Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[N:8]([C:11]1[N:12]([C:35]2[N:36]=[CH:37][N:38]=[C:39]([NH2:42])[C:40]=2[N:41]=1)[C@@H:13]1[O:34][C@H:18]([CH2:19][O:20][S:21](=[O:33])(=[O:32])[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])[C@@H:16]([OH:17])[C@H:14]1[OH:15])=[N+]=[N-]>CO.[Pd]>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:11]1[N:12]([C:35]2[N:36]=[CH:37][N:38]=[C:39]([NH2:42])[C:40]=2[N:41]=1)[C@@H:13]1[O:34][C@H:18]([CH2:19][O:20][S:21](=[O:33])(=[O:32])[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])[C@@H:16]([OH:17])[C@H:14]1[OH:15]
Reactant: [N-]=[N+]=Nc1nc2c(N)ncnc2n1[C@@H]1O[C@H](COS(=O)(=O)NC(=O)c2ccccc2O)[C@@H](O)[C@H]1O
Agent: [Pd]
Agent: CC[NH+](CC)CC
Solvent: CO
Product: Nc1ncnc2c1nc(N)n2[C@@H]1O[C@H](COS(=O)(=O)NC(=O)c2ccccc2O)[C@@H](O)[C@H]1O
Yield: 72.1 %

Procedure:
8-Azido-5′-O—[N-(2-hydroxybenzoyl)sulfamoyl]adenosine triethylammonium salt (100 mg) was treated with Pd/C (5 mg) in MeOH (10 mL) under a H2 (1 atm) for 2 hours. The reaction was filtered thru Celite then concentrated in vacuo. Purification by flash chromatography (10:90 MeOH/EtOAc) afforded the title compound (69 mg, 73%) as a white solid: Rf 0.3 (20:80 MeOH/EtOAc); [α]20D −18.9 (c 1.0, MeOH); 1H NMR (600 MHz, CD3OD) δ 1.28 (t, J=6.6 Hz, 9H), 3.18 (q, J=7.2 Hz, 6H), 4.30 (d, J=2.4 Hz, 1H), 4.38-4.60 (m, 3H), 4.87-4.90 (ovlp m, 1H), 6.04 (d, J=7.2 Hz, 1H), 6.83 (q, J=9.0 Hz, 2H), 7.33 (q, J=7.2 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.98 (s, 1H); 13C NMR (150 MHz, CD3OD) δ 9.35, 48.0, 69.7, 71.9, 72.0, 84.6, 88.6, 117.8, 118.0, 119.4, 120.6, 131.5, 134.6, 150.4, 151.1, 153.5, 153.8, 162.1, 175.2; HRMS (ESI+) calcd for C17H20N7O5S [M+H]+ 482.1088, found 482.1079 (error 1.8)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([N:23]=[N+]=[N-])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([NH2:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a refluxing solution of 500 mg (1.486 mmol) rac-3-azido-3-phenyl-piperidine-1-carboxylic acid benzyl ester (example A.1, step 2) and 281 mg (7.43 mmol) NaBH4 in THF (5 ml) was added dropwise 2.0 ml methanol over 1.5 hour. The mixture was refluxed for another hour and then stirred at room temperature overnight. Another 114 mg (3 mmol) NaBH4 were added and the mixture was refluxed for 2 hours. The mixture was cooled in an ice bath and acidified with HCl 1N. The mixture was basified with 1N NaOH and extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 220 mg (48%) of the title compound as a colorless oil. MS (m/e): MS (m/e): 311.4 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:13]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][C:24](OCC)=[O:25].O.[OH-].[Na+]>O1CCCC1>[NH2:7][C:8]1[C:13]([CH:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[OH:22])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][OH:25]
Reactant: CCOC(=O)Cc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(CCO)cccc1C(O)c1ccc(Cl)cc1
Yield: 44.9 %

