Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21](N)=[O:22])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[Na].[OH-:32].[Na+].Cl>O.C(O)C>[CH:8]1[C:7]([CH:10]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21]([OH:32])=[O:22])[CH2:15][CH2:16]2)[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[CH:6][CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: NC(=O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)COCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
In a round-bottomed flask fitted with a mechanical stirrer, a Nitrogen inlet and a condenser, 30 g (0.065 mole) of 2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide dihydrochloride are added to a mixture of 325 ml of ethanol, 130 ml of a 1 N aqueous sodium hydroxyde solution and 62 ml of a 6.3 N aqueous sodium hydroxide solution. The mixture is heated under reflux and under a Nitrogen atmosphere for 1.5 hours. The reaction mixture is then cooled down to room temperature and its pH is adjusted to 5 with 78 ml of a 5 N aqueous hydrochloric acid solution. Water is added, and ethanol is evaporated off under vacuum using a rotary evaporator. The resulting aqueous phase is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness to give 25 g of crude efletirizine as an amorphous solid, 5 g of which are recrystallized in acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([OH:18])=[C:11]([O:19]C)[CH:10]=2)=[O:8])[CH:2]=1.[BrH:21]>>[BrH:21].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([OH:18])=[C:11]([OH:19])[CH:10]=2)=[O:8])[CH:2]=1
Reactant: COc1cc(C(=O)c2cccnc2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(c1cccnc1)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
3.5 g of 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl ketone dissolved in 70 ml of 48 percent aqueous hydrobromic acid are stirred at 100° for 18 hours. The reaction mixture is subsequently evaporated under reduced pressure. The residue is recrystallized from water. There is obtained 3,4-dihydroxy-5-nitrophenyl 3-pyridyl ketone hydrobromide of m.p. 265°.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16](C(OC(C)(C)C)=O)[C@H:17]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(Cl)Cl>[NH2:16][C@@H:17]([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: NCCCC[C@@H](N)C(=O)O
Reaction time: 1 h

Procedure:
One half (0.5) mmol of BOC3(DTPA) was dissolved in 10 ml DCM. 0.6 mmol of DCC was dissolved in 5 ml DCM and added to the BOC3(DTPA) mixture. The reaction was carried out for 1 hour at room temperature. The white crystals that appeared in the mixture were filtered out. 0.5 mmol of solid BOC-Lys-OtBu was added to the reaction. The reaction was carried out for 20 hours at room temperature. The mixture was filtered and the DCM was evaporated. The product was washed several times with ethanol and air-dried. Cleavage of the protecting groups (BOC, OtBu) was carried out in 1 ml TFA (trifluoroacetic acid)+5% water for 3 hours. The acid was evaporated in a vacuum over a KOH pellet. The final product D-Lys(DTPA) was washed several times with diethyl ether and dried. D-Lys(DTPA) was dissolved in water and lyophilized.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][NH2:17])=[NH:15])[CH:9]=2)[N:5]=[C:4]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:3]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].C[N:41](C)C=O.Cl.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[NH:15][N:41]=[N:17][N:16]=3)[CH:9]=2)[N:5]=[C:4]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=2)(=[O:21])=[O:20])[C:3]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]
Reactant: CN(C)C=O
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C(=N)NN)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(-c3nnn[nH]3)c2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
