Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:26][C:23]([C:20]1[CH:19]=[C:18]([CH2:27][CH2:28][C:29]2[O:30][C:1](=[O:2])[NH:32][N:31]=2)[CH:17]=[C:16]([C:13]([CH3:12])([CH3:14])[CH3:15])[C:21]=1[OH:22])([CH3:24])[CH3:25]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 74 %

Procedure:
A 12.5% solution of phosgene in toluene (10.7 mL, 12.0 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide in tetrahydrofuran (200 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is crystallized from hexane to afford 1.6 g (74%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethyl]-1,3,4-oxadiazol-2(3H)-one, mp 120.0°-123.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)C#N.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][C:13]=1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2ccncc2)cc1B(O)O
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccncc2)cc1-c1ccccc1
Temperature: 80 °C

Procedure:
A stirred mixture of 3-bromobenzonitrile (0.91 g, 5.0 mmol), 2-Methoxy-5-(pyridin-4-yl)phenylboronic acid (0.50 g, 2.3 mmol), tri-o-tolylphosphine (0.152 g, 0.50 mmol), palladium (II) acetate (0.056 g, 0.25 mmol), sodium carbonate (1.59 g, 15 mmol) and water (15 mL) in dimethylformamide (46 mL) is heated at 80° C. for 5 h. The mixture is then treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are dried (Na2SO4). filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, ethyl acetate) to give 4-[4-methoxy-3-(phenyl)phenyl]pyridine base. The base is dissolved in diethylether (5 mL), treated with methanolic HCl (excess), evaporated to dryness under reduced pressure and recrystallised from ethanol-ether to give 4-[2-methoxy-3'-cyano-biphenyl-5-yl]pyridine, hydrochloride as a pale-yellow crystalline solid, m.p. 142-150° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: CC=O
Reactant: COC(=O)C1CCCCO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 113.3 %

Procedure:
A solution of N,N-diisopropylamine (909 mg, 1.25 mL, 9 mmol) in tetrahydrofuran (4 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (3.6 mL, 9 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of tetrahydro-pyran-2-carboxylic acid methyl ester (864 mg, 6 mmol) in tetrahydrofuran (8 mL) was added and the reaction mixture was stirred at −78° C. for 20 minutes. Acetaldehyde (792 mg, 1.0 mL, 18 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.28 g) as an oil and as a 2:1 mixture of diastereoisomers. LCMS (m/z) 189.3 [M+H], Tr=1.23 min.
Reaction SMILES: [Li].C([N-]C(C)C)(C)C.[CH2:9]([O:11][C:12](=[O:18])[CH2:13][O:14][CH2:15][CH2:16][CH3:17])[CH3:10].[CH3:19][Si:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([CH:34]=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>O1CCCC1>[CH2:9]([O:11][C:12](=[O:18])[CH:13]([O:14][CH2:15][CH2:16][CH3:17])[CH:34]([OH:35])[C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:36])([CH3:19])[CH3:37])[CH:26]=[CH:27]2)[CH3:10]
Reactant: CCCOCC(=O)OCC
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C=O)ccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCCOC(C(=O)OCC)C(O)c1ccc2c(ccn2COCC[Si](C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of 30 mmol lithium-diisopropylamide in 50 ml tetrahydrofuran were added at −78° C. 4.39 g propoxy-acetic acid ethyl ester [Journal of the American Chemical Society (1996), 118(41), 9901-9907] dissolved in 25 ml of tetrahydrofuran; after 30 min. stirring at −78° C., a solution of 3.31 g 1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-5-carbaldehyde in 30 ml tetrahydrofuran was added and after another 30 min., the reaction mixture was quenched with 25 ml H2O and then warmed up to ambient temperature. It was then extracted with ethyl acetate and the combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a light brown oil which was purified by chromatography (silicagel, eluent: gradient of n-heptane/EtOAc) to yield 4.65 g 3-hydroxy-2-propoxy-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-5-yl]-propionic acid ethyl ester (mixture of diasteromers) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:7]([C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:15]=[CH:14]2)#[N:8]
Reactant: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Reactant: CN(C)C(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Temperature: 110 °C
Yield: 12 %

