Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:22][CH2:21][CH2:20]C[N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@@H]1N(C(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](O)C1)[OH:61].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:22][C@@H:21]([OH:61])[CH2:20][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)c1ccccc1
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](O)CN2)C1=O
Temperature: 25 °C

Procedure:
Step 14 (A): (3R,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation J, 129 mg, 0.278 mmol) in EtOH (10 mL) was added a solution of LiOH (133 mg, 5.56 mmol) in H2O (2.5 mL). This reaction mixture was stirred at reflux for 3.5 h. After cooling down to rt, the mixture was concentrated to remove EtOH and the mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.00-2.05 (1H, m), 2.13-2.21 (1H, m), 2.40-2.61 (2H, m), 2.79-2.91 (2H, m), 3.21 (2H, d, J=15 Hz), 3.51 (1H, d, J=15 Hz), 4.26 (1H, m), 4.79 (1H, s), 6.62-6.70 (3H, m), 7.14-7.26 (4H, m), 7.30-7.35 (3H, m), 7.37-7.43 (3H, m). HPLC retention time: 1.19 min (method A). MS (ESI) (M+H)+ 439.22.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H](C(OC)=O)[C@H:7]([CH2:14][N:15]=[N+]=[N-])[C@@H:6]1[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:4].[C:27]([O:30][C:31](=[O:33])[CH3:32])(=O)C.[C:34](OCC)(=[O:36])[CH3:35]>[Pd]>[C:34]([NH:15][CH2:14][C@H:7]1[C@H:32]([C:31]([O:30][CH3:27])=[O:33])[CH2:9][C@H:5]([C:3]([OH:2])=[O:4])[C@H:6]1[CH2:18][NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)[C@H](CN=[N+]=[N-])[C@@H]1CNC(=O)OC(C)(C)C
Agent: [Pd]
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](CNC(=O)OC(C)(C)C)[C@H]1CNC(C)=O
Temperature: 25 °C

Procedure:
A mixture of (±)-(1S,2S,3R,4R)-3-azidomethyl-2-(N-t-butoxycarbonylamino)methylcyclopentane-1,4-dicarboxylic acid dimethyl ester (386 mg, 1.04 mmole), acetic anhydride (0.25 mL) and palladium (25 mg, 10% on carbon) in 10 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 75% ethyl acetate in hexanes to provide the title compound. (yield: 232 mg, 58%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12]>>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:17]2[CH2:18][CH2:19][N:14]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:15][CH2:16]2)[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Product: Cc1cc(Cl)nc(N2CCN(S(C)(=O)=O)CC2)n1
Yield: 41 %

