Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:10][C:9]1([Cl:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:15][C:9]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH:8]1[C:6]([OH:7])=[O:5]
Reactant: COC(=O)C1(Cl)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(Cl)CC1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
158 g of methyl 2-tert-butoxycarbonyl-1-chloro-1-cyclopropanecarboxylate was dissolved in 350 ml of dichloromethane. Then 160 ml of trifluoroacetic acid was added thereto and the obtained mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and n-hexane was added to the residue. The crystals thus formed were collected by filtration and washed with n-hexane. Thus 116 g (yield 97%) of 2-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid was obtained as colorless crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(Cl)Cl.O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
1-Isopropylpiperazine (1.8 mL, 12.7 mmol, 2 equiv) was added to a cold (5° C.) solution of 2-chloro-5-nitropyridine (1 g, 6.3 mmol,) in DCM (5 mL). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with DCM and H2O. The aqueous layer was separated and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to provide 1.58 g of the title compound as a yellow solid: ESI-MS: 251.2 [M+H]+; tR=2.20 min.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[NH:3]1.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22](Br)[C:17]=2[O:16][CH2:15]1>>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:10]3([OH:11])[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=4)[NH:3][C:2]3=[O:1])[C:17]=2[O:16][CH2:15]1
Reactant: N#Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Brc1cccc2c1OCO2
Product: N#Cc1ccc2c(c1)C(O)(c1cccc3c1OCO3)C(=O)N2

Procedure:
With 1.70 g of 2,3-dioxo indoline-5-carbonitrile and 1,3-benzodioxol-4-yl bromide (13 ml) as starting materials, 1.37 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: N#Cc1ccc(N)cc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Nc3ccc(C#N)cc3)c2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-7-methoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 371(MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[CH3:24]>>[CH2:23]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH3:24]
Reactant: CCBr
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Product: CCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1

Procedure:
For example, using 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole as compound "E" in this general reaction together with ethyl bromide as "R--X" yields N-ethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is ethyl; and X, Y and Z are each H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:2].[CH2:12]=[O:13].CC([O-])(C)C.[K+]>CS(C)=O.C(O)(C)(C)C>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]([CH3:2])[CH2:12][OH:13])([O-:11])=[O:10]
Reactant: CCc1ccccc1[N+](=O)[O-]
Reactant: C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CC(CO)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1-Ethyl-2-nitrobenzene (13.5 mL, 100 mmol) was dissolved in dimethylsulfoxide (100 mL). Paraformaldehyde (4.50 g, 150 mmol) and KOtBu (2.81 g, 25 mmol) in t-butyl alcohol (30 mL) were added and the mixture was stirred at room temperature for 3 h. The solution was washed with a molar solution of HCl (25 mL), followed by brine (3×100 mL). All the aqueous layers were combined and extracted with ethyl acetate (3×100 mL). The organic portion was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude product was purified on a silica gel column. Elution of the column with 20-30% ethyl acetate in hexanes gave 16.12 g (89 mmol, 89% yield) of 2-(2-nitrophenyl)propanol. 1H-NMR (600 MHz, DMSO-d6): δ 7.75 (d, J=8.10 Hz, 1H, Ar—H), 7.63 (t, J=7.62 Hz, 1H, Ar—H), 7.58 (d, J=7.80 Hz, 1H, Ar—H), 7.42 (t, J=7.50, 1H, Ar—H), 4.73 (t, J=5.30 Hz, 1H, OH), 3.50 (m, 2H, CH2), 3.19 (m, 1H, CH), 1.21 (d, J=6.90 Hz, 3H, CH3). TLC: 20% ethyl acetate in hexane, Rf=0.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11][C:12]1[N:16]([CH2:17][CH2:18][OH:19])[C:15]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:14]=2[N:13]=1.CCOC(/N=N/C(OCC)=O)=O.[C:39]1(O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN1CCOCC1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11][C:12]1[N:16]([CH2:17][CH2:18][O:19][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]2[CH:20]=[C:21]([CH3:25])[C:22]([CH3:24])=[CH:23][C:14]=2[N:13]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CN1CCOCC1
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2n1CCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To 2-((1-(2-hydroxyethyl)-5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid methyl ester (45 mg, 0.23 mmol) in N-methylmorpholine (3 ml), Pph3 (62 mg, 0.24 mmol) and DEAD (10.6 ml, 40% in toluene, 0.24 mmol) were added and the mixture was stirred at room temperature. After 10 minutes, phenol (11.3 mg, 0.12 mmol) was added thereto, which was stirred at room temperature for 12 hours. The solvent was evaporated and the residue was purified by thin layer chromatography (hexane:ethyl acetate=1:1) to obtain 2-((5,6-dimethyl-1-(2-phenoxyethyl)benzimidazole-2-ylthio)methyl)benzoic acid methyl ester (44 mg, yield 81%).
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:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[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]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.5 %

