 3.98 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (2 g, 3.98 mmol) and K3PO4.3H2O (2.12 g, 7.96 mmol) in IPA (20 mL) and H2O (2 mL) was added Pd2(dba)3 (50 mg) and X-Phos (50 mg) under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 16 h, concentrated in vacuo to remove IPA. The residue was diluted with H2O and extracted with DCM. Then the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (PE:EA=1:2) to give 5-(6-(4-fluoro-1H-indol-2-yl)-5-hydroxypyrazin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, yield: 41%). 1H-NMR (CDCl3, 400 MHz) δ 8.52 (d, J=4.0 Hz, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.42 (t, J=8.8 Hz, 2H), 7.33˜7.36 (m, 2H), 7.11˜7.18 (m, 2H), 6.80 (dd, J1=10.4 Hz, J2=8.0 Hz, 2H), 3.27 (s, 3H), 3.10 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 604.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>O>[N:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(N=[N+]=[N-])ncnc2OCCO)cc1
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g), sodium azide (10.7 g) and dimethyformamide (260 ml) is heated with stirring at 75°-80° C. overnight. After cooling, the mixture is treated with water, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is crystallized from hexane to give 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (19.6 g).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[O:18])=[CH:10][CH:9]=1)([O-])=O>[Zn].O>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[O:18])=[CH:12][CH:13]=1
Reactant: O=C(CCCc1ccc([N+](=O)[O-])cc1)N1CCSC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CCCC(=O)N2CCSC2)cc1
Yield: 67 %

Procedure:
To a mixture of 9 ml of acetic acid, 6 ml of water, and 1.0 g of zinc powder was gradually added 2 mmol of N-[4-(4-nitrophenyl)butanoyl]thiazolidine at room temperature in small portions with stirring. After the addition, the mixture was stirred for 2 hours at the same temperature to complete the reaction. Zinc powder was removed by filtration. The filtrate was weakly alkalinized with 10% sodium hydroxide and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel to obtain 335 mg of colorless crystals of N-[4-(4-aminophenyl)butanoyl]thiazolidine (yield: 67%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCN(Cc2ccc(Br)cc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(Br)cc2)CC1)c1ccccc1
Yield: 83.5 %

Procedure:
0.108 g (0.0004 mol) of 1-(4-bromo-benzyl)-piperidin-4-ol and 0.12 ml (0.00085 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.125 g (83.5%) of 1-(4-bromo-benzyl)-piperidin-4-yl benzoate was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:17]2>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][NH:28][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: NCCCN1CC2CCC(CC2)C1
Reactant: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Product: Cc1nnc(NCCCN2CC3CCC(CC3)C2)c2cc3n(c12)CCCC3

Procedure:
Following the procedure in Example 9, compound XII was allowed to react with 3-(3-azabicyclo[3.2.2]non-3-yl)propylamine to give the title compound which was converted to the dihydrochloride salt: m.p.278°-279° C.
Reaction SMILES: Cl[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:18]2[C@@H:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]2)[C@@H:13]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[O:12]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)C.C(N(CC)CC)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:22][CH2:21][C@@H:13]1[C@H:14]2[C@@H:18]([O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:12]1
Reactant: NC1CCCC1
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21

Procedure:
To a solution of 1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzene, a compound of formula (3), (0.125 g, 2.86 mmoles) in 10 mL of ethanol and 1 mL of triethylamine was added cyclopentylamine in excess, and the mixture refluxed under nitrogen for 24 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC using 1:1 EtOAc:Hexanes to give (9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine, a compound of formula (4), as a yellow oil (80 mg, 56%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]([NH2:10])[CH2:8][S:7][C:6]=2[CH:11]=1.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]([NH:10][C:20]([C:17]3([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]3)=[O:21])[CH2:8][S:7][C:6]=2[CH:11]=1
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: NC1CSc2cc(Br)ccc21
Product: O=C(NC1(C(=O)NC2CSc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as yellow oil. MS: 455.4 (M−H−).