Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][O:16][C@@H:17]2[C@@H:21]([CH2:22][OH:23])[O:20][C@@H:19]([N:24]3[CH:31]=[C:30]([F:32])[C:28](=[O:29])[NH:27][C:25]3=[O:26])[CH2:18]2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:1]([N:27]1[C:28](=[O:29])[C:30]([F:32])=[CH:31][N:24]([C@@H:19]2[O:20][C@H:21]([CH2:22][O:23][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:17]([O:16][CH2:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:34][CH:33]=3)[CH2:18]2)[C:25]1=[O:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccc(Cl)cc3)[C@@H](CO)O2)cc1F
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OCc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A 0.23 ml quantity of benzoyl chloride was added to a solution of 0.25 g of 3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine in pyridine. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off. To the residue were added ethyl acetate and water to separate the ethyl acetate layer. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was subjected to silica gel column chromatography using chloroform as an eluent, giving 0.27 g of the title compound in a yield of 70%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:28]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:29]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccccc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:22]([NH:26][C:2]1[N:6]([C@@H:7]2[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 148 °C
Yield: 61 %

Procedure:
A solution of (1R, 2S, 3S, 5S)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (500 mg, 1.26 mmole) was stirred in tert-butylamine (Aldrich, 98%, 20 mL) in a Parr bomb maintained at 148° C. (oil bath) for 48 hours. The bomb was cooled and the resulting pale yellow solution diluted with ethanol containing 1N sodium hydroxide (1.2 mL). Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Title compound was eluted with 10% methanol-chloroform as a colorless oil. The oil was dissolved in absolute ethanol, concentrated to an oil, and triturated with water (3 mL) to give (1R, 2S, 3S, 5S)-5-[2-(tert-butylamino)-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white powder (303 mg, 61%), m.p.: collapses to glass at 116°-150° C.; 1H-NMR(DMSO-d6)δ: 7.63 and 7.43 (both s, 2, aromatic CH), 6.15 (s, 1, NH), 5.08 (t, J=4.3 Hz, 1, OH), 4.85 (d, J=7.4 Hz, 1, OH), 4.71 (d, J=3.8 Hz, 1, OH), 4.7-4.5 (m, 1, NCH), 4.45-4.3 (m, 1, OCH), 3.80 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.2-1.85 (m, 3, CH2 and CH of cyclopentane), 1.47 (s, 9, 3 CH3); mass spectrum (CI): 388(M+1); [α]20589 -4.0°, [α]20578 -4.3°, [α]20546 -6.0°, [α]20436 -22.6°, [α]20365 -82.1° (c=0.420, methanol).
Reaction SMILES: [CH3:1][C@@:2]1(/[CH:28]=[CH:29]/[C:30]2[N:34]=[CH:33][O:32][N:31]=2)[S:8](=[O:10])(=[O:9])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].CCCCCC>C1C(O)=CC=CC=1C>[CH3:1][C@@:2]1(/[CH:28]=[CH:29]/[C:30]2[N:34]=[CH:33][O:32][N:31]=2)[S:8](=[O:9])(=[O:10])[C@H:7]2[N:4]([C:5](=[O:11])[CH2:6]2)[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: C[C@]1(/C=C/c2ncon2)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1(=O)=O
Solvent: CCCCCC
Solvent: Cc1cccc(O)c1
Product: C[C@]1(/C=C/c2ncon2)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
355 mg (0.74 mmol) of benzhydryl (E)-(2S,3S,5R)-3-methyl-3-[2-(1,2,4-oxadiazol-3-yl)-vinyl]-4,4,7-trioxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 3 ml of m-cresol and stirred at 50° C. for 4 hours. 20 ml of n-hexane are added to the pale brown solution, the separated crystals were filtered off under suction and rinsed with n-hexane. The crude crystallizate was recrystallized from ethyl acetate/n-hexane. Yield: 170 mg (73%) of colorless crystals MS: (M--H)- 312.2 IR (KBr): 2900(br), 1811, 1714, 1660, 1331, 1194, 980 cm-1M.p.: 161° C. (dec.) Elementary analysis: C11H11N3O6S (313.284) Calc. C 42.17 H 3.54 N 13.41 Found C 42.41 H 3.64 N 13.18
Reaction SMILES: [Br-:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br-:1].[CH2:2]([P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC
Agent: [Br-]
Product: CCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Decane bromide (7.0 g) and 10 g of triphenylphosphine were stirred at 120° C. under a nitrogen atmosphere for 8 hours. The mixture was recrystallized from acetone-ether to give 14.4 g of colorless, crystalline decyltriphenylphosphonium bromide.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:14]([NH:18][C:19]([C:21]1[N:22]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:24][NH:25][CH:26]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[OH-].[Na+]>O>[C:14]([NH:18][C:19]([C:21]1[N:22]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:24][N:25]([C:1](=[O:3])[CH3:2])[CH:26]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)N1CCNC=C1C(=O)NC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1C=C(C(=O)NC(C)(C)C)N(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
16.7 g (163 mmol) of acetic anhydride and 12.4 g (157 mmol) of pyridine were added to 20.00 g (88.8 mmol) of 1-acetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide and the mixture was stirred for 4 hours at 25° C. 100 ml of water was then added and the pH was adjusted to 6 with 30 ml of sodium hydroxide solution (20%). Extraction was then carried out by shaking with three times 100 ml of methyl ethyl ketone. The combined organic extracts were dried over magnesium sulfate, toluene was added and the mixture was concentrated. The vigorously foaming crude product crystallized and 11.40 g (48%) of the title compound was isolated in the form of a light brown solid. The melting point of the title compound was: 138.0° to 139.2° C. Other data concerning the title compound was:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=3[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>C(O)(=O)C>[Cl:21][C:20]1[C:15]2[C:14](=[O:22])[N:13]3[CH2:23][CH2:24][CH2:25][C@H:12]3[C:11]3[N:10]([CH:9]=[N:8][C:7]=3[C:5]3[O:6][C:2]([CH2:3][N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[CH:1][N:4]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
A solution of 1.07 g (0.003 mol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid prop-2-ynylamide in 10 ml of acetic acid was treated with 1.01 g (0.0045 mol) of N-iodosuccinimide. After stirring at room temperature for 12 hrs. the mixture was heated to 50° for a further 4 hrs. The dark suspension obtained was completely freed from solvent in a vacuum and dried azeotropically several times with toluene. The brown residue was dissolved in 1 0 ml of THF, treated at room temperature with 10 ml (0.073 mol) of dipropylamine and stirred at 50° for 2 hrs. The suspension obtained was completely freed from the solvents and the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the pale brown product was chromatographed over silica gel with dichloromethane/methanol 95:5 as the eluent and digested with diethyl ether. There was obtained 0.65 g (48%) of (S)-8-chloro-1-(5-dipropylaminomethyl-oxazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one; [α]D20 =+11.5° (MeOH, c=1%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[NH2:18]>C(O)(=O)C>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]=[N:18][C:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]=1[OH:16]
Reactant: NNc1nc2ccccc2s1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: CC(=O)O
Product: Oc1c(N=Nc2nc3ccccc3s2)c2ccccc2c2ccccc12
Temperature: 105 °C