Procedure:
To a slurry of 5.5 g (0.145 mole) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran was added dropwise a solution of 21.9 g (0.069 mole) of 2-amino-3-(4-chlorobenzoyl)benzeneacetic acid, ethyl ester in 120 ml of dry tetrahydrofuran. After the addition was complete, the mixture was heated at reflux under a nitrogen atmosphere for 2.5 hours. The mixture was cooled and treated successively with 5.5 ml of water, 5.5 ml of 5% sodium hydroxide and 16.5 ml of water. The mixture was filtered through celite and the filter cake was washed several times with tetrahydrofuran. The combined filtrates were concentrated to give a solid residue. This residue was recrystallized from ethyl acetate to yield 8.6 g (45%) of the titled compound as fluffy white needles, m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:13]=2[N:12]=1.C(N(CC)CC)C.Cl.[NH2:30][OH:31]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]([NH:30][OH:31])=[NH:21])=[CH:19][C:13]=2[N:12]=1
Reactant: N#Cc1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: N=C(NO)c1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a stirred solution of 2-(2-chloro-5-nitro-phenyl)-1H-benzoimidazole-5-carbonitrile (2.00 g; 6.70 mmol) in ethanol (20 ml) in a sealable tube was added triethylamine (1.90 ml; 13.4 mmol). A solution of hydroxylamine hydrochloride (933 mg; 13.4 mmol) in water (4 ml) was added, the tube sealed and the mixture stirred at 75° C. for 2 hours. After cooling to room temperature, water (100 ml) was added, the precipitate filtered and washed with more water to leave 2-(2-chloro-5-nitro-phenyl)-N-hydroxy-1H-benzoimidazole-5-carboxamidine (1.76 g, 82%).
Reaction SMILES: FC1C=CC(CN2C[CH2:11][N:10]3[C:13](=O)[CH:14]=[C:15](O)[C:16](O)=[C:9]3C2=O)=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:27][N:28]1[CH2:33][CH2:32][N:31]2[C:34](=[O:40])[CH:35]=[C:36]([OH:39])[C:37]([OH:38])=[C:30]2[C:29]1=[O:41]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:27][N:28]1[CH2:33][CH2:32][N:31]2[C:34](=[O:40])[C:35]([CH2:11][N:10]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:9]3)=[C:36]([OH:39])[C:37]([OH:38])=[C:30]2[C:29]1=[O:41]
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)c(Cl)c1
Product: O=C1c2c(O)c(O)c(CN3CCCCC3)c(=O)n2CCN1Cc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that described in Example 11, except that 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione was substituted with 2-(3-chloro4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cc1nc(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
5-Methyl-3-phenyl-1H-1,2,4-triazole (120 mg, 754 μmol) was dissolved in DMF (2.4 mL) and potassium carbonate (208 mg, 1.51 mmol) was added. After 20 min tert-butyl 2-bromoethylcarbamate (186 mg, 829 μmol) was added at 0-5° C. and the reaction mixture was stirred at RT for 25 h. The reaction mixture was extracted with ethyl acetate (30 mL) and washed with water (3×50 mL). The aqueous layers were back-extracted with ethyl acetate (20 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (237 mg, 784 μmol, 83.2%).
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][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Cl:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[C:36](Cl)[N:35]=[CH:34][N:33]=1>CC#N>[Cl:31][C:32]1[N:33]=[CH:34][N:35]=[C:36]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ncnc(Cl)c2[N+](=O)[O-])c2ccccc12
Yield: 34.2 %

Procedure:
To a stirred solution of tert-butyl (4-hydroxynaphthalen-1-yl)carbamate (20.0 g, 73.0 mmol) in MeCN (200 mL) under N2 was added DBU (13 mL, 87 mmol) and after 1 hr at RT the resulting mixture was treated dropwise with a solution of 4,6-dichloro-5-nitropyrimidine (15.5 g, 80.0 mmol) in MeCN (150 mL). After 2.5 hr at RT the mixture was evaporated in vacuo and the residue was triturated with DCM (150 mL) and isohexane (200 mL). The insoluble residue was separated and set aside and the triturant was evaporated in vacuo. The residue so obtained was partitioned between DCM (200 mL) and sat aq NaHCO3 (200 mL) and the organic layer was separated and evaporated in vacuo. The residue was triturated with EtOAc to give an off white solid (batch 1). The EtOAc triturant was concentrated in vacuo to ˜20 mL and the precipitate which formed was isolated by filtration and washed with EtOAc to afford a second batch of same material, also as an off white solid. The first and second batches of product were combined to afford tert-butyl (4-((6-chloro-5-nitropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (10.4 g, 34%); Rt 2.69 min (Method 2); m/z 439/441 (M+Na)+ (ES+).
Reaction SMILES: I[C:2]1[N:3]([I:19])[C:4]([OH:18])=[C:5]2[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:6]2[N:7]=1>C(O)(=O)C.O.[Zn]>[I:19][N:3]1[C:4]([OH:18])=[C:5]2[CH:10]=[C:9]([NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:14])[CH3:16])[N:8]=[C:6]2[N:7]=[CH:2]1
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)c(I)nc-2n1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 4.86 g of 2,3-diiodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 100 mL of glacial acetic acid and 25 mL of water are added 1.3 g (20 mmol) of zinc powder. The mixture is stirred at ambient temperature for 18 hours, diluted with 500 mL of water, and cooled. The solid is collected through filtration and dried under vacuum over phosphorus pentoxide to yield 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which can be purified further by chromatography over silica eluting with 2.5% methanol in methylene chloride. mp >240° C. 1NMR (d6 -DMSO) δ 1.20(s, 9H), 7.12 (d, J=1.8 Hz, 1H), 10.82 (s, 1H), 11.79 (s, 1H), 11.89 (s, 1H). Anal. Calc. for C11H13N4O2I: C, 36.69; H 3.64; N, 15.56; I, 35.24. Found: C, 36.91; H, 3.58; N, 15.65; I, 35.56.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:8][CH:7]=[N:6][N:5]2[C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:21][CH:22]=1.[N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[CH:46]=O>>[O:13]1[CH2:12][CH2:11][N:10]([C:9]2[C:4]3[N:5]([C:16]([C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]5)=[N:21][CH:22]=4)=[C:2]([NH:1][CH2:46][C:37]4[CH:38]=[CH:39][C:40]5[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=5)[N:36]=4)[N:3]=3)[N:6]=[CH:7][CH:8]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(N)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(NCc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1

