Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reaction time: 20 h

Procedure:
10.0 g (61.1 mmol) of 2-chloroquinoline is dissolved in 34 ml of concentrated sulfuric acid. At 0° C., 8.4 g (76.4 mmol) of potassium nitrate is added in portions. After 20 hours at room temperature, the reaction mixture is poured onto ice water, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium bicarbonate solution and dried on sodium sulfate. After the solvent is removed in a vacuum and after chromatography on silica gel with hexane-ethyl acetate (10–100%), 5.06 g (40% of theory) of the product is obtained.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Li+].O>C1COCC1>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Yield: 88.1 %

Procedure:
Methyl 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (1.06 g, 2.6 mmol) was dissolved in THF (24 mL) and methanol (8 mL) then 1N lithium hydroxide solution (3.12 mL) added, followed by the dropwise addition of water (10 mL). The resultant solution was stirred for 3 hours at RT, a further portion of 1N lithium hydroxide solution (1.3 mL), the reaction stirred a further 2 hours, then further 1N lithium hydroxide solution (0.6 mL) added and stirring continued for another hour. The organics were removed by evaporation under reduced pressure, the aqueous solution was washed with diethyl ether (10 mL) then acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organics were washed with water (10 mL), brine (10 mL) and evaporated to dryness under reduced pressure to give the desired compound as a white solid (887 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:19](OS(C)(=O)=O)[CH3:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].C1OCCOCCOCCOCCOC1.CCOC(C)=O>CN(P(N(C)C)(N(C)C)=O)C>[N:26]([CH:19]([CH3:20])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of mesylate 108 (500 mg, 1.26 mmol) in HMPA (2 mL), NaN3 (409 mg, 6.29 mmol) and 15-crown-5 ether (252 mg, 1.26 mmol) were added. The solution was stirred at 55° C. for 3 h. The reaction mixture was added to EtOAc (30 mL), washed with brine (10 mL), dried (Na2SO4) and evaporated. The crude oil was purified by column chromatography (silica gel, EtOAc/Hexanes 1/15) to afford azide 109 (160 mg, 34%) as a colorless oil. Rf 0.33 (AcOEt/Hexanes 1/15). [α]D20=−46.6 (c=0.4, CHCl3). 1H-NMR (500 MHz, CDCl3): 0.04 (s, 6H), 0.88 (s, 9H), 1.32 (d, J=6.7 Hz, 3H), 1.48 (s, 9H), 3.51-3.61 (m, 1H), 4.75-4.90 (m, 2H), 4.50-4.62 (m, 1H). 13C-NMR (125 MHz, CDCl3): −5.5, 14.1, 16.5, 25.8, 28.3, 31.6, 55.2, 57.2, 62.4, 174.3. IR (neat) 3326.1, 2954.0, 2931.1, 2857.9, 2359.9, 2107.2, 1718.2, 1005.7, 1471.2, 1366.0, 1254.5, 1167.7, 1098.0, 838.1.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([CH3:23])[C:7]([N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].[Cl:31][C:32]1[N:37]=[C:36](Cl)[CH:35]=[CH:34][N:33]=1>C1COCC1.C(O)C>[Cl:31][C:32]1[N:37]=[C:36]([NH:1][C:2]2[CH:25]=[CH:24][C:5]3[N:6]([CH3:23])[C:7]([N:9]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[N:8][C:4]=3[CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccccc2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Temperature: 75 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
To a solution of tert-butyl 5-amino-1-methyl-1H-benzimidazol-2-yl(phenyl)carbamate (1.03 g, 3.0 mmol) in THF (3 ml) and ethanol (9 ml) was added NaHCO3 (0.76 g, 9.0 mmol) and 2,4-dichloropyrimidine (0.89 g, 6.0 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. The crude material was purified on silica gel to give the title compound as a white foam (0.98 g, 73%). 1H NMR (300 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.10 (d, J=5.7 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.36-7.39 (m, 5H), 7.24-7.34 (m, 1H), 6.70 (d, J=6.0 Hz, 1H), 3.73 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[I:19]Cl>C(O)(=O)C.FC(F)(F)C(O)=O.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:19]
Reactant: ClI
Reactant: CC(=O)NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1