Procedure:
To a solution of 5-fluoro-2-(1H-indazol-5-yloxy)-benzonitrile (44d) (0.200 g, 0.790 mmol) in DMF (6 mL) was added 2-chloro-N,N-dimethylacetamide (0.115 g, 0.948 mmol) and tetrabutyl ammonium iodide (0.088 g, 0.237 mmol), followed by K2CO3 (0.164 g, 1.19 mmol). The mixture was heated to 110° C. for 48 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and chromatographed on Biotage eluting with 5% MeOH in dichloromethane to afford 0.032 g of the product (12% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:6][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccccc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1COc1ccccc1CCc1ccccc1
Yield: 75.9 %

Procedure:
Following a procedure similar to that described in Example 38(a), 1.14 g of (R)-1-t-butoxycarbonyl-2-[2-(2-phenylethyl)phenoxymethyl]pyrrolidine [prepared as described in Example 74(a)] were reacted with 0.227 g of lithium aluminum hydride dispersed in 10 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.670 g (yield 76%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=2[O:19][CH3:20])[C:5]([C:21]#[N:22])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[B:28]1(B2OC(C)(C)C(C)(C)O2)[O:32]C(C)(C)C(C)(C)[O:29]1>O1CCOCC1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[C:21]([C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=2[O:19][CH3:20])=[CH:7][C:2]([B:28]([OH:32])[OH:29])=[CH:3][CH:4]=1)#[N:22]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2C#N)c(OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(B(O)O)ccc2C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of 5-chloro-4′-(ethylsulfonyl)-2′-methoxy-[1,1′-biphenyl]-2-carbonitrile (Preparation 66, 330 mg, 0.985 mmol) in dioxane (5 mL) was added bis(diphenylphosphino)ferrocene-palladium(II)dichloride (30 mg, 0.12 mmol), potassium acetate (290 mg, 2.95 mmol) and bis(pinacolato)diboron (3.75 mg, 1.48 mmol). The reaction was degassed and then placed on a preheated hot plate (100° C.) for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite and the solvent removed in vacuo. The crude material was purified by reverse phase column chromatography eluting with MeCN/H2O to hydrolyse the boronic ester to afford the title compound in 25% yield, 85 mg.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[Br:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][NH2:30])=O)[CH:24]=[N:25][CH:26]=1>>[Br:20][C:21]1[CH:22]=[C:23]([C:27]2[O:15][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)=[N:30][N:29]=2)[CH:24]=[N:25][CH:26]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: NNC(=O)c1cncc(Br)c1
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3cncc(Br)c3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 5-bromo-3-pyridinecarbohydrazide: MS (ES) m/z 448 and 450 (M+1 Br isotopes).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.OO.[ClH:23]>CO>[Cl:23][C:3]1[CH:4]=[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cl
Reactant: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Agent: OO
Solvent: CO
Product: O=S(=O)(Nc1cc(Cl)c(O)c2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
0.987 g N-(4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (3) was suspended in 10 ml methanol, to which was added 3 ml hydrogen peroxide solution (35%). The mixture was stirred at r.t. for 2 h. Additional 3 ml hydrogen peroxide solution was added followed by 1 ml HCl solution (4 M in dioxane). The reaction was continued for another 2 h. The organic solvent was removed via rotavap and the residue was redissolved in ethyl acetate (100 ml). Washed with water (20 ml×3) and brine (20 ml×2), the organic phase was dried over Mg2SO4. The organic phase was filtered and concentrated. The crude product was separated via flash chromatography (Hex/EtOAc) affording 244 mg (22.2%) brown solid, m.p.: 113-115° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:39]([O:38][C:36]([N:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate (1.0 g, 2.8 mmol) in CH2Cl2 (50 mL) was added Et3N (2.0 mL, 14.3 mmol), BOC2O (3.1 mL, 13.5 mmol) and catalytic amount of DMAP. After stirring at room temperature for 18 h, the reaction was quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted once with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Chromatography (5% EtOAc in Hexane) gave butyl 1-[(tert-butoxycarbonyl)(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate. HPLC/MS: m/z=416.3 (M−56+1), 438.3 (M−56+23), Rt=3.07 min. 1H NMR (CDCl3): δ 7.90 (1H, d, J=8.5 Hz), 7.89 (1H, s), 7.16 (1H, m), 4.75 (1H, br s), 4.35 (2H, t, J=6.5 Hz), 4.19 (1H, br s), 3.10-3.05 (1H, m), 2.97-2.87 (1H, m), 2.36 (2H, m), 1.91-1.77 (5H, m), 1.52 (2H, m), 1.07-1.00 (8H, m), 0.90 (9H, s), 0.89 (9H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1[N+]([O-])=O)#[N:2].[F-:25].[Cs+]>CN1CCCN(C)C1=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1[F:25])#[N:2]
Reactant: [F-]
Reactant: CCCCCC12CCC(c3ccc(C#N)c([N+](=O)[O-])c3)(CC1)CC2
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Product: CCCCCC12CCC(c3ccc(C#N)c(F)c3)(CC1)CC2
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
0 85 g of 1-(4-cyano-3-nitrophenyl)-4-n-pentylbicyclo[2.2.2]octane is dissolved in 8 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, 2.16 g of caesium fluoride are added and the mixture is heated, with stirring, at 120° C. for 2.5 hours. Dilution with water and workingup after extraction gives 1-(4-cyano-3-fluorophenyl)-4-n-pentylbicyclo[2.2.2]octane, which is purified by chromatography and crystallization. m.p. 63°; c.p. 53.3°
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH:17]12[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][CH2:19][CH:18]2[C:25](O)=O>>[C@@H:17]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:20][CH2:19][C@H:18]2[C:25]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=S
Reactant: O=C(O)C1CCC2CCCC21
Product: CCCn1c(=O)c2[nH]c([C@@H]3CC[C@H]4CCC[C@H]43)nc2n(CCC)c1=S
Yield: 57 %