20 g (35 mmol) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-2-[2-(hydrazino-imino-methyl)-pyridine-4-yl]-5-(2-methoxy-phenoxy)-pyrimidine-4-yl]-amide were added to 160 ml of N,N-dimethyl formamide. The solution was kept at 15° C. to 20° C. and 23 ml of 6 N aqueous hydrochloric acid were added, followed by addition of a solution containing 4.8 g (7 mmol) of sodium nitrite in 20 ml de-ionized water within 10 min. The mixture was stirred at 20° C. for 1 hr, then 140 ml of de-ionized water were added and the suspension was stirred at 0° C. for 1 hr. The solid was filtered, firstly washed with 80 ml of de-ionized water and thereafter with 80 ml of t-butylmethylether. Then the solid was dried at 70° C. and 2000 Pa for 16 hr. The crude product (23.4 g) was taken up with 117 ml of tetrahydrofuran for 1 hr. After filtration at 0° C. the crystallized product was washed with 25 ml of t-butylmethylether and was then dried at 70° C., 2000 Pa for 16 hr. There were obtained 17.3 g (84% of theory) of 5-isopropyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide with a HPLC purity of 91.1% (w/w).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[Cl-].[Cl-].C([Al+2])C.[C:12]([O:15][C@@H:16]1[C@@:34]2([CH3:35])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:24]3[CH2:25][CH2:26]/[C:27]/2=[CH:28]/[CH3:29])[CH2:19][C@@H:18]([O:37][C:38](=[O:40])[CH3:39])[CH2:17]1)(=[O:14])[CH3:13].P([O-])(O)(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C@H:28]([C:27]1[C@:30]2([CH3:36])[C@H:24]([C@H:23]3[C@H:33]([CH2:32][CH2:31]2)[C@:34]2([CH3:35])[C:20]([CH2:19][C@@H:18]([O:37][C:38](=[O:40])[CH3:39])[CH2:17][C@@H:16]2[O:15][C:12](=[O:14])[CH3:13])=[CH:21][CH2:22]3)[CH2:25][CH:26]=1)[CH3:29]
Reactant: C#CC(=O)OC
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC[Al+2]
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C=C[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 88.7 %

Procedure:
To a magnetically-stirred solution of 3.9 ml (45 mmol) of methyl propiolate and 150 ml of dry methylene chloride under an argon atmosphere was added by syringe 58 ml (107 mmol) of 25% ethylaluminum dichloride in toluene, followed as rapidly as possible by a solution of 12.0 g (30 mmol) of Z-pregna-5,17(20)-diene-1α,3β-diol diacetate in 150 ml of dry methylene chloride. The temperature rose to 35° after the catalyst addition. After 1.75 hr., the yellow reaction solution was poured into a well-stirred, ice-cold 1 l. of saturated sodium dihydrogen phosphate solution. About 600 ml of ethyl acetate was added, and the phases were separated. The aqueous phase was extracted with 2×600 ml of ethyl acetate, and the organic phases were washed in a countercurrent manner with 500 ml of water and 500 ml of brine, dried (Na2SO4), filtered and evaporated to give 15.32 g of crude product. High-pressure liquid chromatography on 1 kg of silica gel using 9:1 hexane--ethyl acetate for elution afforded after three passes 12.9 g (89%) of 1α,3β-diacetyloxychola-5,16,22-trien-24-oic acid methyl ester as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C:18]#[N:19])([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+]>O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C:8](=[O:9])[NH:19][CH2:18]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccs1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC1(c2cccs2)CNC(=O)C1

Procedure:
Prepare by the method of example 1.2 using 3-cyano-3-(thiophen-2-yl)-pentanedioic acid diethyl ester (28 mmol), cobalt (II) chloride hexahydrate (55.5 mmol), and NaBH4 (290 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:41])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:19][C:13]=3[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)[C:11]2=[O:40])=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:41])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:19][C:13]=3[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)[C:11]2=[O:40])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a mixture of 4′-{[3-[2-(4-fluorophenyl)-2-oxoethyl]-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.9 g), tetrahydrofuran (20 mL) and methanol (20 mL) was added sodium borohydride (0.19 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.41 g, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:4]=1[CH2:5][O:6][C:7]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)=[O:8].C(Cl)(=O)C(Cl)=O.[CH2:31]([O:33][CH:34](O)[CH3:35])[CH3:32].O>C1COCC1.CN(C=O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:4]=1[CH2:5][O:6][C:7]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:32][CH2:31][O:33][CH2:34][CH3:35])=[O:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCOC(C)O