Procedure:
94 mg (0.346 mmol) of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dichloromethane (3.4 mL), and 70 μL (0.676 mmol) of benzylalcohol and 98 mg (0.511 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride were added, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and subsequently the residue was diluted with ethyl acetate and washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 41.2 mg of the title compound (yield 33%). Enantiomeric excess: 99.8% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 33.2 min.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:33])=[C:4]([NH:20][C:21]2[S:25][N:24]=[C:23]([CH3:26])[CH:22]=2)[CH:5]=1)[CH2:14][C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3cccs3)C(N)=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(thiophen-2-yl)propanamide (13 mg, 0.034 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (10 mg). MS 402.1 (M+H); UV 224.1, 302.6 nm.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:29][CH2:30]C)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])S(C1C=CC(C)=CC=1)(=O)=O)C.Cl.[CH2:33](O)C>[Pd]>[CH3:30][O:29][CH:4]([O:3][CH3:1])[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])[CH3:33]
Reactant: CCO
Reactant: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: [Pd]
Agent: Cl
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Yield: 56 %

Procedure:
7.81 g (40 mmol) of 2-methoxy-3,4-methylenedioxybenzaldoxime (2) thus obtained, 3.67 ml (44 mmol) of concentrated hydrochloric acid and 500 mg of 5% palladium on carbon catalyst were added to 80 ml of ethanol to carry out hydrogenation at room temperature for 4 hours and 45 minutes. The catalyst was filtered out, the filtrate was concentrated and the residue is recrystallized from 60 ml of ethanol to obtain 4.86 g of 2-methoxy-3,4-methylenedioxybenzylamine hydrochloride (3). Yield 56%, m.p. 208°-210° C. IR and NMR spectra of the resultant product are listed below. ##STR29##
Reaction SMILES: S[C:2]1[N:3]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][N:6]=1.[N+:25]([O-:28])([OH:27])=[O:26].[OH-].[Na+]>O>[N+:25]([O-:28])([OH:27])=[O:26].[C:9]1([C:7]([C:4]2[N:3]([CH:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH:2]=[N:6][CH:5]=2)=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccccc1)c1cnc(S)n1C1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(c1ccccc1)c1cncn1C1CCCc2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 8.4 %