Procedure:
Prepared in analogy to example 98a), using 2,4-dichloro-6-methylpyrimidine and 1-methanesulfonyl-piperazine. The title compound was isolated as a yellow solid in a yield of 41%. MS ISP (m/e): 291.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.81 (s, 1H), 3.80-3.70 (m, 4H), 3.20-3.15 (m, 4H), 2.90 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15]C(Cl)C.[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27]1[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:28]=1[C:29]([NH:31][C:32]1[CH:40]=[C:39]2[C:35]([C:36]([CH3:43])([CH3:42])[C:37](=[O:41])[NH:38]2)=[CH:34][CH:33]=1)=[O:30].[C:52]1(=O)[CH2:56][CH2:55][CH2:54][CH2:53]1.[OH-].[Na+]>C(O)(=O)C>[ClH:15].[CH:52]1([NH:19][C@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[NH:26][C:27]2[CH:47]=[C:46]([C:48]([F:51])([F:49])[F:50])[CH:45]=[CH:44][C:28]=2[C:29]([NH:31][C:32]2[CH:40]=[C:39]3[C:35]([C:36]([CH3:43])([CH3:42])[C:37](=[O:41])[NH:38]3)=[CH:34][CH:33]=2)=[O:30])[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: O=C1CCCC1
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccc(C(F)(F)F)cc3N[C@H]3CCCC[C@@H]3N)ccc21
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc(NC(=O)c3ccc(C(F)(F)F)cc3N[C@H]3CCCC[C@@H]3NC3CCCC3)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (138 mg) was added to a dichloroethane (20 mL) solution of 2-{[(1S,2S)-2-aminocyclohexyl]amino}-N-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-(trifluoromethyl)benzamide (200 mg), cyclopentanone (40 mg) and acetic acid (29 mg), followed by stirring at room temperature for 1 day. Acetic acid (260 mg), cyclopentanone (140 mg) and sodium triacetoxyborohydride (140 mg) were added to the reaction liquid, followed by stirring for 1 day. A 1 M sodium hydroxide aqueous solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol, 1:0 to 85:15). By treating the resulting free base with 4 M hydrogen chloride/ethyl acetate, 2-{[(1S,2S)-2-(cyclopentylamino)cyclohexyl]amino}-N-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-4-(trifluoromethyl)benzamide hydrochloride (53 mg) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH2:19][NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:5][C:6]([O:8][CH3:9])=[O:7].FC(F)(F)C(O)=O.COC(=O)[C@@H](CC1C=CC(OC)=CC=1CNCC(F)(F)F)CC(OC)=O>C1(C)C=CC=CC=1.CC#N>[CH3:9][O:8][C:6](=[O:7])[CH2:5][C@H:4]1[C:3](=[O:2])[N:20]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:19][C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[CH2:10]1
Reactant: COC(=O)CC(Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Agent: COC(=O)C[C@H](Cc1ccc(OC)cc1CNCC(F)(F)F)C(=O)OC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
A toluene solution S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinic acid dimethyl ester (950 mL, 212 mmol) was placed in a 2 L round bottom flask and concentrated under rotary evaporation to a volume of 460 mL (to remove residual water). Toluene (450 mL) was added and the mixture was transferred to a 3 neck 2 L flask. The flask was fitted with reflux condenser, thermometer, nitrogen inlet/outlet, and stir bar. The mixture was de-gassed under a flow of nitrogen gas. The mixture was heated to 50° C. and trifluoroacetic acid (200 mmol, 22.8 g) was added over a 5 min period. The mixture was heated to reflux. After 2.5 h, HPLC analysis (Waters Cosmosil 4.6×150 mm, 60% CH3CN/40% 0.1% TFA, 220 nm, 0.5 mL/min) showed less than 0.2% (area %) of (S)-2-{4-methoxy-2-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-succinic acid dimethyl ester remaining. The mixture was cooled to 25° C. and was washed with 1×400 ml NaHCO3 solution (satd.), and 1×400 mL water. The solvent was removed by vacuum distillation. The residue was treated with hexane (800 ml) and was heated to reflux with rapid stirring. This resulted in a solution with some oily residue. Toluene (20 mL) was added and a clear solution was obtained. The mixture was allowed to cool to 25° C. with rapid stirring over a 1 hour period. The mixture was then cooled to 0-5° C. for 1 hour. The resulting solid was isolated by filtration, washed with hexane (70 mL) and air dried to provide the product as an off-white solid (64.4 g, 88%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[CH2:8][CH2:7]1)=[O:5].[N:29]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][C@H:30]1[C:39](O)=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:3]([NH:2][C:39]([C@@H:30]2[CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:38][N:29]2[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:40])[C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[CH2:8][CH2:7]2)=[O:5])=[CH:27][CH:26]=1
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1
Yield: 85 %

Procedure:
Using the procedure described for the synthesis of Preparation V, tert-butyl 3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-nitrophenyl) piperazinyl]-2-oxoethyl{carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-[4-(2-nitrophenyl)piperazinyl]propan-1-one hydrochloride (570 mg, 1.3 mmol) in DMF (10 mL), Boc-L-Tic-OH (Bachem) (410, 1.5 mmol), HOAT (Aldrich) (180 mg, 1.4 mmol), EDC (Aldrich) (520 mg, 2.70 mmol), and DIEA (Aldrich) (240 μL, 1.4 mmol). The crude material was purified by column chromatography (1:1 hexanes-EtOAc) to give the title compound as a white foam (716 mg). MS (ESI, pos. ion) m/z: 648 (M+H). Calc'd for C34H38ClN5O6: 647.25.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=1.CCOCC.N.[Li]>C(O)C>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH2:8][CH2:7]1
Reactant: CN(C)CCCC1=CCc2ccccc21
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCCC1CCC2=C1CC=CC2
Reaction time: 1 h