Procedure:
(S)-N-[[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]- acetamide (PREPARATION 17, 0.280 g, 1.11 mmol) is dissolved in a mixture of acetic acid (20 ml) and trifluoroacetic acid (5 ml) and then treated with iodine monochloride (2.343 g, 14.43 mmol) at 20-25°. The mixture is stirred at 20-25° under nitrogen. After about 24 hr the reaction mixture is diluted with ether and the solids collected under reduced pressure through a medium-porosity sintered glass filter, washing with ether. The crude solids are dissolved in hot chloroform (a little methanol is added), transferred to a separatory funnel, and washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, mp 185.5-186.5°; [α]25D -37.6° (c 1.0, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=O)[C:10]=2[C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:12]=[N:13][C:14]([CH3:15])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Product: COc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
2.06 g of 5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.14 g of 3-chloro-5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xix) of the present invention).
Reaction SMILES: O1CCNC1=O.[NH2:7][CH2:8][C@@H:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([N:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:23]3=[O:48])=[C:17]([CH3:49])[CH:16]=2)[CH2:10]1.[Cl:50][C:51]1[S:55][C:54]([C:56](Cl)=[O:57])=[CH:53][CH:52]=1>>[C:44]([Si:31]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:30][CH2:29][CH2:28][C:24]1[C:23](=[O:48])[N:22]([C:18]2[C:17]([CH3:49])=[CH:16][C:15]([N:11]3[CH2:10][C@H:9]([CH2:8][NH:7][C:56]([C:54]4[S:55][C:51]([Cl:50])=[CH:52][CH:53]=4)=[O:57])[O:13][C:12]3=[O:14])=[CH:20][C:19]=2[CH3:21])[CH:27]=[CH:26][CH:25]=1)([CH3:45])([CH3:46])[CH3:47]
Reactant: Cc1cc(N2C[C@H](CN)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: O=C1NCCO1
Product: Cc1cc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
To prepare the compound of the Formula (Ia), 3-bromopyridin-2(1H)-one (III) is reacted with 1-fluoro-2,5-dimethyl-4-nitrobenzene (IV) to give 3-bromo-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (V). Then, (V) is converted with tributylvinyl tin and tetrakis(triphenylphosphine)palladium into 1-(2,6-dimethyl-4-nitrophenyl)-3-vinylpyridin-2(1H)-one (VI). Hydroboration and oxidation of (VI) produces 1-(2,6-dimethyl-4-nitrophenyl)-3-(2-hydroxyethyl)pyridin-2(1H)-one (VII). In order to protect the hydroxy group, (VII) is reacted with tert-butyl(chloro)diphenylsilane in the presence of a base, giving 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (VIII). The reduction of the nitro group in (VIII) leads to 1-(4-amino-2,6-dimethylphenyl)-3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (IX). Then follows the reaction of (IX) with (S)-epoxyphthalimide (X) to give 2-[(2R)-3-({4-[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}amino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (XI). Ring closure to the oxazolidinone and cleaving off the phthalimide group produces starting from (XI) 1-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-dimethylphenyl}-3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (XII), which is reacted with 5-chlorothiophene-2-carbonyl chloride (XIII) to give N-[((5S)-3-{4-[3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chlorothiophene-2-carboxamide (XIV). Cleaving off the protective group in (XIV) produces 5-chloro-N-[((5S)-3-{4-[3-(2-hydroxyethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide (IIa), which is reacted with trans-4-aminohexanol (XV) to give 5-chloro-N-{[(5S)-3-{4-[3-{2-[(trans-4-hydroxycyclohexyl)amino]ethyl}-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide (Ia).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: OCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-c2nc(N)nc(OCc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 392 (M+, 40), 91 ([PhCH2]+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][OH:10].C[O-].[Na+]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: CO
Reactant: Brc1ccc(Br)nc1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
2,5-Dibromopyridine (200 g) and 28% sodium methoxide methanol solution (1535 g) were heated under reflux for 30 minutes, followed by cooling to room temperature. The mixture was partitioned between water (1.6 L) and tert-butylmethyl ether (1.6 L). The resulting organic layer was washed with brine (1 L) for 3 times, and then dried over anhydrous magnesium sulfate overnight. The dried organic layer was evaporated at 65° C., to give 160 g (96%) of the title compound as a brown oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+]>O>[C:1]([C:29]1[C:28]([CH3:31])=[CH:27][C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])=[C:9]([CH3:8])[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(C)=O)cc1C
Yield: 81 %