Procedure:
To a stirred solution of 7 parts of [2-mercapto-1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazol-5-yl] phenylmethanone in 30 parts of water were added 30 parts of concentrated nitric acid. The whole was stirred for 15 minutes at 50° C. (intense reaction). After cooling, the reaction mixture was poured into crushed ice and treated with a sodium hydroxide solution. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was converted into the nitrate salt in 1,1'-oxybisethane. The salt was filtered off and dried, yielding 0.9 parts (8.4%) of phenyl [1-(1,2,3,4-tetrahydro-1-naphthalenyl)-1H-imidazol-5-yl]methanone mononitrate; mp. 150.2° C. (compound 2.43).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1)=[N+]=[N-].O>O1CCCC1>[NH2:20][CH2:23][C@@H:24]1[O:28][C:27](=[O:29])[N:26]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:38])=[O:37])=[C:32]([F:39])[CH:31]=2)[CH2:25]1
Reactant: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A mixture of triphenylphosphine (0.092 g, 0.352 mmol) and 5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.335 mmol) in tetrahydrofuran (2 ml) was stirred at r.t. for 4 h. Water (0.1 ml, 5.36 mmol) was added, and the mixture heated at 40° C. overnight. Solvent was evaporated under vacuum and the residue purified by PTLC (10% methanol in DCM) to give product as a white solid (0.082 g, 86%). MS (m/z): [M+H]+=273.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:17]([Cl:20])(=[O:19])=[O:18])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Br)cc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Under N2 atmosphere, 2.23 g 1-benzyloxy-3-bromo-5-chloro-benzene was dissolved in 50 mL dry THF, and the mixture was cooled in an ice bath. Dropwise, 14.84 mL of a 1M solution of isopropyl magnesium chloride-lithium chloride complex was added, and the mixture was stirred at room temperature overnight. After cooling to −40° C., 2.41 mL of sulfuryl chloride was added in one portion (T raised to 10° C.), and the mixture was stirred for 15 minutes at room temperature. After cooling with an ice bath, the mixture was quenched with water and acidified with 1M aqueous HCl. The mixture was extracted with MTBE, and the organic phase was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (PA→PA/Et2O 95:5) to yield 1.53 g (62%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.14 (s, 2H), 7.30 (t, J=2 Hz, 1H), 7.34-7.47 (m, 5H), 7.50 (t, J=2 Hz, 1H), 7.62 (t, J=1.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15](B(O)O)[CH:14]=1>>[Cl:12][C:8]1[N:9]=[C:10]([NH2:11])[C:5]2[S:4][CH:3]=[C:2]([C:15]3[CH:14]=[N:13][C:22]4[C:17]([CH:16]=3)=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)nc2c(Br)csc12
Reactant: OB(O)c1cnc2ccccc2c1
Product: Nc1nc(Cl)nc2c(-c3cnc4ccccc4c3)csc12
Yield: 43.8 %

Procedure:
The target compound (260 mg, 43% yield) was prepared in the same manner as Step 1 of Example 11 using 7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (500 mg, 1.90 mmol) and quinolin-3-ylboronic acid (329 mg, 1.90 mmol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:39](Br)[CH3:40])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>C(#N)C.C(=O)(O)[O-].[Na+]>[F:27][C:28]([F:42])([F:43])[C:29]1[CH:30]=[C:31]([CH:39]([NH:1][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@@H:3]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH3:40])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N)[C@H]1c1ccc(F)cc1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC[C@H](NC(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Yield: 37.3 %

Procedure:
A solution of 200 mg of amine from Example 62, 0.3 mL of DIPEA and 350 mg of 1-(RS)-(3,5-bis(trifluoromethyl)phenyl)ethyl bromide (prepared in Example 24) in 2 mL of acetonitrile was heated at 50° C. in a sealed vial for 40 h. The reaction was diluted with saturated sodium bicarbonate and extracted twice with methylene chloride. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 10 to 15% ethyl acetate in hexanes to obtain 150 mg of title compound as a mixture of methyl isomers. Mass spec (NH3 /CI): 478 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][OH:7])(=O)[CH3:2].[H-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15]C(F)=C[C:12]=1[C:18]([F:21])([F:20])[F:19]>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:1]([O:4][CH2:5][CH2:6][OH:7])=[CH:2][C:12]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CC(=O)OCCO
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In an atmosphere of nitrogen, a mixture of 2-hydroxyethyl acetate, sodium hydride and DMF was stirred at room temperature for 15 minutes and then 1-bromo-4-fluoro-2-(trifluoromethyl)benzene was added, followed by stirring at room temperature for 1.5 hours to obtain 2-[4-bromo-3-(trifluoromethyl)phenoxy]ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH2:17])[CH2:14][O:15][CH3:16])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[N:30]([CH3:36])[N:31]=[C:32]([CH2:34][CH3:35])[CH:33]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:17][C:27]([NH:28][C:29]3[N:30]([CH3:36])[N:31]=[C:32]([CH2:34][CH3:35])[CH:33]=3)=[O:26])[CH2:14][O:15][CH3:16])[CH2:8]2)=[CH:18][CH:19]=1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(C)n1
Reactant: COC[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Solvent: CS(C)=O
Product: CCc1cc(NC(=O)N[C@@H](CCN2CC(Oc3ccc(Cl)cc3)C2)COC)n(C)n1

