Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([NH:11][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: c1ccc(Nc2ncnc3[nH]ccc23)cc1
Yield: 16 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 16% yield from 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and aniline (5.0 eq) in pyridine. (M.P. 234-236° C.; GC-MS: 211(MH+); anal. RP18-HPLC RT: 3.11 min.)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[CH2:11]([O:14][CH2:15]Br)[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:14][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CCCOCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOCOc1ccccc1[N+](=O)[O-]

Procedure:
2-Nitrophenol, bromomethyl propyl ether, anhydrous potassium carbonate and acetone were reacted according to the procedure outlined in Example 1 to yield 2-propoxymethoxynitrobenzene, which was reduced to the corresponding aniline, and isolated by a vacuum distillation.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O>[CH:14]1([O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC1CCCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of vanillin (50 g) in N,N-dimethylformamide (600 ml) are added 62.5% sodium hydride (13.9 g) and cyclopentyl bromide (38.8 ml) under ice-cooling, and the mixture is stirred at 90° C. overnight. The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide, and to the residue is added water. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 4-cyclopentyloxy-3-methoxybenzaldehyde (65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[S:6][CH:7]=[C:8]([CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[C:4]=2[CH:3]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:8]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=3[S:6][CH:7]=2)[C:11]1=[O:19])[CH3:28]
Reactant: O=c1[nH]c2ccccc2n1Cc1csc2ccc(Cl)cc12
Reactant: C=CC(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1c(=O)n(Cc2csc3ccc(Cl)cc23)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.16 mmol) in DMF (2 mL) were added ethyl acrylate (0.02 mL) and benzyltrimethyl ammonium hydroxide (20 mg, 0.01 mmol). The resulting mixture was stirred at room temperature overnight. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 50 mg of the desired product as a colorless oil. LCMS (ESMS): m/z 415.78 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([C:38](=[O:49])[NH:39][C:40]3([C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:42][CH2:41]3)[CH:31]=2)=[CH:28][C:5]2[C:6]([C:16]3[N:17](C(OC(C)(C)C)=O)[CH:18]=[CH:19][N:20]=3)=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N[C:51]1C(C2C=CC(OC)=C(C=2)C(NC2(C3N=CC=CN=3)CC2)=O)=CC2C(C3NC=CN=3)=C(C3C=CC(F)=CC=3)OC=2[CH:52]=1.C(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:51]([NH:1][C:2]1[C:29]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([CH:31]=2)[C:38]([NH:39][C:40]2([C:43]3[N:44]=[CH:45][CH:46]=[CH:47][N:48]=3)[CH2:42][CH2:41]2)=[O:49])=[CH:28][C:5]2[C:6]([C:16]3[NH:17][CH:18]=[CH:19][N:20]=3)=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1)[CH3:52]
Reactant: COc1ccc(-c2cc3c(-c4nccn4C(=O)OC(C)(C)C)c(-c4ccc(F)cc4)oc3cc2N)cc1C(=O)NC1(c2ncccn2)CC1
Reactant: COc1ccc(-c2cc3c(-c4ncc[nH]4)c(-c4ccc(F)cc4)oc3cc2N)cc1C(=O)NC1(c2ncccn2)CC1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cc2oc(-c3ccc(F)cc3)c(-c3ncc[nH]3)c2cc1-c1ccc(OC)c(C(=O)NC2(c3ncccn3)CC2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The above obtained mixture of tert-butyl 2-(6-amino-2-(4-fluorophenyl)-5-(4-methoxy-3-((1-(pyrimidin-2-yl)cyclopropyl)carbamoyl)phenyl)benzofuran-3-yl)-1H-imidazole-1-carboxylate and 5-(6-amino-2-(4-fluorophenyl)-3-(1H-imidazol-2-yl)benzofuran-5-yl)-2-methoxy-N-(1-(pyrimidin-2-yl)cyclopropyl)benzamide (170 mg, 0.257 mmol) in MeOH (25 mL) was cooled to 0° C. and then added with acetaldehyde (45.3 mg, 1.029 mmol). The reaction mixture was allowed to warm to rt and stirred for 45 min. The reaction mixture was again cooled to 0° C. and then added with sodium cyanoborohydride (32.3 mg, 0.515 mmol). The reaction mixture was allowed to warm to rt and stirring continued at rt for 2 hr. The reaction mixture was concentrated completely at reduced pressure at 35° C. The residue was diluted with water and 10% NaHCO3 solution, filtered, and the solid obtained dried under suction. The crude product was purified by preparative HPLC to separate the two compounds. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.32 (br s, 1H) 8.92 (s, 1H) 8.69 (d, J=4.8 Hz, 2H) 7.94-8.03 (m, 2H) 7.86 (d, J=2.51 Hz, 1H) 7.55 (dd, J=8.53, 2.51 Hz, 1H) 7.22-7.33 (m, 5H) 7.21 (s, 1H) 7.13 (s, 1H) 6.91 (s, 1H) 4.58 (t, J=5.65 Hz, 1H) 3.99 (s, 3H) 3.13-3.22 (m, 2H) 1.59-1.66 (m, 2H) 1.38-1.46 (m, 2H) 1.10-1.21 (m, 3H). 19F NMR (376.6 MHz, DMSO-d6) δ ppm: 112.76. LCMS: (ES−) m/z=587.2 (M−H); Column—Acentis Express C8 (50×2.1 mm; 2.7 u); M phase A: 2% MeCN-98% H2O-10 mM NH4COOH; M phase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22](I)=[CH:21][N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][N:41]=1)CCC>CC(N(C)C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:37]4[O:38][CH:39]=[CH:40][N:41]=4)=[CH:21][N:20]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(c2)c(I)cn3COCC[Si](C)(C)C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(c2)c(-c2ncco2)cn3COCC[Si](C)(C)C)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 22.5 %