Procedure:
Acetic anhydride (26 mL, 5 eq) was stirred together with methane sulfonyl (18 mL, 5 eq) at room temperature for 30 min and then combined with 18.0 g (55.16 mmol) of (E)-methyl 2-(2-((2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in step 1 at room temperature for an additional one hour. After completion of the reaction, the reaction mixture was dropwise added to water (500 mL), adjusted to pH 7 with 25%-NaOH and extracted twice with 250 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered after which the solvent was removed by concentration in a vacuum. Crystallization in 100 mL of isopropyl ether (IPE) afforded 16.5 g of (E)-methyl 2-(2-((4-acetyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate in 81% yield as an ivory solid.
Reaction SMILES: CC1C=CC(S([O:11][CH:12]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]2)(=O)=O)=CC=1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22](O)=[CH:21][C:20]=1[CH3:27]>>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:11][CH:12]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]2)=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Product: Cc1cc(OC2CCC(O)C2)cc(C)c1Br

Procedure:
The title compound is prepared from 3-hydroxycyclopentyl 4-methylbenzenesulfonate and 4-bromo-3,5-dimethylphenol following a procedure analogous to that described in Step 3 of Intermediate 2. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=285 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cncc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cncc(OCC(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A mixture of tert-butyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyridin-3-yl)oxy]acetate obtained in Example 35 (500 mg) and trifluoroacetic acid (7 mL) was stirred at room temperature for 3 h. Water was added to the reaction solution, and subsequently 1 M sodium hydroxide solution was added to the mixture to pH 5-6. The resulting precipitate was collected and dried under reduced pressure to provide the title compound (405 mg, 93%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[I:12])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(I)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: ClCCl
Product: OCc1ccc(I)c(Br)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A solution of methyl 3-bromo-4-iodobenzoate (Preparation 23, 4.3 g, 12.6 mmol) in CH2Cl2 was cooled, under N2, to −78° C. DIBAL-H was added slowly to the solution, which was stirred at −78° C. for 45 minutes and then allowed to come to room temperature. Next, the reaction mixture was diluted with 1M HCL (40 mL) and stirred for 30 minutes. The reaction was further diluted with water and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under vacuum to afford the intermediate (3.2 g, 82%) as a solid. 1HNMR (CDCl3): 7.85 (1H), 7.67 (1H), 7.02 (1H), 4.65 (2H), 1.76 (1H, OH).
Reaction SMILES: [CH2:1]([CH:8]=[CH:9]CCCCC)[C:2]1C=CC=C[CH:3]=1.CCOCC.[C:20]([OH:23])(=[O:22])[CH3:21].O>C1COCC1>[C:20]([OH:23])([OH:22])=[CH:21][CH2:3][CH2:2][CH2:1][CH2:8][CH3:9]
Reactant: CCCCCC=CCc1ccccc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCC=C(O)O