Procedure:
A solution of 35 g. (0.174 mole) of N,N-dimethylinden-3-propylamine in a total volume of 125 ml. of ether is added to 2 liters of liquid ammonia. Over 1 hr., 44 g. (6.3 g-atoms) of lithium ribbon is added at the reflux temperature. After a total of 3 hours, the reaction mixture is blue. 550 ml. of ethanol is added over 135 min. whereupon the blue color fades. The ammonia is allowed to evaporate overnight and the residue dissolved in 1500 ml. of water and extracted twice with ether. The ether extract gives 34.5 g. (98.6%) of crude diene upon drying and solvent removal which contains ca, 10% of the corresponding aromatic compound by nmr integration.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:47]=[C:17]2[N:18]([CH:41]3[CH2:45][CH:44]([CH3:46])[O:43][CH2:42]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:47]=[C:17]2[N:18]([CH:41]3[CH2:45][CH:44]([CH3:46])[O:43][CH2:42]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2COC(C)C2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2COC(C)C2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.22 g), sodium hydrogen carbonate (0.36 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-4-(5-methyltetrahydrofuran-3-yl)-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.042 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.035 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.076 g, 67%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12]3)O1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]=[CH:12]4)[C:35]=12
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (212 mg, 0.61 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.25 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA86 (9.3 mg, 9% yield). ESI-MS (M+H)+ m/z calcd 362.1, found 362.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]O)=O.[N:12]1([C:18]([O-:20])=O)[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.CC[O:23]CC>C(Cl)Cl>[CH:14]12[O:23][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:7][CH2:5][C:4]1[CH:3]=[CH:2][CH:11]=[CH:10][CH:9]=1)=[O:20])[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([O-])N1CC=CCC1
Reactant: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
3-Chlorobenzoperoxoic acid (51.1 g, 228 mmol) was added portion wise to a solution of 5,6-dihydropyridine-1(2H)-carboxylate (33.0 g, 152 mmol) in DCM (200 mL) at 0° C. After 10 minutes at 0° C., the reaction was warmed to room temperature and stirred at room temperature for 4 hours. The reaction mixture was diluted with ether (800 mL), washed with 1N NaOH solution (2×200 mL), saturated N2SO3 solution (2×100 mL), brine (100 mL), dried (sodium sulfate) and concentrated in vacuo to give benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (35.0 g, 99%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:21][S+](C)C.[OH-].[K+]>C(#N)C.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@:8]([CH3:11])([CH:9]1[CH2:21][O:10]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[S+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C1CO1
Temperature: 60 °C

