Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][O:6][C:7]2=[O:8].[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([N+:31]([O-])=O)=[C:27]([CH:30]=1)[CH:28]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:31][C:7]3[C:9]4[C:4]([C:5](=[O:6])[C:28]=3[C:27]=2[CH:30]=1)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=4)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:31][C:5]3[C:4]4[C:9]([C:7](=[O:8])[C:28]=3[C:27]=2[CH:30]=1)=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: COc1cc(OC)c2c(c1)C(=O)OC2
Product: COc1cc(OC)c2c(c1)-c1[nH]c3ccc(OCc4ccccc4)cc3c1C2=O
Product: COc1cc(OC)c2c(c1)C(=O)c1c-2[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
By proceeding in accordance with the process described in Example 1 starting from 4,6-dimethoxy-phthalide and 5-benzyloxy-2-nitro-benzaldehyde, the expected product is obtained in a mixture with 8-benzyloxy-2,4-dimethoxy-indeno[1,2-b]indol-10(5H)-one.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:7]1([N:13]2[C:17]([NH2:18])=[C:16]([C:19]#[N:20])[CH:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[C:7]1([N:13]2[C:17]([NH:18][C:1]([CH2:2][CH2:3][CH3:4])=[O:5])=[C:16]([C:19]#[N:20])[CH:15]=[N:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC(=O)Cl
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1c(C#N)cnn1-c1ccccc1
Temperature: 50 °C
Yield: 50 %

Procedure:
6.8 ml (66 mmol) of butyryl chloride were added to a solution of 5.52 g (30 mmol) of 1-phenyl-4-cyano-5-aminopyrazole [known from J. Org. Chem. 21 (1956), 1240] in 70 ml of pyridine. The mixture was heated for 15 hours at 50° C. and then poured into 500 ml of 5% strength by weight aqueous hydrochloric acid. The product was extracted from the aqueous phase with methylene chloride and then isolated in a conventional manner. Yield: 50%.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].Br[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.Cl.[C:20]1([C@@H:26]2[CH2:28][C@H:27]2[NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([CH:26]2[CH2:28][CH:27]2[NH:29][S:2]([N:5]2[CH2:9][CH2:10][O:11][C:6]2=[O:7])(=[O:4])=[O:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCBr
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCCN1S(=O)(=O)NC1CC1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask was added chlorosulfonyl isocyanate (0.4 mL, 4.64 mmol) and methylene chloride (5 mL) under an atmosphere of argon. The mixture was cooled in an ice bath and 2-bromoethanol (0.535 mL, 7.55 mmol) in methylene chloride (1 mL) was added dropwise. After stirring for 30 minutes at 0° C., triethylamine (2.28 mL, 16.4 mmol) and trans-2-phenylcyclopropylamine hydrochloride (0.867 g, 5.11 mmol), 6a, in methylene chloride (5 mL) was added at such a rate that the reaction temperature was maintained between 0° C. and 10° C. The resulting solution was stirred at rt for 5 h and then partitioned between 1N HCl and water. The organic layer was dried with sodium sulfate, filtered and concentrated. The crude was purified by chromatography to give 569 mg of a waxy solid, 8a.
Reaction SMILES: [C:1]([C:4](=[C:9](OC)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15].[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+:23].Cl>C1COCC1.CO.CC(C)=O>[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+:23].[CH3:15][C:14]1[N:17]=[C:1]([CH3:2])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:9]([CH3:10])[N:16]=1
Reactant: COC(=O)C(C(C)=O)=C(C)OC
Reactant: CC(=N)N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1c(C)nc(C)nc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-acetyl-3-methoxy-2-butenoate (34.4 g, 0.2 mole), acetamidine hydrochloride (22.7 g), acetone (136 ml) and methyl alcohol (100 ml) were charged into a 1 L 3-necked, flask (fitted with addition funnel, condenser, agitator and nitrogen inlet). The reaction was blanketed with nitrogen, the agitator started and the batch cooled to between −5 and 0° C. While the batch was cooling, a solution of potassium t-butoxide was prepared (27 g in THF, 100 ml) under nitrogen. When the batch reached the correct temperature, the potassium t-butoxide solution was slowly charged, keeping the temperature below 5° C. The batch was allowed to warm to about 25° C. The reaction was complete after about 1.5 hours. Concentrated hydrochloric acid was charged dropwise to bring the pH to 7. The batch was concentrated under vacuum until no more volatiles were collected. Methyl t-butylether (140 ml) and water (85 ml) were charged. The batch was agitated for 10 minutes and the layers were then separated. The organic layer was concentrated under vacuum to afford a solid residue of methyl 2,4,6-trimethylpyrimidine-5-carboxylate, 35.8 g. The product was purified by crystallizing from methanol. m. p. 61–62° C., 1H NMR (CDCl3): δ2.44 (6H, s, CH3), δ2.61 (3H, s, CH3), δ3.88 (3H, s, OCH3). 13H CMR (CDCl3): δ168.57, δ168.00, δ164.83, δ123.71, δ52.87, δ26.38, δ23.26. HR-MS; Calculated for C9H13N2O2, m/z=181.0977. Found 181.0972.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccccc1C#N
Yield: 90.6 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.602 g, 2.25 mmol), α-bromo-o-tolunitrile (0.668 g, 3.41 mmol), KI (100 mg, 0.60 mmol), and DIPEA (0.80 mL, 4.59 mmol) in DMF (11 mL) was heated at 60° C. for 23 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.78 g (91%) of 2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a tan solid. 1H NMR (CDCl3) δ 1.63-1.73 (m, 3H), 2.02-2.07 (m, 1H), 2.26-2.38 (m, 2H), 2.48 (s, 6H), 3.69 (s, 2H), 4.12 (d, 2H, J=10.8 Hz), 6.83-6.89 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 7.19-7.26 (m, 3H), 7.64 (d, 1H, J=7.8 Hz), 8.27 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 19.44, 25.53, 29.42, 52.72, 67.05, 109.86, 118.06, 122.19, 125.90, 130.68, 131.41, 131.54, 132.02, 138.18, 145.77, 147.23, 159.61; ES-MS m/z 383 (M+H). Anal. Calcd. For C25H26N4 C, 78.50; H, 6.852; N, 14.65. Found: C, 78.28; H, 6.93; N, 14.57.
Reaction SMILES: S1C=CC2C(=O)CCCCC1=2.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH:22]C=O)[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2.C(N)=O.[ClH:28]>>[ClH:28].[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2
Reactant: O=CNC1CCCCc2sccc21
Agent: Cl
Agent: O=C1CCCCc2sccc21
Solvent: NC=O
Product: NC1CCCCc2sccc21