Reactant: COc1ccc(OC)c(COC(=O)Nc2ccc(C(=O)O)cc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOCCOC(=O)c1ccc(NC(=O)OCc2cc(OC)ccc2OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of N-(2,5-dimethoxybenzyloxy-carbonyl)-para-aminobenzoic acid (3.31g) in dry THF (30ml) was treated with oxalyl chloride (1.65g) and one drop of dry DMF. After 0.5 hour the reaction had subsided and the acid chloride solution was added dropwise to a stirred solution of ethoxyethanol (1.2g) in dry pyridine, then poured into water (ca 250ml) and the crude product extracted into ether. The ether was washed with 1N HCl 1N NaOH, water and dried with Mg SO4. The solvent was concentrated in vacuo leaving a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:4]1.[OH:24]S(O)(=O)=O>>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:17])=[O:24])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:4]1
Reactant: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 70 °C
Yield: 78 %

Procedure:
Solid 126 (500 mg, 1.48 mmol), was added to 90% H2SO4 (5 μL) and heated to 70° C. for 1 h. After cooling to room temperature, the mixture was poured into ice-water and extracted with EtOAc (3×50 mL). The extracts were dried and concentrated under reduced pressure. Chromatography of the residue on silica gel (EtOAc/petroleum ether, from 1:1 to 1:0) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carboxamide (128) (410 mg, 78%) as a white solid: mp (EtOAc/petroleum ether) 190-193° C.; 1H NMR (CDCl3) δ 8.54-8.45 (m, 2H), 7.89 (d, J=5.8 Hz, 1H), 7.69 (dd, J=7.1, 1.1 Hz, 1H), 7.59 (dd, J=8.4, 7.1 Hz, 1H), 5.91 (br, 2H), 4.69-4.61 (m, 1H), 4.48-4.40 (m, 1H), 4.25-4.17 (m, 1H), 3.97-3.89 (m, 1H), 3.58-3.50 (m, 1H; 13C NMR δ 170.7, 153.8 (q, JC-F 38.0 Hz), 140.5, 134.6, 129.7, 128.6, 126.5, 125.6, 125.4, 124.8, 118.4, 115.4 (q, JC-F 288 Hz), 53.4, 45.4, 43.0. Anal. (C16H12ClF3N2O2) C, H, N, Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:23][CH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][N:16]=1)=[O:9]
Reactant: NCc1cnccn1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(NCc1cnccn1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
To a suspension of 5-chlorosalicylic acid (0.96 g, 5.6 mmol) in dichloromethane (13 mL) was added thionyl chloride (2 mL, 28 mmol) and N,N-dimethylformamide (˜3 drops). The reaction mixture was heated at reflux for 1 h, at which point a clear solution was obtained. The mixture was allowed to cool to ambient temperature and was concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL), and pyrazin-2-ylmethanamine (0.80 g, 4.6 mmol), N,N-diisopropylethylamine (1.6 mL, 9.3 mmol), and 4-(N,N-dimethylamino)pyridine (0.056 m, 0.5 mmol) were added. The reaction mixture was stirred at ambient temperature for 16 h, diluted with dichloromethane (70 mL) and washed with 1 N hydrochloric acid (2×7 mL), water (2×7 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a 10-60% gradient of ethyl acetate in hexanes to afford 5-chloro-2-hydroxy-N-(pyrazin-2-ylmethyl)benzamide as a yellow solid in 31% yield (0.379 g): 1H NMR (300 MHz, CDCl3) δ12.10 (s, 1H), 8.67 (s, 1H), 8.57 (s, 2H), 7.57 (br s, 1H), 7.46 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.9, 1.8 Hz, 1H), 6.93 (d, J=8.9 Hz, 1H), 4.78 (d, J=4.8 Hz, 2H); MS (ES+) m/z 264.0 (M+1), 266.0 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]4[N:16]=[C:17]([NH:19][C:20]5[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:27])[NH:18][C:9]=4[C:7]=3[N:8]=2)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[C:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].[H-].[Na+]>C1COCC1.C1C=CC=CC=1>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:13]([C:12]2[C:6]3[O:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:8][C:7]=3[C:9]3[NH:18][C:17]([NH:19][C:20]4[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:27])=[N:16][C:10]=3[CH:11]=2)=[O:15])=[CH:41][CH:42]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)[nH]c3c3nc(C4CC4)oc23)cc1
