Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:15]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cccc(N2CCNCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixed solution of 1-(3-bromophenyl)-piperazine (300 mg, 1.24 mmol), 3-thienylboronic acid (239 mg, 1.87 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.149 mmol), 2N aqueous solution of sodium carbonate (4.98 ml, 9.95 mmol), and toluene (12 ml) was stirred at 95° C. for 15 hours under a nitrogen atmosphere. After cooling to room temperature, water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound 254 mg (83.5%) as an oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.[Cl:19][C:20]1[C:25]2[N:26]([CH3:31])[C:27]([CH2:29]Cl)=[N:28][C:24]=2[CH:23]=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[C:25]2[N:26]([CH3:31])[C:27]([CH2:29][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[N:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Cn1c(CCl)nc2cccc(Cl)c21
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(CCC#C[Si](C)(C)C)nc2cccc(Cl)c21
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of the trimethyl(prop-1-ynyl)silane (0.21 mL, 1.4 mmol) in THF (4 mL), was added at −78° C. nBuLi 2.5M in hexane (0.56 mL, 1.3 mmol). After 90 min at −78° C., a solution of 7-chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (250 mg, 1.2 mmol) in THF (2 mL) was added. Mixture went from purple to orange and then dark brown. The reaction was quenched after 1 h at −78° C. with water and the solvent was evaporated to dryness to afford 338 mg of 7-chloro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 100%) as a brown oily solid. It was carried through to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:36]CC6C=CC=CC=6)=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(O)(=O)C.ClCCl.CO>[H][H].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Yield: 95.6 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (7.5 g, 12.6 mmol), acetic acid (few drops), dichloromethane (50 ml) and methanol (100 ml) was added 10% Pd/C (700 mg). The mixture was agitated in hydrogen gas (40 psi) until the reaction was complete (ca 4 hr). The solution was filtered through celite and concentrated to give a crude product as a solid. The crude product was triturated with ether, and filtered. The filter cake was dried in vacuo to yield cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluorophenyl)-amide (6.1 g, 95% yield). 1H NMR (dmso-d6): 10.86 (1H, br. s), 10.34 (1H, br. s), 10.04 (1H, br. s), 8.46 (1H, s), 7.84-7.80 (1H, dd), 7.66-7.62 (2H, m), 7.55 (1H, s), 7.47-7.45 (1H, m), 7.41-7.37 (1H, m), 7.24 (1H, s), 7.18-7.13 (2-H, t), 3.98 (3H, s), 1.46 (4H, s).
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])=[N-].S(=O)(=O)(O)[OH:32]>O1CCOCC1.O>[C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH2:3][OH:32]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)C=[N+]=[N-])OC(C)=O
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)CO)OC(C)=O
Yield: 96 %

Procedure:
A clear, yellow solution of ethyl 8-diazoacetyl-12-acetoxyheptadecanoate (8.4 g., 0.02 mole) in dioxane (50 ml.) is vigorously stirred at 20° and treated with 2N sulfuric acid (30 ml.) added dropwise over 5 minutes. The resulting turbid solution is warmed to and maintained at 65° for 30 minutes. The reaction solution is cooled to 20°, diluted with water to a total volume of one liter and extracted with ether (5 × 200 ml.). The organic extract is washed with water (2 × 200 ml.), 5% aqueous sodium bicarbonate (200 ml.), water (200 ml.), and saturated brine (2 × 200 ml.), dried over sodium sulfate and filtered. Evaporation (in vacuo at 40°-65°) of the filtrate gives the title compound as a deep yellow oil (7.9 g., 96%), pmr (CDCl3)δ0.86 (3H,t), 1.28 (27H,e), 2.0 (3H,s), 2.25 (3H,t), 3.36 (H,b), 4.10 (2H,q), 4.21 (2H,s) and 4.84 (H,b).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[NH:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:14]([C:8]1[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])[CH:15]([CH3:19])[C:16](=[O:18])[CH3:17])=[O:4]
Reactant: CC(=O)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CC(=O)C(C)N(C(=O)CCl)c1c(C)cccc1C

Procedure:
A 152.6-g (1.35-mol) sample of chloroacetyl chloride was added over 0.25 hour in small portions to a stirred solution of 170.8 g (0.89 mol) 3-(2,6-dimethylphenylamino)-2-butanone in 500 ml toluene. The reaction mixture was heated under reflux for 3 hours, cooled and filtered. The filtrate was concentrated and chromatographed on silica gel using dichloromethane eluant. The eluted material was recrystallized several times from ethyl ether/hexane to give the 3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone product, as a brown solid, m.p. 78°-82° C. The infrared spectrum of the product showed strong carbonyl absorption at 5.8 and 6.1 microns. This product is tabulated in Table I as Compound No. 5-A.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:33][CH:34](I)[CH3:35])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].[I-].[Na+]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:34]([O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:35])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)C(C)(C)C
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(=O)C(C)(C)C)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 1, sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer) was reacted with 1-iodoethyl pivalate in the presence of sodium iodide to give 1-pivaloyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 110°-115° C. (decompn.).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].[C:13]([N:17]1[C:21]([NH2:22])=[C:20]([C:23]([NH2:25])=[O:24])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].CS(O)(=O)=O>C(O)C>[C:13]([N:17]1[C:21]2=[N:22][C:7]([C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])=[N:25][C:23](=[O:24])[C:20]2=[CH:19][NH:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)n1ncc(C(N)=O)c1N
Reactant: CCCOc1ccccc1C=O
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2n(C(C)(C)C)[nH]cc-2c(=O)n1
Yield: 21.9 %