Procedure:
Using the procedure described in Example 21, Step C, the title compound was prepared from Compound 23b and 2-quinolinecarbaldehyde. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.66 (d, J=2.2 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.97-8.07 (m, 2H), 7.89 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.70 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.46-7.56 (m, 2H), 6.81 (d, J=9.0 Hz, 1H), 6.03 (d, J=5.6 Hz, 1H), 5.30 (t, J=5.3 Hz, 1H), 4.91 (d, J=5.4 Hz, 2H), 3.81 (s, 8H), 3.49-3.69 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H39N9O3: 622.3 (M+H). Found: 622.3.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[C:17]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[N:18][C:19]([C:22](OCC)=[O:23])=[N:20][CH:21]=1.O.[OH-].[Na+]>C(OCC)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[C:17]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[N:18][C:19]([CH2:22][OH:23])=[N:20][CH:21]=1
Reactant: CCOC(=O)c1ncc(-c2cc(OC)ccc2F)c(OCC(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(F)c(-c2cnc(CO)nc2OCC(C)C)c1
Reaction time: 0.17 h
Yield: 44.4 %

Procedure:
To a suspension of lithium aluminum hydride (93 mg) in diethyl ether (5.0 mL) was added a solution of ethyl 5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyrimidine-2-carboxylate (284 mg) in diethyl ether (2.0 mL) at 0° C., and the mixture was stirred for 10 min. To the reaction mixture were added water and aqueous sodium hydroxide solution, and the resulting white precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was dissolved in toluene (2.0 mL) and THF (1.0 mL). To the obtained solution was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (277 mg), and the mixture was stirred at room temperature for 20 min. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (111 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared using the standard reductive amination conditions with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and tert-butyl-1-piperazinecarboxylate.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:18][F:19])([CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[N+:15]([O-:17])=[O:16])[CH2:4][O:3]1.Cl>C(#N)C>[OH:3][CH2:4][C:5]([CH2:6][OH:7])([CH2:18][F:19])[CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[N+:15]([O-:17])=[O:16]
Reactant: CC1(C)OCC(CF)(CCn2ccnc2[N+](=O)[O-])CO1
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])c1nccn1CCC(CO)(CO)CF
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2,2-Dimethyl-5-fluoromethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane was dissolved in 0.5 mL of acetonitrile, 0.5 mL of 1 mol/L hydrochloric acid was added thereto, and the mixture was stirred at 80° C. for 30 minutes. After completion of the reaction, the mixture was concentrated under vacuum to give a trace amount of 1-(3,3-dihydroxymethyl-4-fluorobutyl)-2-nitroimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[CH:22]=[CH:21][O:20][CH:19]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[CH:22]=[CH:21][O:20][CH:19]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccoc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccoc1
Yield: 86 %

Procedure:
8.5 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-furylcarbonyl)propionate, 50 ml of chloroform and 18.6 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 6.93 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-furyl)-4-oxazolyl]acetate are thereby obtained. Yield: 85.5%
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][N:31]([CH3:38])[C:32](=[O:37])[CH2:33][CH2:34][NH:35][CH3:36]>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:35]([CH3:36])[CH2:34][CH2:33][C:32]([N:31]([CH3:38])[CH3:30])=[O:37])[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNCCC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCC(=O)N(C)C)nc2c1C#N