Procedure:
5,6,7,8-Tetrahydro-4H-cyclohepta[b]thiophen-4-one is converted to N-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)formamide, m.p. 164°-166° C., by the method of Kloetzel et al., Journal of Organic Chemistry 18, 1511 (1953). Hydrolysis of the formamide is accomplished by refluxing for one hour in 1N hydrochloric acid and evaporating to dryness to afford 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride, m.p. 233°-236° C. dec. The amine hydrochloride is then allowed to react with methyl isocyanate in dry tetrahydrofuran as solvent in the presence of a stoichiometric equivalent of triethylamine to afford 1-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea, m.p. 220°-222° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=2)=[S:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O.C(O)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17][C@@H:18]([CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=2)=[S:20])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of K2CO3 (962 mg) in water (15 ml) was added to a solution of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.23 g) in ethanol (50 ml). The whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and then the mixture was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure and the crude product was recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-methylthiobutanamide (800 mg).
Reaction SMILES: [NH2:1]/[C:2](=[N:15]\O)/[C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4].[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19](OC)=[O:20].C([O:31]C)(C)(C)C>CO>[CH3:14][C:11]1[O:10][C:9]([C:7]([NH:6][C:3]([C:2]2[NH:1][C:19](=[O:20])[C:18]([OH:31])=[C:17]([C:23]([O:25][CH3:26])=[O:24])[N:15]=2)([CH3:5])[CH3:4])=[O:8])=[N:13][N:12]=1
Reactant: Cc1nnc(C(=O)NC(C)(C)/C(N)=N/O)o1
Reactant: COC(C)(C)C
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1nc(C(C)(C)NC(=O)c2nnc(C)o2)[nH]c(=O)c1O
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
N-[(1Z)-1-amino-1-(hydroxyimino)-2-methylpropan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide (IVa) (198 gms) was suspended in methanol (1188 ml) and cooled to 15 to 25° C. Dimethyl acetylenedicarboxylate (DMAD; 152.8 gms) was added and the reaction mass was stirred for 2 to 3 hours at 25° C. The reaction mass was concentrated under reduced pressure and xylene was added and stirred between 135° C. and 125° C. for 6 hour. After completion of reaction, the mixture was cooled to 60° C. and methanol (170 ml) & methyl tert-butyl ether (MTBE) were added to the reaction mass and stirred for 1 hour. The resultant slurry was filtered and washed with a 9:1 mixture of methanol & methyl tert-butyl ether (MTBE) and dried to give methyl 2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-1,6-dihydro-5-hydroxy-6-oxopyrimidine-4-carboxylate (Va).
Reaction SMILES: [C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([O-:17])=[O:16])#[N:2].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>C(OCC)(=O)C>[C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])#[N:2]
Reactant: CC(C)C1(C)N=C(c2ncccc2C(=O)[O-])N(C#N)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)C1(C)N=C(c2ncccc2C(=O)O)N(C#N)C1=O
Yield: 46.2 %