Procedure:
A reaction flask was loaded with acetic acid (50 ml) and 9,10-phenanthrenequinone (4.2 g), and the temperature was raised to 105° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 2-hydrazinobenzothiazole (3.3 g) was added in three hours. After stirring at 100 to 110° C. for one hour, the reaction mixture was filtrated. The filtrated crystals were washed with methanol and dried to give intended crystals (3.9 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][NH2:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>CC(C)=O>[CH2:26]([O:28][C:29](=[O:30])[NH:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([O:13][C:12]2[CH:24]=[CH:25][C:9]([Cl:8])=[CH:10][CH:11]=2)=[CH:15][CH:16]=1)[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: NCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NCCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 7 h
Yield: 81.6 %

Procedure:
18.4 g of potassium carbonate, 8.0 g of 2-[p-(p-chlorophenoxy)phenoxy]ethylamine hydrochloride and 16.0 g of chloroformic acid ethyl ester in 210 ml of acetone are heated to reflux with stirring for 7 hours. Undissolved salt is vacuum filtered and washed well with acetone. The filtrate is evaporated in vacuo. The crystalline residue remaining is dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is recrystallized from diisopropyl ether to yield 7.3 g (81.5%) of 2-[p-(p-chlorophenoxy)phenoxy]ethylcarbamic acid ethyl ester, m.p.--99°-100° C.
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[P:15](Cl)(Cl)[Cl:16]>>[P:15]1([Cl:16])[O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:14]1
Reactant: ClP(Cl)Cl
Reactant: Oc1ccccc1-c1ccccc1O
Product: Clp1oc2ccccc2c2ccccc2o1
Yield: 81 %