Procedure:
A mixture of 2-hydroxy-2-{5-[3-iodo-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide (50 mg, 0.09 mmol), 2-tri-n-butylstannyloxazole (28 ul, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), CuI (2 mg, 0.009 mmol) in DMA (1 ml) was stirred at 120° C. in a microwave for 20 minutes. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (2X). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-hydroxy-N,N-dimethyl-2-{5-[3-oxazol-2-yl-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-acetamide (10 mg, 22% yield).
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[N:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:8]=[CH:7][C:6]=1[C:14]([O:16]CC)=[O:15])#[N:4]>C(O)C>[C:3]([C:5]1[N:9]([C:10]([CH3:12])([CH3:13])[CH3:11])[N:8]=[CH:7][C:6]=1[C:14]([OH:16])=[O:15])#[N:4]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(C(=O)O)c1C#N
Temperature: 0 °C
Yield: 72 %

Procedure:
Potassium hydroxide (1.7 grams, 0.027 mole) was dissolved in 20 ml of ethanol. This solution was poured into a refluxing solution of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester, in 50 ml of ethanol. The reaction mixture was heated on a steam bath for five minutes, then poured into ice-water, filtered, and acidified with concentrated hydrochloric acid. The precipitated product was collected and dried, yielding 3.2 grams of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid (72% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl.[OH-].[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: Fc1cccc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol (0.20 g, 0.91 mmol), 3-fluorobenzyl chloride (0.11 mL, 0.91 mmol), 1 M aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) and water (4 mL) was stirred overnight at room temperature. The precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.21 g, yield 74%) as colorless crystals.
Reaction SMILES: C[Al](C)C.Cl.[CH2:6]([NH2:8])[CH3:7].[C:9]1([C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=2)[C:18](OC)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1(C)C=CC=CC=1>[CH2:6]([NH:8][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=1)[CH3:7]
Reactant: COC(=O)c1cccc(-c2ccccc2)c1
Reactant: CCN
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Yield: 62 %

Procedure:
Trimethylaluminum (920 μL of 2M solution in toluene, 1.84 mmol) was added drop wise to a suspension of ethylamine hydrochloride (151 mg, 1.84 mmol) in 2.76 mL of dry toluene at 0° C. The reaction was then warmed to room temperature and stirred until no gas evolution was observed. The clear solution was then canulated onto a solution of Methyl 3-phenylbenzoate in 6 mL of toluene. The reaction was then heated to 80° C. and stirred for 18 hours. The reaction mixture was then carefully treated with 5% HCl at 0° C. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The oil obtained was purified by flash chromatography using SiO2 with CH2Cl2/MeOH 99:1 to give a pale yellow oil (129 mg, 62%). NMR 1H (ppm, CDCl3): 8.0 (s, 1H), 7.72 (d, J3=8.1 Hz, 2H), 7.61 (d, J3=5.4 Hz, 2H), 7.52-7.35 (m, 4H), 6.14 (br. s., 1H), 3.58-3.49 (m, 2H), 1.28 (t, J3=7.5 Hz, 3H).
Reaction SMILES: ClCCl.C[O:5][C:6]1[C:15]2[C:10](=[C:11]([CH2:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.B(Br)(Br)Br>O>[CH2:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][CH:7]=[C:6]2[OH:5])[CH3:17]
Reactant: CCc1cccc2c(OC)cccc12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCc1cccc2c(O)cccc12
Temperature: 0 °C
Yield: 75 %