Procedure:
The substantially same operations as in Example 1 were repeated except for using 2.00 g (8.26 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil [J. Med. Chem., 32, 1873 (1989)] and 1.42 ml (9.92 mmol) of bicyclo[3.3.01octan-2-carboxylic acid to afford 1.70 g (overall yield: 57%) of the captioned Compound 24 as a white crystal.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1)=[O:4].[CH3:26][NH:27][CH3:28]>CN(C)C(=O)C>[CH3:26][N:27]([CH3:28])[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1)=[O:4]
Reactant: CNc1nccc(-c2cc(NC(=O)CCl)c3cc(OC)ccc3c2)n1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: CNc1nccc(-c2cc(NC(=O)CN(C)C)c3cc(OC)ccc3c2)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-N-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)acetamide 34 (0.125 mg, 0.35 mmol) in N,N-dimethylacetamide (1 mL), dimethylamine (1.5 mL, 2M solution in methanol, 3 mmol) was added. The reaction mixture was stirred at 60° C. overnight. The crude reaction mixture was concentrated under high vacuum and which was purified by reverse phase chromatography on preparative LC/UV/MS system using a mass triggered fractionation. Compound was eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 mL/min with acetonitrile/water gradient using 0.1% FA as a modifier. 2-(dimethylamino)-N-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)acetamide 137 was isolated as a yellow-orange solid (0.050 g). M.p.=70-73° C. 400 MHz 1H NMR (DMSO-d6) δ: 9.96 (s, 1H), 8.49 (s, 1H), 8.38 (s, 2H), 8.01 (d, J=8.6 Hz, 1H), 7.29-7.14 (m, 4H), 3.92 (s, 3H), 3.24 (s, 2H), 2.90 (br s, 3H), 2.42 (s, 6H); Experimental Elemental Analysis (0.13 equivalents of water)=65.32% C, 6.36% H, 18.75% N; Calculated Elemental Analysis 65.32% C, 6.37% H, 19.04% N; LCMS (m/z): 367 [M+H].
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C[N:11](C)C1C=CC=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CN(C)c1ccccc1
Reactant: c1cc(C2CC2)ccn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(C2CC2)ccn1
Yield: 12 %