Yield: 11.3 %

Procedure:
The title compound was prepared following the procedure as described for Example-177 using 2-cyclopropyl-7-[(2,6-dichlorophenyl)amino]-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-58, 0.100 g, 0.248 mmol), benzene (4 mL), thionyl chloride (5.0 mL), 4-tert-butylaniline (0.055 g, 0.369 mmol), THF (5.0 mL) and 60% NaH (0.095 g, 0.744 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.20 (s, 4H), 1.29 (s, 9H), 2.32 (m, 1H), 7.28 (d, J=7.8 Hz, 3H), 7.59 (s, 3H), 7.68 (d, J=8.4 Hz, 2H), 9.36 (s, 1H), 9.90 (s, 1H), 11.55 (s, 1H); MS [M+H]+: 534.32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([O:16]C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[Si](C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([OH:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccc(Cl)cc2)n(C)c1=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cn1c(-c2ccc(Cl)cc2)ccc(O)c1=O
Temperature: 150 °C
Yield: 19.44 %

Procedure:
To a solution of crude 6-(4-chlorophenyl)-3-methoxy-1-methylpyridin-2(1H)-one in 5 mL acetonitrile was added iodotrimethylsilane (154 μL, 1.132 mmol) and the mixture was heated to 150° C. for 10 minutes. The reaction mixture was quenched with excess methanol, evaporated and purified using reversed-phase HPLC to afford 6-(4-chlorophenyl)-3-hydroxy-1-methylpyridin-2(1H)-one (17.3 mg, 19.44% yield).1H NMR (499 MHz, DMSO-d6): δ 7.68 (d, 1 H), 7.49 (dd, 1 H), 3.74 (s, 1 H), 2.54 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:20])=[C:7]2[O:11][C:10]([N:12]([CH3:14])[CH3:13])=[N:9][C:8]2=[C:15]([C:18]#[N:19])[C:16]=1[CH3:17])=O.[C:21]([NH2:24])(=[S:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:13][N:12]([CH3:14])[C:10]1[O:11][C:7]2[C:8](=[C:15]([C:18]#[N:19])[C:16]([CH3:17])=[C:5]([C:3]3[N:24]=[C:21]([CH3:22])[S:23][CH:2]=3)[C:6]=2[F:20])[N:9]=1
Reactant: CC(N)=S
Reactant: Cc1c(C(=O)CBr)c(F)c2oc(N(C)C)nc2c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2c(C)c(C#N)c3nc(N(C)C)oc3c2F)cs1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
6-(Bromoacetyl)-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-170) (0.60 g, 1.76 mmol) was dissolved in toluene (30 ml), then thioacetamide (0.16 g, 2.13 mmol) and cesium carbonate (0.75 g, 2.30 mmol) were added, followed by stirring at an external temperature of 100° C. for 16 hours. The reaction liquid was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain a yellow solid (0.44 g, 79%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([F:25])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:3]=1.[CH2:34]([Sn](CCCC)(CCCC)C=C)[CH2:35]CC.CC1C=CC(C)=CC=1>C(OCC)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Si:27]([O:26][C:4]1[CH:3]=[C:2]([CH:34]=[CH2:35])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([F:25])[CH:12]=3)=[N:7][C:6]=2[CH:5]=1)([C:30]([CH3:33])([CH3:31])[CH3:32])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)c2oc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)nc2c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: CCOCC
Solvent: Cc1ccc(C)cc1
Product: C=Cc1cc(O[Si](C)(C)C(C)(C)C)cc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Dichlorobis(tri-o-tolylphosphine)palladium (II) (0.63 g, 0.79 mmol) was added into a mixture of 7-bromo-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-1,3-benzoxazole (14.7 g, 26.6 mmol), tributyl(vinyl)tin. (10.5 g, 33.25 mmol) and p-xylene (85 mL). The reaction mixture was stirred at 90° C. for 24 h, cooled to room temperature, diluted with ethyl ether (100 mL) and treated with activated carbon. The mixture was filtered through MgSO4 and concentrated. Purification by flash chromatography (hexanes/EtOAc 50/1) gave a white solid (11.8 g, 89% yield, m.p. 93–95° C.); MS m/e 500 (M+H)+.