Procedure:
A solution of (S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine (1.6 g, 5.6 mmol) and (5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (1.65 g, 6.7 mmol, see preparation below) in DMSO (7 ml) is stirred at ambient temperature for 4 hours, then partitioned between water and ethylacetate. The organic phase is washed again with water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 5:95 methanol/dichloromethane) to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea. [M+H] 436.37.
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[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[CH:21]1([NH:26][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]2[O:13][CH3:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21

Procedure:
To 1.5 g of 6-chloro-9-(2′-O-methyl-β-D-ribofuranosyl)-9H-purine and 510 mg of cyclopentylamine, 1.5 ml of triethylamine and 70 ml of ethanol were added. The solution was refluxed with heating for several ten minutes to 8 hours. After washing the residue with water, methanol was added and the solution was concentrated to dryness again. The residue was recrystallized with ethyl acetate to give N6-cyclopentyl-2′-O-methyladenosine (Compound 1). yield: 80%
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]1[CH2:11][CH:10](O)[C:9](=[CH2:13])[CH:8]1[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:44][C:45]1[N:53]=[C:52]2[C:48]([NH:49][CH:50]=[N:51]2)=[C:47]([Cl:54])[N:46]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[Cl:54][C:47]1[N:46]=[C:45]([NH2:44])[N:53]=[C:52]2[C:48]=1[N:49]=[CH:50][N:51]2[CH:10]1[CH2:11][CH:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:8]([CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:1])[CH3:3])([CH3:24])[CH3:23])[C:9]1=[CH2:13]
Reactant: C=C1C(O)CC(O[Si](C)(C)C(C)(C)C)C1CO[Si](C)(C)C(C)(C)C
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1C(CO[Si](C)(C)C(C)(C)C)C(O[Si](C)(C)C(C)(C)C)CC1n1cnc2c(Cl)nc(N)nc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a suspension of 56 (120 mg, 0.32 mmol), triphenylphosphine (84.5 mg, 0.64 mmol), and 2-amino-6-chloropurine (108 mg, 0.64 mmol) in THF (10 mL) was added diethyl azodicarboxylate (111 mg, 0.64 mmol) at −20° C. The reaction mixture was stirred at −20° C. for 1 hour. It was poured into DCM (50 mL), washed with 0.5 N sodium hydroxide (3×10 mL), dried over sodium sulfate, and concentrated in vacuo. Purification via silica gel chromatography gave the title compound (0.11 g, 63%).
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(O)C>[C:12]([N:16]1[C:9]([NH2:10])=[C:6]([C:7]#[N:8])[C:4]([CH3:5])=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(C)=C(C#N)C#N
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.1 %

Procedure:
To a slurry of 1-ethoxyethylidene malononitrile (68.0 g, 0.5 mol), tert-butylhydrazine hydrochloride (62.3 g, 0.5 mol) in ethanol (500 ml) was added triethylamine (70 ml, 0.5 mol). The reaction mixture was stirred at room temperature for 2 hours, cooled in an ice-bath and a solid was collected by filtration and was washed with ether. The mother liquor was concentrated and the solid residue was recrystallized from ethanol. The two solid fractions were combined and dried at 65° C. in high vacuum for 24 hours to afford 132 g of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as a white solid which is contaminated with triethylamine hydrochloride (approximately 2/3mol).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:5])=[O:4])[CH3:2].[Cl:20]Cl>O1CCOCC1.O>[Cl:20][C:8]1[C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:18][C:11]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:10]([F:19])[CH:9]=1
Reactant: CCOC(=O)Nc1cc(NS(=O)(=O)CC)ccc1F
Reactant: ClCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1cc(NS(=O)(=O)CC)c(Cl)cc1F
Yield: 86 %

Procedure:
0.50 g (1.72 mmol) of ethyl 5-ethylsulfonylamino-2-fluorocarbanilate was dissolved in a mixture of 5 ml of dioxane and 1 ml of water, and chlorine gas was added to the resultant solution at a temperature of not higher than 25° C. until the starting material disappeared. After the reaction was completed, the surplus chlorine gas was removed by blowing nitrogen gas thereinto, and water was added. The precipitates crystals were filtered out and dried to obtain 0.48 g of the objective product (yield: 86%) in the form of light brown crystals.