Procedure:
A solution of 2,2'-biphenol (28.1 g, 0.151 mol) in 49 mL phosphorus trichloride was heated at reflux for 2 hours. The excess PCl3 was removed by distillation. The residue was purified by vacuum distillation (140°-143° C. at 0.5 mm Hg) to give 30.70 g (81% yield) 1,1'-biphenyl-2,2'-diyl phosphorochloridite (as a clear viscous oil which solidified to a white solid upon standing at room temperature in an inert atmosphere for an extended period of time). 31P{1H}NMR (121.4 MHz, d8 -toluene): δ 180.1 (s) , 85% H3PO4 external reference. To a solution containing 1.018 g (2.84 mmoles) of 2,2'-dihydroxy-3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl and 0.575 g (5.68 mmoles) of NEt3 in 15 ml of tetrahydrofuran (THF) was added 1.412 g (5.68 mmoles) of 1,1'-biphenyl-2,2'-diyl phosphorochloridite in 5 ml of THF. The mixture was stirred overnight at room temperature. The mixture was filtered through celite, washed with THF and solvent removed to give 2.2 g of white solid. 31P{1H} nmr (121.4 MHz, C6D6): 145.15 s and 138.5 s. 1H nmr (300 MHz,C6D6): singlet at 3.15 and 1.3 along with aromatic resonances.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1)#[N:3].C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1)#[N:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N#Cc1cc(F)cc(N2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)cc(N2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In 30 ml of dichloromethane was suspended 2.54 g of 1-(3-cyano-5-fluorophenyl)piperazine hydrochloride, and the suspension was cooled to 0° C. To the suspension were added 7.3 ml of triethylamine and 3 ml of 2,2,2-trichloroethyl chloroformate, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform as a developing solvent. The fraction containing the desired compound was concentrated to give 4.79 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[C:5](Cl)[N:4]=1.[CH3:20][NH2:21]>C1COCC1.[OH-].[Na+]>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[C:5]([NH:21][CH3:20])[N:4]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccccc2)n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNc1cc(NS(=O)(=O)c2ccccc2)nc(NC)n1
Temperature: 130 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
0.25 g (0.00084 mol) of N-(2-methylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of 2M methylamine in THF and stirred in an autoclave at 130° C. for 3 hours. The mixture was freed from solvent, the residue was dissolved in 25 ml of 2N NaOH, filtered and the pH value of the filtrate was adjusted to 6 with 1N HCl. The precipitate was filtered off under suction, dried and chromatographed on silica gel with dichloromethane/methanol 95:5. There was obtained 0.09 g (36%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide as yellowish crystals; m.p.: >260° C. (dec).
Reaction SMILES: N1C(N)=C2C(N=CN2)=NC=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1.Cl.[I:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>C(O)C>[I:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:14]1[N:13]=[C:12]([Cl:11])[N:20]=[C:19]2[C:15]=1[NH:16][CH:17]=[N:18]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cccc(I)c1
Agent: Cl
Agent: Nc1ncnc2nc[nH]c12
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2cccc(I)c2)c2[nH]cnc2n1