Procedure:
Tetrabutylammonium 2-(1-cyano-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (0.36 g, 0.00068 mol) is placed into a mixture of cyclohexane and ethyl acetate for 3 months. The mixture is filtered to yield the title compound as a tan solid (0.09 g, 42%), mp 150°-153° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].CS(C)=O.[CH3:25][C:26](OC(C)=O)=[O:27]>O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][C:26](=[O:27])[CH3:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC(C)=O)OCC3
Yield: 78 %

Procedure:
A solution of compound 1 (273 mg, 1.0 mmol), dry DMSO (3 mL), dry Ac2O (2 mL), and dry TEA (1 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted three times with EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried with Na2SO4, concentrated, and purified by column chromatography using 10:90:EtOAc:Hexane to give a yellow solid (245 mg, 78%): mp 126–127° C. 1HNMR (CDCl3, δ TMS): 0.91 (t, 3H), 1.38 (t, 3H), 1.88 (s, 3H), 1.90 (m, 2H), 2.21 (t, 2H), 2.78 (m, 2H), 2.87 (q, 2H), 4.01 (t, 2H), 4.14 (m, 2H), 7.02–7.37 (m 3H, Ar—H), 7.71 (br, 1H, NH). MS−: m/z 350 (MCl−), 314 ([M−H]−). Anal. (C19H25NO3): C, H, N.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)O)=CC=1[N+]([O-])=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33].[Mg].[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([N+:48]([O-:50])=[O:49])=[C:44]([CH:47]=1)[CH:45]=[O:46]>>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([N+:48]([O-:50])=[O:49])=[C:44]([CH:45]([C:28]2[CH:27]=[C:26]([O:25][CH3:24])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[OH:46])[CH:47]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: [Mg]
Product: COc1ccc([N+](=O)[O-])c(C(O)c2cc(OC)c(OC)c(OC)c2)c1
Yield: 53.6 %

Procedure:
(5-Methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using 3,4,5-trimethoxy-bromobenzene (4.6 g, 18.5 mmol), magnesium turning (0.5 g, 18.5 mmol) and 5-methoxy-2-nitro-benzaldehyde (2.8 g, 15.5 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.9 g, 53%); 1H NMR (CDCl3) δ 8.08 (d, J=9 Hz, 1H), 7.20 (d, J=2 Hz, 1H), 6.91-6.87 (dd, J=3, 9 Hz, 1H), 6.57 (s, 2H), 6.45 (d, J=4 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.80 (s, 6H), 3.04 (d, J=4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([NH2:16])[CH2:14][CH3:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)C.C(O)C>[ClH:1].[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:2]=1[NH:16][CH2:13][CH2:14][CH3:15]
Reactant: CCCN
Reactant: COC(=O)c1ccc(C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCCNc1nc(C)ccc1C(=O)OC