Reaction SMILES: CC(C)([O:4][C:5](=[O:23])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][N:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:18]=2)=[CH:10][CH:9]=1)C>FC(F)(F)C(O)=O>[CH3:22][C:19]([N:17]1[N:16]=[N:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][C:5]([OH:23])=[O:4])=[CH:9][CH:10]=2)=[N:18]1)([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)CCc1ccc(-c2nnn(C(C)(C)C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(-c2ccc(CCC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
5-[4-(3-(1,1-dimethylethoxy)-3-oxopropyl)phenyl]-2-(1,1-dimethylethyl)-2H-tetrazole (1.0 g, 3.7 mmol) was dissolved in trifluoroacetic acid (14 mL) and stirred at room temperature under argon for 12 hours. The mixture was concentrated and then dissolved in water (35 ml). After adding enough sat. NaHCO3 to raise the pH to 8, the solution was washed with diethyl ether (2×10 mL). The aqueous layer was acidified to pH 3 with 1N HCl and the product was collected by suction filtration to give 4-[2-(1,1-dimethylethyl)-2H-tetrazole-5-yl]benzenepropanoic acid (0.7 g, 3.1 mmol) in 84% yield, mp. 88°-90° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:14]1[N:19]=[C:18](Cl)[C:17]2[N:21]=[CH:22][N:23]([C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[C:16]=2[N:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][NH:13][C:18]2[C:17]3[N:21]=[CH:22][N:23]([C:16]=3[N:15]=[CH:14][N:19]=2)[C@@H:24]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]2[OH:32])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CONc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1

Procedure:
The title compound was prepared according to Method A described above (R2, R3 =H) by reacting O-[(4-nitrophenyl)methyl]hydroxylamine hydrochloride (1.43 g, 7 mmol) with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-6-chloro-9H-purine) (1.0 g, 3.5 mmol) in DMF (40 ml) at 110° C. for 2 h with diisopropylethylamine (1.80 g, 14 mmol) present. The reaction mixture was evaporated and to the resultant residue was added saturated sodium bicarbonate solution (20 ml) and water (20 ml). Methanol was gradually added until the residue dissolved, and the solid which gradually precipitated was removed by filtration. The flitrate was concentrated to a residue which was purified by flash chromatography on silica gel. Elution with ethyl acetate/ethanol (30/1) initially, followed by a (8/1) mixture of these solvents provided a solid which was recrystallized from ethanol. The first crop of material was discarded, but the second crop was confirmed as the title compound (70 mg, 7%) mp 115°-117 ° C. TLC rf 0.20 [SiO2, ethyl acetate/methanol (9/1)]; 1H NMR (DMSO-d6)γ 3.46-3.57 (2H, m, H-5'a and H-5'b), 3.90 (1H, q, H-4'), 4.08 (1H, q, H-3'), 4.43 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.44, 5.74 (2H, 2d, 2'and 3'-OH), 5.82 (1H, d, H-1'), 7.67 (2H, d, Ar-H), 8.08 (1h, s, H-8), 8.22 (2H, d, Ar-H), 9.34 (1H, br s, N-H).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[CH2:10](N(CC)CC)C.IC>C(#N)C>[O:6]=[C:4]1[CH:1]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][O:5]1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1CCOC1=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Cyclopropane-1,1-dicarboxylic acid (10 g) in acetonitrile(200 ml) was treated with triethylamine (43 ml) and iodomethane (19 ml) at room temperature. The solution was stirred for 2 h then heated at 75° C. for 16 h. The solvent was removed under reduced pressure, the residue dissolved in water, extracted with ethyl acetate, dried(MgSO4) and evaporated to a brown oil (6.70 g).