Procedure:
A mixture of 2-propoxybenzaldehyde (3.0 g, 18.27 mmol), 1-tert-butyl-5-amino-1H-pyrazole-4-carboxamide (2.5 g, 13.7 mmol), methanesulfonic acid (0.2 ml) and xylenes (50 ml) was refluxed overnight. The reaction mixture was stripped to dryness, treated with ethanol and again stripped to dryness. The residue was partitioned between chloroform and 10% KHCO3, the layers were separated, and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined, and concentrated in vacuo and the residue was dissolved in CH2Cl2 (30 ml) and combined with silica gel (20 g). The preloaded silica gel was placed on a silica gel column and eluted with 70% ether/hexanes, followed by ether (100%) to afford 0.98 g (22%) of 1-tert-butyl-6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4-one 1/100 hydrate, m.p. 130-131° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[CH2:32][CH2:31]3)=[C:20]([NH:25][CH2:26][CH:27]([F:29])[F:28])[N:21]=2)[CH:16]1[CH3:45])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:29][CH:27]([F:28])[CH2:26][NH:25][C:20]1[N:21]=[C:22]2[CH2:23][CH2:24][NH:15][CH:16]([CH3:45])[C:17]2=[N:18][C:19]=1[N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[CH2:32][CH2:31]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (160 mg, 0.249 mmol) and Pd(OH)2 on carbon (17.5 mg, 0.025 mmol) in THF (1.24 mL) was purged and placed under hydrogen atmosphere (balloon) overnight. The mixture was filtered through Celite™ and concentrated to give title compound as its TFA salt (136 mg).
Reaction SMILES: C([N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]([O:19][C@@H:20]2[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]2[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:5]1)(=O)C.C(=O)(O)[O-].[Na+].O>CO>[CH2:12]([C:7]1[C:6]([O:19][C@@H:20]2[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:51])([CH3:53])[CH3:52])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C@H:21]2[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])=[N:5][NH:4][C:8]=1[CH:9]([CH3:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccccc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 1-acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2.68 g) in methanol (27 mL) was added sodium bicarbonate (0.596 g) under stirring at room temperature. The reaction mixture was stirred at room temperature for 17 hours. After confirming the completion of the reaction, water was added to the reaction mixture in order to precipitate the crystals. The crystals were collected by filtration, and the obtained crystals were washed with water and dried under reduced pressure to give 4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (2.45 g).
Reaction SMILES: C([N:4]([C:6](=O)[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([Br:20])=[N:9]1)[NH2:5])(=O)C.[P+3]=[S:23].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl.[CH2:33]1[CH2:37]OCC1>>[Br:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[N:8]([CH2:7][C:6]2[S:23][C:37]([CH3:33])=[N:5][N:4]=2)[N:9]=1
Reactant: [P+3]=S
Reactant: CC(=O)N(N)C(=O)Cn1nc(Br)c2c([N+](=O)[O-])cccc21
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of N-acetyl-2-(3-bromo-4-nitro-1H-indazol-1-yl)acetohydrazide (0.4 g) in anhydrous THF (5 mL) was treated at ambient temperature with phosphorus(V) sulfide (0.77 g). The mixture was heated at reflux under a nitrogen atmosphere for 2.5 hours. The reaction mixture was diluted with a large excess of saturated aqueous sodium carbonate solution (50 mL) and DCM (50 mL). The resulting mixture was stirred at ambient temperature for 20 minutes, the phases were separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by preparative thin-layer chromatography (silica, 7% MeOH-DCM as eluent) to afford the product (235 mg) as a pale yellow solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[O:20]([C:27]1[CH:35]=[CH:34][C:30](C(Cl)=O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:36]([N:38]1[C:50]2[CH:49]=[CH:48][C:47]([NH2:51])=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH3:37]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[C:30]2[CH:29]=[CH:28][C:27]([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:35][CH:34]=2)[C@H:9]([C:17]([NH:51][C:47]2[CH:48]=[CH:49][C:50]3[N:38]([CH2:36][CH3:37])[C:39]4[C:44]([C:45]=3[CH:46]=2)=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:19])[CH2:10]1)[CH3:16]
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccc(Oc3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 99% purity by LC/MS. MS(ESI+): m/z=561.4.
Reaction SMILES: [C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[OH:64])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:72](Cl)([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:24][C@@H:23]([N:47]2[C:56]3[N:55]=[CH:54][N:53]([CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[C:51](=[O:52])[C:50]=3[N:49]=[CH:48]2)[C@@H:22]1[O:64][S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3O)c2ncn1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2ncn([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3OS(=O)(=O)C(F)(F)F)c2ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 3',5'-di-O-trityl-1-benzylinosine (2.0 g, 2.4 mmol), 4-dimethylaminopyridine (290 mg, 2.4 mmol) and triethylamine (480 mg, 4.8 mmol) in methylene chloride (40 mL) is added triflyl chloride (800 mg, 4.8 mmol), and the mixture is stirred at room temperature for 1 hour, and then concentrated in vacuo. The residue is chromatographed on a silica gel column using a mixture of tetrachloromethane and ethyl acetate (5:1 v/v) as the eluent to give 3',5'-di-O-trityl-2'-O-triflyl-1-benzylinosine as a foam (1.82 g, 78% yield), 1H NMR (Me2SO-d6) δ 2.92-2.96 (2H, m, H-5',5"), 3.62-3.69 (1H, m, H-4'), 4.41-4.43 (1H, m, H-3'), 5.23 (2H, s, CH2Ph), 5.89-5.95 (1H, m, H-2'), 6.66 (1H, d, H-1', J1',2' =6.3 Hz), 7.18-7.34 (35H, m, 2×Tr and CH2 Ph), 8.29, 8.32 (1H each, s, H-2, H-8). Analyses calculated for C56 H45F3N4O5S: C, 68.98, H, 4.65, N, 5.63. Found: C, 68.94, H, 4.76, N, 5.63.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][OH:16].[C:17]1([C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:35][C:33](=[O:34])[NH:32]2)=[CH:4][C:3]=1[O:13][CH2:14][CH2:15][OH:16]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(OCCO)c(O)c([N+](=O)[O-])c2)N1
Yield: 23.2 %

Procedure:
To the solution of 4-hydroxy-3-(2-hydroxyethoxy)-5-nitrobenzaldehyde (Intermediate 71) (60 mg, 0.27 mmol), 1,2-diphenyl-ethanone (53 mg, 0.27 mmol) and urea (48.6 mg, 0.81 mmol) in 4 mL of ethanol was added 0.2 mL of concentrated HCl, and the mixture was stirred at reflux for 2 days. The mixture was concentrated and purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 137 (28 mg, yield 23.7%). 1H NMR (DMSO-d6 400 MHz): δ 10.23 (s, 1H), 8.75 (s, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.26 (m, 6H), 7.02 (m, 3H), 6.83 (d, J=7.2 Hz, 2H), 5.19 (d, J=2.4 Hz, 1H), 3.99 (m, 2H), 3.75 (m, 2H); MS (ESI): m/z 448.1 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:36]([OH:37])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:39].CCOC(C)=O>CO.C(Cl)Cl>[ClH:39].[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[C:36]([OH:37])[N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1

Procedure:
To a solution of tert-butyl{1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6a) (1.14 g, 2.25 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (22 mL, 88 mmol) at room temperature. After 4 hours the reaction mixture was concentrated in vacuo to give 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol hydrochloride (1-16) as a yellow solid. HRMS (M+H)+: observed=408.1803, calculated=408.1819.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:20][CH:21]([CH3:23])[CH3:22])[CH3:19]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:20]([CH2:18][CH3:19])[CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CCNC(C)C
Product: CCN(C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1)C(C)C

Procedure:
500 mg (1.86 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-ethylpropan-2-amine to give after working up and purification 513 mg (82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=[O:6]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
To a four-necked 500 ml flask equipped with a mechanical stirrer, thermometer, and condenser, was added -nopol glycidyl ether (48.2 g, 205.4 mmol), and methylene chloride (250 ml). To the solution was added 70% m-chloroperoxybenzoic acid (53 g, 215 mmol) over a period of time of about 2 hours. The reaction temperature was maintained below about 15° C. with an ice/water bath during the addition. After the addition was complete, the reaction mixture was stirred overnight and maintained at a temperature below about 20° C. with an ice water bath. m-Chlorobenzoic acid was formed as a precipitate, and filtered the organic filtrate washed off, twice with 200 ml portions of 10% aq. Na2SO3, twice with 200 ml portions sat. aq. NaHCO3, and twice with 200 ml portions of water. The organic layer was separated, dried over anhydrous MgSO4, and filtered. Solvent was removed under reduced pressure, and the crude product was vacuum distilled. Nopol epoxide glycidyl ether was obtained in a yield of about 46.5 g (91%), with a boiling point of about 110-113° C. at 800 mTorr. 1H NMR (CDCl3) δ 2.8-3.7 (m, 8, OCH, OCH2), 2.0-2.4 (m, 8, CH, CH2), 1.3 (s, 3, CH3) (see FIG. 17), 0.9 (s, 3, CH3); FT-IR 2917, 1470, 1110, 911, 855, 761 cm−1 (see FIG. 18).