Procedure:
A stirred mixture of 37.1 g. (0.2 mole) of methyl 2-chloro-6-methyl-nicotinate, 11.8 g. (0.02 mole) of propylamine and 21.2 g. (0.02 mole) of sodium carbonate in 200 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 200 ml. of water and was extracted with 100 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated to give 31 g. of an oil. A small amount of this oil was dissolved in diethyl ether and was acidified with an etheral hydrochloric acid solution. On cooling, the oil which separated crystallized to yield 6-methyl-2-propylaminonicotinic acid methyl ester, hydrochloride. The solid was collected and was recrystallized from ethyl acetate to give the analytical sample, m.p. 113°-15° C.
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:5]1[OH:27])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+].C(O)(C)(C)C>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:29]([O:28][C@:4]1([CH2:1][CH2:2][OH:37])[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:5]1[OH:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CCO)(OCc3ccccc3)[C@@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of nucleoside 4 (2.26 g, 4.68 mmol) in THF (12 cm3) and water (12 cm3) was added sodium periodate (3.04 g, 14.2 mmol) and a 2.5% solution of osmium tetraoxide in tert-butanol (w/w, 0.603 cm3, 40 μmol). The solution was stirred at room temperature for 45 min. Water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was redissolved in THF (12 cm3) and water (12 cm3). The mixture was stirred at room temperature and sodium boronhydride (182 mg, 4.71 mmol) was added. After stirring for 1.5 h, water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give 5 as a white solid material (1.13 g, 49%). δH (CDCl3) 9.29 (1H, br s, NH), 7.47 (1H, d, J 1.1, 6-H), 7.38-7.25 (10H, m, Bn), 6.22 (1H, d, J 3.4, 1′-H), 4.62 (2H, s, Bn), 4.60 (1H, m, 4′-H), 4.46 (2H, s, Bn), 4.35 (1H, dd, J 3.4, 7.5, 2′-H), 3.83-3.73 (4H, m, 2×5′-H, 2×2″-H), 2.67 (1H, br s, OH), 2.07-2.01 (2H, m, 2×1″-H), 1.77 (3H, d, J 0.5, CH3). δC (CDCl3) 164.3 (C-4), 150.3 (C-2), 137.6, 137.4 (Bn, C-6), 136.7 (Bn), 128.6, 128.4, 128.2, 127.8, 127.6, 127.3, 127.1 (Bn), 108.4 (C-5), 88.0, 87.7, 81.6, 74.7 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.6 (Bn), 64.6 (C-5′), 57.7 (C-2″), 28.6 (C-1″), 12.4 (CH3). FAB-MS m/z 483 [M+H]+, 505 [M+Na]+ (Found: C, 63.6; H, 6.2; N, 5.4. C26H30N2O7,0.5H2O requires C, 63.5; H, 6.4; N, 5.7%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([CH2:21][NH:22][CH3:23])[S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CCN(CC)CC.[N+:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([O-:33])=[O:32].O>C(Cl)Cl>[C:2]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([CH2:21][N:22]([CH3:23])[CH2:38][C:37]3[CH:40]=[CH:41][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=3)[S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CNCc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)Cc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a cold solution of 1.1 g (3.31 mmol) of 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine (Intermediate 58.3) and 0.7 ml (4.96 mmol) of Et3N in 50 ml CH2Cl2 was added portionwise 1.07 (4.96 mmol) of 4-nitrobenzylbromide. After overnight stirring, another portion (0.35 g; 1.65 mmol) of 4-nitrobenzylbromide was added. Twenty four hours later, the reaction mixture was poured into 100 ml of cold water and diluted with 50 ml CH2Cl2. The organic layer was decanted, washed with brine, dried over MgSO4 and filtered. The solvent was eliminated under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1/1) as eluent. The pure fractions were collected and concentrated to yield 0.98 g (63%) of a yellow solid. Melting point: 111.4-11.7° C.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5]([C:7]1[C:8]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Cl:35])=[C:9]([Cl:26])[C:10]2[N:11]([C:13]([CH2:16][NH:17][CH2:18]C(OC(C)(C)C)=O)=[CH:14][N:15]=2)[CH:12]=1)=[O:6].[CH3:36][OH:37].O.Cl>O>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:8]2[C:7]([C:5]([OH:4])=[O:6])=[CH:12][N:11]3[C:13]([CH2:16][N:17]([C:36]([O:37][C:7]([CH3:8])([CH3:12])[CH3:5])=[O:1])[CH3:18])=[CH:14][N:15]=[C:10]3[C:9]=2[Cl:26])=[C:29]([Cl:35])[CH:30]=1
Reactant: CO
Reactant: COC(=O)c1cn2c(CNCC(=O)OC(C)(C)C)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(Cc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cn12)C(=O)OC(C)(C)C
Yield: 84 %

Procedure:
Sodium hydroxide (1.0 M aqueous solution, 0.16 mL, 0.16 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-3-[(tert-butoxycarbonylmethylamino)-methyl]-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (60) (15 mg, 0.026 mmol) in 4:1 MeOH/water (5 mL). When the reaction was complete, the solution was diluted with water, acidified to pH 3 by addition of 1.0 M aqueous HCl, and extracted with ethyl acetate. The organic extracts were dried over NaSO4, filtered, concentrated in vacuo to provide the desired product as a white crystalline solid (12 mg, 84%). MS (APCI−) m/z 541, 543, 545 (M−; Cl, Br pattern) detected.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][C:10]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:25])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][C:10]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1=O
Agent: B
Solvent: C1CCOC1
Product: CC1(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To compound 148H ((75 mg, 0.15 mmol) was added BH3THF (1M, 1.5 mL, 1.5 mmol) at RT under Argon. After addition, the reaction was stirred at RT for 24 h, then quenched by carefully adding MeOH (1 mL). The resulting mixture was stirred at RT for 2 h, then partitioned between saturated aqueous Na2CO3 (10 mL) and EtOAc. The aqueous layer was extracted with EtOAc (15 mL×3) and the combined EtOAc extracts washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (0-40%) in hexane to give the title compound as an off-white solid (40 mg, 55%). HPLC: 99% at 8.50 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−110% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4), Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 487 [M+H]+.