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.84 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.16 ml, 0.94 mmol) and N,N-dimethyl-3-(methylamino)propionamide (I-149) (0.11 g, 0.84 mmol) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane.
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH3:37])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[O:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:8])=[O:4].[O:39]=C1O[C@H]([C@H](CO)O)C(O)=C1O.O=O>C(O)(=O)C.O>[NH2:1][C:2]([CH3:37])([CH3:38])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[C:14]([N:20]3[C:24](=[O:39])[CH2:23][CH2:22][CH:21]3[OH:25])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[C:11]1=[O:32])=[O:8])=[O:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3C(=O)CCC3O)c2N(Cc2ccsc2)C1=O

Procedure:
(2R)-2-(2-Amino-2-methylpropanamido)-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (1.08 g) was dissolved in acetic acid (30 mL), and a solution of L-(+)-ascorbic acid (3.52 g) and Cu(ClO4)2.6H2O (741 mg) in water (40 mL) was added thereto, followed by stirring at room temperature for 15 minutes while oxygen gas was bubbled into the mixture. Saturated aqueous sodium chloride solution was added to the reaction mixture, and the mixture was washed with ethyl acetate twice. Sodium bicarbonate (88.2 g) was added to the aqueous layer, and the mixture was extracted with chloroform twice. The organic layer was concentrated under reduced pressure, and the thus-recovered residue was purified through chromatography, whereby the title compound (0.5 mg) was yielded.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1([N:10]2[C:14]3=[N:15][C:16]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH2:27][CH3:28])[NH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([N:10]2[C:14]3=[N:15][C:16]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:1]([O-:4])=[O:2])=[CH:25][CH:26]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH2:27][CH3:28])[NH:11]2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccc3)nc(=O)c1-2
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 90% HNO3 (95 mL) at -10 to -15° C. was added 1-cyclopentyl-3-ethyl-6-(phenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one (9.62 g, 30 mmol) . The reaction mixture was stirred as such for 1.5 hours, and then was poured into ice water. A precipitate formed which was collected by filtration, recrystallized from ethyl acetate and dried at 100° C. and 0.2 mm Hg to afford 2.31 g of 1-cyclopentyl-3-ethyl-6-(4-nitrophenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 221-223° C. [labelled as Example 25 (a)]. The mother liquors were combined and concentrated in vacuo to afford a mixture of 1-cyclopentyl-3-ethyl-6-(2-nitrophenylmethyl)pyrazolo [3,4-d]pyrimidin-4-one and 1-cyclopentyl-3-ethyl-6-(3-nitrophenyl methyl)pyrazolo[3,4-d]pyrimidin-4-one [ labelled as Example 25 (b)].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH:17]([C:14]1([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15]1)=[O:18]
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccc3ccccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=CC1(c2ccc3ccccc3c2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[(Benzyloxy)carbonyl]-4-(2-naphthyl)piperidine-4-carboxylic acid To a solution of 1.60 g (3.59 mmol) of Intermediate 9 in 10 mL of anhydrous dichloromethane was added 10 mL of trifluoroacetic acid. The resulting mixture was stirred at ambient temperature for 2 h and then all volatiles were removed in vacuo. The resulting residue was dissolved in 15 mL of anhydrous toluene and all volatiles were again removed in vacuo to afford the title compound as a white solid. LC/MS 390.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][C:3]=1[F:10].O=[C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[F:10])[NH:8][C:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:14][C:13]2=1
Reactant: NNc1ccc(Br)c(F)c1
Reactant: CC(C)C(=O)NC1CCC(=O)CC1
Product: CC(C)C(=O)NC1CCc2[nH]c3cc(F)c(Br)cc3c2C1

Procedure:
Prepare the title compounds by essentially following the procedure as described in Preparation 4 (Method 2) with (4-bromo-3-fluoro-phenyl)-hydrazine (Preparation 12) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain a tan solid containing a 65:35 mixture of isomers in 20% overall yield. MS (ES): m/z 353, 355 (M+H), 351, 353 (M−H); HPLC (Method A): Rt=2.22 min, (95%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:6]4[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
(2S,6R)-2,6-Dimethylpiperazine (228 mg, 2.00 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1.00 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (164 mg, 35%) as a cream solid.