Procedure:
N6 -(3-iodobenzyl)-2-substituted adenosine derivatives can be synthesized from the corresponding adenine derivative. 2,6-Dichloropurine reacted with 3-iodobenzylamine hydrochloride in the presence of triethylamine in ethanol at room temperature provides N6 -(3-iodobenzyl)-2-chloroadenine, which can be silylated before coupling to yield the silylated derivative. The glycosidic bond is formed upon treatment of the 1'-O-acetyl riboside derivative N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide with the aforesaid 9-silylated adenine derivative in the presence of TMSOTf as a Lewis acid catalyst. Condensation of N-methyl 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronamide with the aforesaid 9-silylated adenine derivative produces ribose ring-opened product. Benzoyl groups of 2-chloro-N6 -(3-iodobenzyl)-9-[5-(methylamido)-2,3-di-O-benzoyl-β-D-ribofuranosyl]-adenine are deprotected with NH3 /MeOH to produce 2-chloro-N6 -(3-iodobenzyl)-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine, which reacted with various nucleophiles such as methylamine/THF and sodium thiomethoxide/DME yield compounds N6 -(3-iodobenzyl)-2-methylamino-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine and N6 -(3-iodobenzyl)-2-methylthio-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine. The benzoyl groups of 2-chloro-N6 -(3-iodobenzyl)-9-[2,3,5-tri-O-benzoyl-β-D-ribofuranosyl]-adenine can be similarly deprotected to produce the riboside derivative 2-chloro-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[N-:13]=[C:14]=S.[Br-].[OH-].[Na+]>CO>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[C:14]1[NH2:13]
Reactant: [N-]=C=S
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(N)nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N1-Methyl-4-nitro-benzene-1,2-diamine (5 g, 30 mmol) in MeOH was added bromide isothiocyanate (4.4 g, 42 mmol) and the mixture was stirred at rt. After 16 h. 6N NaOH solution was added to the reaction mixture until Ph˜10 and MeOH was then removed in vacuo. H2O was added and the solid was filtered and dried to give the title compound as an off white solid (5.2 g, 90%). MS (ESI) m/z=193 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](=[N:11][OH:12])[CH3:10])[CH:3]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18]Cl>CN(C)C=O>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH2:18][O:12][N:11]=[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: COc1cccc(F)c1CCl
Reactant: CC(=NO)c1cc(C)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CON=C(C)c1cc(C)cc(C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
On the other hand, 0.46 g (2.80 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone oxime was dissolved in 10 ml of N,N-dimethylformamide, and the resultant solution was added with 0.13 g (3.36 mmol) of sodium hydride (60%, oiliness) while cooling the solution with ice. Then, the obtained solution was stirred for 30 min. at the same temperature and subsequently added with the whole amount of the crude product of 2-fluoro-6-methoxybenzyl chloride obtained as described above while cooling the solution with ice. The resultant mixture was. further stirred for 40 min. at a room temperature, and the reacted mixture was poured into ice water and then subjected to an extraction with diethyl ether. The resultant nonaqueous layer was washed with water and the dried with anhydrous magnesium sulfate. The dried nonaqueous layer was then condensed under reduced pressure to obtain a crude product. Then, said crude product was purified by means of silica gel column chromatography (eluate; hexane:ethyl acetate=7:3 v/v) to obtain the target compound in an amount of 0.55 g. Melting point: 87-89° C.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A suspension of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 1.76 g, 6.05 mmol), 1-(benzyloxy)-4-isocyanatobenzene (1.50 g, 6.66 mmol) and triethylamine (2.11 mL, 15.1 mmol) in THF (15 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide N-[4-(benzyloxy)phenyl]-4-(2-tert-butylphenyl)piperazine-1-carboxamide (2.65 g, 99%) as a off white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC1CCN(Cc2ccccc2)CC1
Yield: 83.9 %

Procedure:
2.58 g (11.1 mmol) of 1-benzyl-4-hydroxypropylpiperidine and 3.26 ml (23.4 mmol) of triethylamine were dissolved in 50 ml of tetrahydrofuran, and 1.67 ml (21.6 mmol) of methanesulfonyl chloride wasaddeddropwise. After completion of the reaction, the mixture was partitioned between ethyl acetate and brine. The organic layer was dried over magnesium sulfate, and then evaporated, to give a crude product. The crude product was subjected to 50 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:1), to give 2.90 g (9.31 mmol, 83.9%) the title compound as a yellow oil. The physico-chemical data of the target compound was as indicated below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(OC1C=CC(C(F)(F)F)=CC=1C1[S:29][C:28]([NH:30][C:31](=[O:40])[C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[N:27][C:26]=1[C:41]([O:43][CH3:44])=[O:42])C=C>>[F:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[C:31]([NH:30][C:28]1[S:29][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:26]([C:41]([O:43][CH3:44])=[O:42])[N:27]=1)=[O:40]
Reactant: C=CCOc1ccc(C(F)(F)F)cc1-c1sc(NC(=O)c2c(F)cccc2F)nc1C(=O)OC
Reactant: COc1cccc(C=O)c1
Product: COC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(OC)c1

Procedure:
Compound 113 was prepared as from 3-methoxybenzaldehyde as described for the preparation of Compound 63.