Procedure:
Anhydrous dichloromethane (20 mL) was added to 8 (870 mg, 4.6 mmol). After cooling to 0° C., BBr3 (boron tribromide 1.0M in dichloromethane) (14 mL, 14 mmol) was added dropwise. The reaction mixture was heated to reflux for 5 h. After cooling, a large amount of water was slowly added and the mixture was extracted three times with dichloromethane. The organic layer was evaporated and the residue was purified on MPLC to afford compound 9c, 75% yield; MS-ESI− (m/z, %): 171 (M+−1 , 100), 172 (M+, 45); 1H NMR δ 1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 5.19 (1H, s, OH), 6.82 (1H, d, J=7.8 Hz, H-2), 7.31-7.45 (3H, m, H-3, 6, 7), 7.65 (1H, d, J=8.7 Hz, H-4), 8.06 (1H, d, J=8.1 Hz, H-8).
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18]>CC#N>[C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:18][C:17]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:15]([F:14])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Reactant: Cc1ccc(N)cc1F
Solvent: CC#N
Product: Cc1ccc(NCC(O)CCO[Si](C)(C)C(C)(C)C)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (4.4 g, 200 mmol; prepared as in J. Org. Chem. (2008), 73, 1093) in MeCN (60 mL) was added LiClO4 (6.31 g, 3 eq.). 3-fluoro-4-methylaniline (commercial; 2.28 g, 0.92 eq.) was added and the mixture was stirred at 50° C. for 5 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:25:2) to afford the title intermediate as a brown oil (5.56 g, 86% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH2:11][CH2:10]1.[CH3:20][NH2:21]>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:21][CH3:20])[CH2:11][CH2:10]1
Reactant: CN
Reactant: Cc1cccc(N2CCN(CCC3CO3)CC2)c1C
Solvent: CCO
Product: CNCC(O)CCN1CCN(c2cccc(C)c2C)CC1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(2,3-dimethylphenyl)-4-(2-(oxiran-2-yl)ethyl)piperazine obtained in step 2 (0.10 g, 0.38 mmol) and methylamine (8.0 M) in ethanol (1.0 ml) was stirred at 90° C. for 20 hours. After the reaction complete, the resulting reaction mixture was concentrated under reduced pressure to obtain the title compound (0.10 g). The compound was used for the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[C:20](OC)=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8].O>C1COCC1>[C:7]([O:11][C:12](=[O:13])[NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][OH:21])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
To a well stirred suspension of 0.94 g (24.7 mmol, 2 equiv.) of LiAlH4 in 30 ml of THF at 0° C. was added dropwise at 0° C. a solution of (1S,2R)-methyl 2-(tert-butoxycarbonylamino)-cyclopentanecarboxylate (CAS: 592503-55-4) (3.0 g, 12.3 mmol) (gas evolution, lightly exotherm). After 15 minutes at 0° C. the reaction mixture was allowed to warm up to room temperature and was stirred for 2 h. The mixture was cooled to 0° C. and water was added dropwise. The precipitated inorganic salts were filtered through Celite and were washed with ethyl acetate. The filtrate was evaporated and the residue was purified by column chromatography on silica gel eluting with a 0% to 50% ethyl acetate in heptane gradient to yield 1.99 g (75%) of the title compound as a crystalline white solid which was directly used in the next step.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[SiH:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]>O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][CH3:8])[CH3:17]
Reactant: COc1ccccc1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1ccccc1OC
Yield: 53.1 %

Procedure:
The reaction was conducted according to the General Procedure by heating anisole (54 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 59 mg (54%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.40-7.17 (m, 2H), 7.01-6.81 (m, 2H), 3.77 (s, 3H), 1.02-0.85 (m, 9H), 0.87-0.74 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 164.58, 135.52, 130.42, 123.92, 120.08, 109.23, 54.09, 6.93, 3.22.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:6](OCC)=[O:7])C.CC(C[AlH]CC(C)C)C.Cl.C(OCC)(=O)C>C1COCC1>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:5]([CH2:4][OH:3])[CH2:6][OH:7])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC(CO)Cc1ccc(Br)cc1
Reaction time: 3 h
Yield: 96.6 %

Procedure:
2-(4-Bromo-benzyl)-malonic acid diethyl ester 21 (1.5 g, 3.8 mmol) was dissolved in 5 mL THF and the solution was added slowly to DIBALH (1M in toluene, 25 mL) via a syringe at 0° C. and stirred at the same temperature for 3 hr. HCl (2N, 50 mL) was then added to break the complex. After standard work up with ethyl acetate, crude product 22 (0.9 g, 99%) was obtained, which was used directly for the next step without further purification: 1H NMR δ 7.39 (d, 2H, J=8.2 Hz), 7.04 (d, 2H, J=8.2 Hz), 3.60 (m, 4H), 2.55 (d, 2H, J=7.4 Hz), 1.96 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:16]=2[C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)CCc3ccccc32)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2c(-c3ccccc3)ccc3ccccc23)cc1