Procedure:
Reflux 4-cyclopropyl-pyridine (600 mg, 5 mmol), N,N-dimethylaniline (1.4 mL, 11 mmol) and NaNH2 (50% in toluene, 468 mg, 6 mmol) at 150-160° C. under nitrogen in toluene for overnight. Cool the mixture and dilute with water and ethyl acetate. Extract the organic layer by minimal amount of water. Dry the organic layer (combination of anhydrous MgSO4, Na2SO4 and K2CO3), concentrate and purify by silica gel column chromatography to obtain the title compound in 12% yield. LCMS (ES), m/z 135 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][C:9]([O:11]CC)=O)[CH:4]=[CH:5][N:6]=1.[C:14]1([Li])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[OH:11])[CH:4]=[CH:5][N:6]=1
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)CCn1ccnc1C
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccn1CCC(O)(c1ccccc1)c1ccccc1
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 6 %

Procedure:
In a 200 ml two-neck flask, under an atmosphere of argon, a solution of ethyl 3-(2-methyl-1-imidazolyl)propionate (3.37 g, 18.5 mmol) in anhydrous tetrahydrofuran was added to 50 ml of 1.8M phenyllithium solution at 0° C. After stirred for 3.5 hours at 10° C., the mixture was allowed to stand overnight at room temperature. The solution was poured into water, which was extracted with ethyl acetate. The organic extract was washed with saturated saline solution and dried over anhydrous sodium sulfate, followed by concentration. The residue was purified by silica gel chromatography (elution solvent; ethyl acetate-ethanol=10:1) and then recrystallized from n-hexane-ethyl acetate. This was further recrystallized from ethanol-benzene to give 320 mg of title compound as white needle-like crystals. Yield: 6%
Reaction SMILES: [CH3:1][C:2]([CH3:29])=[CH:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[S:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([S:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[N:5]([CH2:4][CH:3]=[C:2]([CH3:29])[CH3:1])[C:9]=2[CH:10]=1
Reactant: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)=CCn1c(SCCCNC(=O)OC(C)(C)C)nc2ccc(N)cc21
Yield: 107.1 %

Procedure:
A solution of 140 mg (0.33 mmol) of tert-butyl {3-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-ylsulfanyl]propyl}carbamate in 15 ml of ethanol was added dropwise to a suspension of 93 mg (1.66 mmol) of iron and 16 mg (0.30 mmol) of ammonium chloride in 1.5 ml of water and boiled at reflux for 3 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. The 138 mg of the desired product thus obtained were used in the next stage without further purification.
Reaction SMILES: [OH:1][C:2](/[C:5](=[CH:11]/[I:12])/[C:6](OCC)=[O:7])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:1][C:2](/[C:5](=[CH:11]/[I:12])/[CH2:6][OH:7])([CH3:4])[CH3:3]
Reactant: CCOC(=O)/C(=C\I)C(C)(C)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(O)/C(=C/I)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of ethyl Z-2-(1-hydroxy-1-methylethyl)-3-iodoacrylate (II) (4.9 mmol, 1.4 g) in anhydrous ether (30 ml), lithium aluminum hydride (2.9 mmol, 0.112 g) is added. The reaction is stirred for 1 h under an inert atmosphere (argon) at room temperature (rt). After destroying the excess lithium aluminum hydride by adding a saturated sodium sulfate solution (30 μl), the alumina precipitate is filtered. The filtrate, dried (MgSO4) and evaporated under reduced pressure, gives a white residue of E-2-(1-hydroxy-1-methylethyl)-3-iodoprop-2-en-1-ol (III) (0.9 g, 75%).
Reaction SMILES: [NH2:1][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:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:53])[C@H:22]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[NH:23][C:24](=[O:43])[C@H:25]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[NH:26]C(OC(C)(C)C)=O)[C@H:12]1[OH:13]>C(O)=O>[NH2:1][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:16][C@H:15]([C:17]([OH:19])=[O:18])[C@@H:14]([NH:20][C:21](=[O:53])[C@H:22]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[NH:23][C:24](=[O:43])[C@H:25]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[NH2:26])[C@H:12]1[OH:13]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OC)cc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Solvent: O=CO
Product: COc1ccc(C[C@H](NC(=O)[C@@H](N)Cc2ccc(OC)cc2)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 53.3 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[N-(O-methyl-L-tyrosyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (46 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-3-[N-(N-tert-butoxycarbonyl-O-methyl-L-tyrosyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (100 mg) prepared in Example 86 with formic acid according to a similar manner to that of Example 45, mp. 175°-177° C. (dec.).