Procedure:
A solution of the benzyl ether 4, 80 ml of acetic acid and 20 ml of water in 50 ml of THF was stirred at 70° C. overnight. The solution was then concentrated under vacuum and the residue purified by chromatography over silica gel (3 EtOAc: 2 hexanes) to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[C:7]([F:32])[CH2:6]1)[CH3:3].N1CC[CH2:35][CH2:34]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[CH:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[O:16])=[C:7]([F:32])[CH2:6]2)[CH2:1][CH2:35][CH2:34][CH2:3]1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2)=C(F)C1
Reactant: C1CCNC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=C(F)CC(=NN2CCCC2)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.284 mmol) from EXAMPLE 33, a pre-mixed pyrrolidine (0.119 mL, 1.43 mmol) and HOAc (0.122 mL, 2.14 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (17 mg). MS 494.1 and 496.2 (M+H, Cl pattern).
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(N(CC)CC)C.[CH2:25]([O:29][C:30](Cl)=[O:31])[CH2:26][CH2:27][CH3:28]>CC(N(C)C)=O.C(O)C>[CH2:25]([O:29][C:30]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)Cl
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 5.0 g of triethylamine and 3.37 g of butyloxycarbonyl chloride. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After completion of the reaction, the solvent is evaoprated under reduced pressure. The residue is diluted with 20 ml of ethanol, followed by addition of 150 ml of petroleum ether. After the mixture is stirred at 0° to 5° C. for one hour, the resultant precipitates are collected by filtration. The precipitates are dissolved in 15 ml of methanol and then 100 ml of water is added to the resultant solution. The mixture is left to stand in a refrigerator and the precipitated crystals are filtered to give 2.8 g of N4 -butyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:50%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[CH2:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].B.CSC.[OH:31]O.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:24])([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:23][OH:31])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: OO
Reactant: C=C(CCCCC(C)(C)C(=O)OCC)CCCCC(C)(C)C(=O)OCC
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)C(C)(C)CCCCC(CO)CCCCC(C)(C)C(=O)OCC
Reaction time: 6 h
Yield: 75 %

Procedure:
Into a stirred solution of 2,2,12,12-tetramethyl-7-methylene-tridecanedioic acid diethyl ester (3.7 g, 10 mmol) in anhydrous THF (50 mL) was added borane-methyl sulfide complex (2.0 M in THF, 6 mL, 12 mmol) at room temperature and the solution was stirred for 6 h under argon atmosphere. Hydrogen peroxide (50 wt. % solution in water, 9 mL, 144 mmol) and an aqueous solution of sodium hydroxide (30 mL, 2.5 M, 75 mmol) were slowly introduced at 0-5° C. The reaction mixture was stirred for an additional h at room temperature and then extracted with dichloromethane (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, evaporated, and purified by column chromatography on silica (hexanes:ethyl acetate=95:5, then 90:10) to furnish the product (2.9 g, 77%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): 8 (ppm): 4.11 (q, 4 H, J=7.0 Hz), 3.51 (d, 2 H, J=5.4 Hz), 1.60-1.16 (m, 18 H), 1.25 (t, 6 H, J=7.0 Hz), 1.15 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 65.3, 60.1, 42.0, 40.6, 40.4, 30.7, 27.2, 25.4, 25.1, 14.2. HRMS (LSIMS, nba): Calcd. for C22H43O5 (MH+): 387.3110, found 387.3108.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+].Cl.C([NH+](CC)CC)C>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Combine methyl 2-methoxy-5-cyanobenzoate (0.67 mmol), sodium azide (0.13 g, 2.04 mmol), and triethylammonium hydrochloride (0.14 g, 1.03 mmol) in N-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the aqueous layer three times with ethyl acetate. Adjust the pH of the aqueous layer to about 1 using a 1M aqueous hydrochloric acid solution. The aqueous layer is again extracted three times with ethyl acetate, and twice with dichloromethane. The aqueous layer is saturated with sodium chloride and again extracted four times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate.