Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1(C)C=CC=CC=1>[CH3:23][S:24]([O:15][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(OS(C)(=O)=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
2.50 g (0.012 mol) of 3,5-di-tert-butylphenol and 1.27 g (0.013 mol) of triethylamine were dissolved in 15 mL of toluene followed by dropping in 1.45 g (0.013 mol) of methanesulfonyl chloride over the course of 10 minutes at 5° C. Following completion of dropping, the mixture was stirred for 3 hours at 25° C. and the 3,5-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in ice water and following separation of the organic layer, was washed twice with saturated brine followed by drying with MgSO4 and concentrating to obtain 3.21 g (yield: 98%) of 3,5-di-tert-butylphenyl methanesulfonate. A purified product crystallized with n-hexane (white crystals, melting point: 76° C.) was used in a battery test.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[C:41](Cl)(=[O:65])[O:42][CH2:43][O:44][C:45](=[O:64])[C:46]1[CH:51]=[C:50]([S:52]([NH2:55])(=[O:54])=[O:53])[C:49]([Cl:56])=[CH:48][C:47]=1[NH:57][CH2:58][C:59]1[O:60][CH:61]=[CH:62][CH:63]=1>C(#N)C>[NH2:55][S:52]([C:50]1[C:49]([Cl:56])=[CH:48][C:47]([NH:57][CH2:58][C:59]2[O:60][CH:61]=[CH:62][CH:63]=2)=[C:46]([CH:51]=1)[C:45]([O:44][CH2:43][O:42][C:41]([N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:65])=[O:64])(=[O:53])=[O:54]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)OCOC(=O)Cl)c(NCc2ccco2)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C(=O)c1cccc(Cl)c1)N(C(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. Nos. 3,819,706 and 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl carbonochloridate (1010) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (1020). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:25])(=[O:21])[CH3:20]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cccc(N)c1C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-6-methoxybenzamide (1.7 g) in methylene chloride (20 ml) is added pyridine (1.6 ml), and thereto is added dropwise acetoxyacetyl chloride (1.1 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 2 hours, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and then are recrystallized from ethanol to give the title compound (2.1 g) having the following physical properties.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13](=[O:54])[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:53])[NH:22][C:23]2[CH:28]=[C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37](=[NH:40])[NH:38]O)=[CH:33][CH:32]=3)[CH:26]=[C:25]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49](=[NH:52])[NH:50]O)=[CH:45][CH:44]=3)[CH:24]=2)[CH2:17][CH2:16]1)([CH3:11])([CH3:10])[CH3:9]>C(O)(=O)C.[Zn]>[C:8]([O:12][C:13](=[O:54])[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:53])[NH:22][C:23]2[CH:24]=[C:25]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([C:49](=[NH:50])[NH2:52])=[CH:45][CH:44]=3)[CH:26]=[C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37](=[NH:38])[NH2:40])=[CH:35][CH:36]=3)[CH:28]=2)[CH2:17][CH2:16]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3ccc(C(=N)NO)cc3)cc(OCc3ccc(C(=N)NO)cc3)c2)CC1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2cc(OCc3ccc(C(=N)N)cc3)cc(OCc3ccc(C(=N)N)cc3)c2)CC1
Reaction time: 3 h
Yield: 136.4 %

Procedure:
Acetic anhydride (0.36 ml, 3.72 mmol) was added to the solution of (4-{3,5-bis-[4-(N-hydroxycarbamimidoyl)-benzyloxy]-phenylcarbamoyl}-cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, 0.62 mmol) in 10 ml of acetic acid and reaction mixture was stirred for 3 h. After completion of reaction, at RT zinc dust (0.4 g, 6.2 mmol) was added and resulting mixture was stirred over night. Recation mixture was filtered through celite and filterate was concentrated to dryness. Product was washed with cold diethyl ether and dried to afford 0.52 g of the required product. Percentage purity (LCMS): 100.0%, (M−1)=615.2-1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NCCS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(O)CCNc1cc(Cl)nc(Cl)n1
Yield: 254.4 %

Procedure:
A stirred mixture of 2,4,6-trichloropyrimidine (6.9 g) in 75 ml of tetrahydrofuran is treated with diisopropylethylamine (15 ml) and solid taurine (4.7 g). The resulting suspension is heated at reflux for 48 hours. The reaction mixture is cooled to 20°-25° followed by solvent evaporation which gives 26 g of an oil which is chromatographed on 170 g of silica gel and eluting with chloroform/5.0M ammonia in methanol (7/3). An initial fraction of 250 mL is collected followed by 20 ml fractions. Fractions 23-57 contained the desired product. Solvent evaporation gives a semi-solid which is taken up in chloroform/methanol (10/1) and stirred at 20°-25° for 30 minutes. Filtration provided 3.71 g of a solid.
Reaction SMILES: [CH2:1]1[CH2:5]O[CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[CH:9][C:10](I)=[C:11]([CH:13]=1)[NH2:12].C(N(CC)CC)C.C#CCC>C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:5]([C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:13][C:11]=1[NH2:12])#[C:1][CH2:2][CH3:3]
Reactant: Nc1cc(F)ccc1I
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: C#CCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCC#Cc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
160 mL of THF were placed in the flask and degassed with argon. Then 10 g (45 mmol) 5-fluoro-2-iodo-aniline, 1.5 g (2.1 mmol) PdCl2(PPh3)2 and 0.40 g (2.1 mmol) copper iodide were added and the flask was rinsed with argon. Then 18 mL (0.13 mol) triethylamine were added and 3.0 g (55 mmol) 1-butyne (in gaseous form) were passed through the solution. The reaction mixture was stirred for 3 h at RT, then diluted with diethyl ether, filtered through kieselguhr and evaporated down.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([Cl:15])=[O:10]
Reactant: O=C(O)c1sccc1OC(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1sccc1OC(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
At 80° C., a mixture of 4.2 g (0.022 mol) of 3-difluoromethoxy-thiophene-2-carboxylic acid in 45 ml of toluene is admixed with 3.1 g (0.026 mol) of thionyl chloride. After the addition has ended, the reaction mixture is heated to 90° C. and stirred at this temperature for another 2 hours. The reaction mixture is subsequently concentrated under reduced pressure at 60° C. This gives 4.6 (98.3% of theory) of 3-difluoromethoxy-thiophene-2-carbonyl chloride in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:45])[CH:20]([NH:29][C:30]([C:32]1([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19](=[O:45])[CH:20]([NH:29][C:30]([C:32]1([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:24][CH:23]=1)[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.2 mL of Trifluoromethanesulfonic anhydride (7.1 mmol) is added slowly dropwise to a solution of 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.70 g, 6.4 mmol) and 0.7 mL (8.7 mmol) of pyridine in 20 mL of CH2Cl2 at 0° C., and the solution is stirred at 0° C. for 1 hour. The reaction mixture is then partitioned between water and CH2Cl2. The organic phase is separated and washed with saturated aqueous NaHCO3 solution, dried over MgSO4, filtered, and concentrated to yield 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid ethyl ester as a tan solid; 1H NMR (250 MHz, CDCl3) δ 7.25 (d, 2H), 7.17 (d, 2H), 4.80 (q, 1H), 4.75 (s, 1H), 4.10 (two quartets, 2H), 3.12 (ABX m, 2H), 2.00-2.20 (m, 2H), 1.60-2.00 (m, 6H), 1.40 (s, 9H), 1.18 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28](O)=[O:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)[C:46]2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:28]([NH:42][CH3:46])=[O:29])[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCN(C)CC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
4-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-1-methylpiperidine-4-carboxylic acid (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and N,N-diisopropylethylamine (89 μl, 0.51 mmol) were added. After a few minutes methylamine hydrochloride (10 mg, 0.15 mmol) was added and the mixture stirred for 1 hour at room temperature. The mixture was absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. Appropriate fractions were combined and concentrated. The residue was purified by column chromatography on silica, eluting with 5% 7N ammonia in methanol/dichloromethane, to give the title product (40 mg, 77%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.82 (m, 2H); 2.02 (m, 2H); 2.13 (m, 8H); 2.65 (m, 5H); 3.60 (s, 2H); 3.94 (s, 3H); 7.18 (s, 1H); 7.30 (t, 1H); 7.50 (m, 1H); 7.58 (m, 2H); 8.32 (s, 1H); 8.73 (s, 1H); 9.68 (s, 1H). Mass Spectrum: (M+H)+ 501.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@@H:3]1[OH:7].CCN(C(C)C)C(C)C.[C:17](=O)(OC(Cl)(Cl)Cl)[O:18]C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:7]1[C@H:3]2[CH2:4][O:5][CH2:6][C@H:2]2[NH:1][C:17]1=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H]1COC[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N[C@@H]2COC[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.9 %

Procedure:
To a solution of (3R,4R)-4-aminotetrahydrofuran-3-ol (1.1 g, 7.88 mmol) and DIEA (4.54 ml, 26.0 mmol) in CH2Cl2 (30 mL) was added (bis(trichloromethyl) carbonate (1.75 g, 5.91 mmol) dissolved in CH2Cl2 (5 mL) at RT over a period of 30 min. After stirring for 0.5 h at 25° C., the reaction mixture was added to aqueous K2CO3 solution, stirred for 1 h and the CH2Cl2 was evaporated. The aqueous phase was washed with Et2O and afterwards evaporated to dryness. The residue was triturated with EtOH/THF 1:1, the inorganic salts removed by filtration through a plug of silica gel, and the filtrate was concentrated to provide the title compound as a beige solid (930 mg, 90%): ESI-MS: 147 [M+NH]+.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[N+:13]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:3]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:15])=[O:14]
Reactant: NCCCCCCNC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Product: O=C(NCCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1

Procedure:
Using the general method of Example 9 Part B, 4-chloro-3-nitroquinoline hydrochloride (10 g, 41 mmol) was reacted with N-(6-aminohexyl)benzamide to provide 12.85 g of N1-{6-[(3-nitroquinolin-4-yl)amino]hexyl}benzamide as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.[H][H]>CN(C)C=O.CO.[Ni]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[O:18][C:17](=[O:19])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:5]=2[CH:6]=1
Reactant: [H][H]
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2oc(=O)c3c(c2cc1N)CCNC3
Yield: 81.2 %

Procedure:
A solution of 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.0 g, 0.023 moles) in N,N-dimethylformamide (100 ml) and methanol (50 ml) is hydrogenated at 50 psi in the presence of Raney Nickel (0.5 g) at room temperature for 20 hours. Additional Raney Nickel (0.5 g) in N,N-dimethylformamide (50 ml) is then added, and hydrogenation resumed until hydrogen uptake ceases. The catalyst is filtered off and rinsed with warm N,N-dimethylformamide. The filtrate is concentrated under reduced pressure and filtered to afford the product (4.3 g), mp 283°-284° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:45][CH2:46][C:47]1[N:48]=[CH:49][NH:50][CH:51]=1>CN(C=O)C>[NH:50]1[CH:51]=[C:47]([CH2:46][NH:45][C:8]([C:4]2[N:5]([CH3:7])[CH:6]=[C:2]([Cl:1])[CH:3]=2)=[O:10])[N:48]=[CH:49]1
Reactant: Cn1cc(Cl)cc1C(=O)O
Reactant: NCc1c[nH]cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(Cl)cc1C(=O)NCc1c[nH]cn1
Reaction time: 0.08 h

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid (55 mg, 0.34 mmol) and triethylamine (0.100 mL, 0.72 mmol) in DMF (2 mL), BOP (217 mg, 0.49 mmol) was added. After 5 min of stirring, a solution of 4-aminomethylimidazole II-2 (100 mg, 1.03 mmol) in DMF (2 mL) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide (81 mg).
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.Cl.Cl[CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.O>CO>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:17][S:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH:23]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Sc1ncnc2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccnc(CSc2ncnc3ccccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
13 ml of 28% methanolic solution of sodium methoxide were added to a solution of 5.0 g of 4-mercaptoquinazoline and 5.5 g of 2-chloromethyl-4-methylpyridine hydrochloride in 50 ml of methanol and stirred at room temperature for 5 hours. A reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with an aqueous sodium carbonate solution, dried over sodium sulfate and distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The fraction eluted with 10% ethyl acetate/chloroform was crystallized from isopropyl ether to obtain 1.84 g (22.3%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:7]=1.[O:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:19][C:15]1([CH2:16][CH2:17][CH2:18][O:13][CH2:14]1)[CH:9]([CH3:10])[C:8]2=[O:11]
Reactant: CCC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCCOC1
Solvent: C1CCNC1
Solvent: CO
Product: CC1C(=O)c2cc(Br)ccc2OC12CCCOC2
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxyphenyl)propan-1-one (5.7 g, 25 mol), dihydro-2H-pyran-3(4H)-one (5 g, 50 mmol) and pyrrolidine (3.4 g, 48 mmol) in methanol (80 mL) was stirred overnight. The reaction mixture was removed in vacuo, and H2O was added. The resulting solution was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.2 g, 16%). 1HNMR (CDCl3): 1.16-1.27 (m, 3H), 1.51-1.57 (m, 1H), 1.66-1.73 (m, 1H), 1.91-2.08 (m, 2H), 2.59-2.69 (m, 1H), 3.46-3.56 (m, 2H), 3.88-3.98 (m, 2H), 6.97 (m, 1H), 7.58 (m, 1H), 7.95 (s, 1H).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=O)C>CO>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (1 g, 4.52 mmol) (Evans in U.S. Pat. No. 4,665,171) in 20 mL of anhydrous methanol was treated hourly with 5 equivalents of acetyl chloride, for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after evaporation of the MeOH was redissolved in 30 mL of CH2Cl2 and treated with 50 mL of saturated aqueous Na2CO3. The organic layer was evaporated and dried (MgSO4) to yield the title compound as a colorless oil (1.001 g, 94%); 1H NMR (CDCl3) δ 3.37 (d, J=18.0 Hz, 1H), 3.69 (s, 3H), 4.13 (t, J=8.3 Hz, 1H), 4.28 (d, J=18.0 Hz, 1H), 4.69 (t, J=8.8 Hz, 1H), 5.04 (t, J=8.4 Hz, 1H), 7.26-7.29 (m, 2H), 7.36-7.42 (m, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@@H:10]([NH:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:11][CH2:12][CH3:13].O>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([NH2:30])[N:16]=[C:15]([NH:14][C@H:10]([CH3:9])[CH2:11][CH2:12][CH3:13])[N:23]=2
Reactant: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Yield: 29.6 %

Procedure:
N-Bromosuccinimide (2.08 g, 11.69 mmol) was added portionwise to a stirred solution of N2-[(1R)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl) -9H-purine-2,6-diamine (2.27 g, 7.46 mmol) in chloroform (30 ml) at 0° C. under at atmosphere of nitrogen. The reaction mixture was allowed to stir for 1.5 hours when chloroform (20 ml) and water (50 ml) were added. After mixing the layers were separated using a hydrophobic frit, the aqueous layer was washed with an additional portion of chloroform and the combined organic extracts were evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white foam (0.846 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
Pd(OH)2/C (690 mg) was added to a solution of 3′,6′-dihydro-2′H-[2,4]bipyridinyl-3,1′-dicarboxylic acid 1′-t-butyl ester 3-methyl ester (2.0 g, 6.3 mmol, 1.0 eq.) in PE (220 mL) and EtOAc (50 mL). Hydrogen gas (1 atm) was introduced into the reaction vessel, and the solution was stirred for 20 hours at room temperature. The reaction mixture was filtered and the remaining mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:8) to yield 3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-3,1′-dicarboxylic acid 1′-t-butyl ester 3-methyl ester (1.2 g) as a colorless oil.