Procedure:
The title product was prepared as described in U.S. Pat. No. 4,230,862. To 30 ml of dioxane were added 3-phenyl-4-(4-methoxybenzoyl)-1,2-dihydronaphthalene (1.90 g, 5.58 mmol), prepared as described in Example 3, supra, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.00 g, 8.81 mmol). The resulting mixture was heated to reflux and refluxed for twelve hours under a nitrogen atmosphere. The mixture was then cooled and evaporated to dryness. The residue was partitioned between ether and water. The organic fraction was washed 5N sodium hydroxide (5×20 ml), followed by a wash with brine. The mixture was then dried over magnesium sulfate and evaporated to give 1.9 grams of substantially pure 1-(4-methoxybenzoyl)-2-phenylnaphthalene.
Reaction SMILES: [CH:1]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])=[CH2:2].[NH3:11]>O>[NH:11]([CH2:2][CH2:1][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[CH2:2][CH2:1][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: C=CP(=O)(OCC)OCC
Reactant: N
Solvent: O
Product: CCOP(=O)(CCNCCP(=O)(OCC)OCC)OCC
Yield: 73 %

Procedure:
A solution of diethyl vinylphosphonate (10.52 g; 0.062 moles) in concentrated ammonia (14.4 g) is stirred for 2 days at room temperature. The reaction mixture is diluted with water (100 ml), extracted with dichloromethane (4×30 ml) and dried over MgSO4. Stripping of the solvent in vacuo until constant weight affords a colorless liquid (8.36 g; yield 73%).
Reaction SMILES: ClCl.IC1N=C(N)C2N=CN(C=2N=1)[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1[OH:13].[Cl:23][C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37]Cl)[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[Cl:23][C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:13])[C@@H:34]([OH:35])[C@H:32]1[OH:33]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: ClCl
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
In yet another route the 5′-substituent was introduced prior to C2-substitution to circumvent all problems met in the previous routes. The method of Robins20 yielded 5′-deoxy-2-iodo-5′-chloroadenosine from 2-iodoadenosine (1). However, besides the 5′-hydroxyl group, also the 2-iodo group of 1 was replaced by chlorine to some extent, and a mixture of 5′-deoxy-2-iodo-5′-chloroadenosine with 2,5′-dichloro-5′-deoxyadenosine was obtained. Separation of the two products by column chromatography proved impossible. Thus, it was necessary to go further back in the synthesis route, since pure 2,5′-dichloro-5′-deoxyadenosine, obtained by chlorination of 2-chloroadenosine, failed to react with ethanethiol under different conditions (either with KOtBu in MeOH at different temperatures that all regained starting material, or in 2 M NaOH at elevated temperatures yielding the 2,5′-diethylthio substituted derivatives). Finally, in Scheme 1 the successful synthesis of the desired compounds is depicted. The 5′-substituents were introduced at guanosine, which is also the precursor of 2-iodoadenosine (1). Although more laborious, this route starts with the introduction of the 5′-alkylthio substituents at guanosine to circumvent all described problems. Chlorination20 of guanosine gave 5′-chloro-5′-deoxy-guanosine (16) in 93% yield. Compound 16 was reacted with the appropriate thiol in 2 M NaOH1,5 and the 2′- and 3′-hydroxyl groups of compounds 17–20 were subsequently protected to yield the 2′,3′-O-acetyl-5′-(alkylthio)-substituted derivatives 21–24. Several laboratories have described chlorination on the 6-position of purine nucleosides with phosphoryl chloride (POCl3).18,21 To prevent decomposition of the starting materials, the chemicals used were either properly dried or freshly distilled, and compounds 25–28 were obtained in reasonable to good yields (40%–74%). Subsequently, the 2-amino group of compounds 25–28 was replaced by iodine. The method used26 was a variation of the originally diazotization-iodine substitution procedure.22 With this efficient method 29–32 were obtained in good yields (71–82%). Stirring 29–32 in ethanol freshly saturated with NH3 readily removed the protecting groups and slowly aminated the 6-position to give the intermediates 33–36. NMR showed that amination at the 6-position needed stirring at room temperature for at least two days. Subsequent introduction of the C2-substituents was done as described above,7,8 and compounds 37–40 and 45–48 were obtained in good yields.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].I[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Ic1cnccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cc(-c2cnccn2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-iodo-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.12 min; Mass spectrum (ESI+): m/z=263/265 (Br) [M+H]+.