Procedure:
To a solution of N-(tert-butyl((1R)-1-benzyl-1-methyl-2-oxoethyl)carbamate (Intermediate XLIX, 1 g, 3.80 mmol) in acetonitrile (15 mL) was added 6 drops water, trimethylsulfonium iodide (775 mg, 3.80 mmol) and potassium hydroxide (511 mg, 9.11 mmol). The reaction was stirred at 60° C., sealed, for 1.5 h, additional trimethylsulfonium iodide (775 mg, 3.80 mmol) and potassium hydroxide (511 mg, 9.11 mmol) were added and the reaction was stirred at 60° C., sealed, for 3 h. the reaction mixture was diluted with EtOAc, washed with sat'd aq NaHCO3, brine, dried over sodium sulfate, and concentrated in vacuo to provide tert-butyl((1R)-1-methyl-1-oxiran-2-yl-2-phenylethyl)carbamate as an oil. MS (ES, M+H) 278.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2([CH2:10]S(Cl)(=O)=O)[C:7]([CH2:9][CH:3]1[CH2:4][CH2:5]2)=[O:8].C(Cl)(=O)C(Cl)=[O:18].[NH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH:27]1[O:32][C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:32]1[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][CH2:28][CH:27]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22][C:10]([C:6]12[C:2]([CH3:15])([CH3:1])[CH:3]([CH2:4][CH2:5]1)[CH2:9][C:7]2=[O:8])=[O:18]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCNCC1COc2ccccc2O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)C2CCC1(C(=O)NCCNCC1COc3ccccc3O1)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+)-Ketopinic acid (900 mg, 5.0 mmole), prepared from (+)-10-camphorsulfonyl chloride by the procedure of Bartlett and Knox, Org. Syn., 45, p. 55, was converted to the acid chloride by treatment of a solution of the compound in 50 ml of methylene chloride with 1.0 ml (11.5 mmole) of oxalyl chloride. After stirring for 2 hours at room temperature, the mixture was concentrated in vacuum. It was then redissolved in 50 ml of methylenechloride and added at 0° C. to a solution of 1.04 g (10 mmole) of 2-[N-(2-aminoethyl)]aminomethyl-2,3-dihydrobenzodioxin and 1.3 g (10 mmole) of diisopropylethylamine in 50 ml of dichloromethane. After stirring overnight at room temperature, the mixture was washed with saturated sodium bicarbonate solution, with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 75 g of silica gel with chloroform as eluant and the title compound crystallized from isopropanol with the addition of 4 N HCl/isopropyl alcohol and 3 volumes of diethyl ether. This procedure gave 835 mg of title compound as the monohydrochloride, m.p. 172°-173° C., with an [α]D25 =+32.7 (MeOH).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH2:10][C:11]([CH3:20])([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH3:12])=[CH:4][N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH:23]1[C:28](O)=[O:29].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH2:10][C:11]([CH3:20])([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH3:12])[C:28](=[O:29])[CH:23]3[CH2:24][O:25][CH2:26][CH2:27][N:22]3[C:6]=2[N:7]=1
Reactant: O=C(O)C1COCCN1
Reactant: CC(C)(CNc1cnc(Cl)nc1Cl)OC1CCCCO1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(CN1C(=O)C2COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Temperature: 95 °C
Reaction time: 4 h
Yield: 24.6 %

Procedure:
To a mixture of 2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine (315 mg, 0.982 mmol) and morpholine-3-carboxylic acid hydrochloride (247 mg, 1.47 mmol) in DMSO (6 ml) was added diisopropylethylamine (0.686 ml, 3.93 mmol), and the reaction mixture was stirred at 95° C. for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude residue was chromatographed by silica gel (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (96.2 mg, 0.242 mmol, 25% yield) as a pale yellow oil which was used in the next reaction without further purification. MS [M+H] found 397.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:16][CH3:17])[CH2:13][CH2:14]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH2:13][CH:12]([CH3:11])[CH2:16][CH3:17])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC[C@H](C)CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)CCOC(=O)c1ccc(O)cc1
Yield: 80.7 %

Procedure:
13.7 g of p-hydroxybenzoic acid and 11.4 g of (S)-(+)-3-methyl-1-pentanol were refluxed for 10 hours in toluene in the presence of sulfuric acid, while removing out the generated water from the reaction system. Subsequently, the reaction solution was washed with water to remove the sulfuric acid out. The reaction solution was then dried, concentrated, and purified by column chromatography, to obtain 17.8 g of the objective ester compound (liquid state at room temperature ([α]D23 =+7.8° (CHCl3)). (Yield: 80%)
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(C)cc3)CCC2)cc1
Yield: 92 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 260 mg (1.9 mmol) of 4-methylphenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 240 mg (92%) of 1-[2-(4-methylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 64.5°-66.5° C.; NMR (CDCl3) d 2.03 (m, J=7 Hz, 2H), 2.30 (s, 3H), 2.45 (s, 3H), 2.86 (t, J=7 Hz, 4H), 6.99-7.15 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.C([Li])CCC.[I:23]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([I:23])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1ccnc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,4-dichloropyridine (5.2 g, 35.14 mmol) and DIPEA (3.91 g, 38.65 mmol) in dry THF (40 mL) cooled at −78° C. under a nitrogen atmosphere, was added n-butyllithium (24.16 mL, 38.65 mmol, 1.6 M in hexanes) dropwise. The resulting reaction mixture was stirred at −78° C. for 45 min. and then a solution of iodine (9.81 g, 38.651 mmol) in dry THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h., allowed to warm to r.t., diluted with EtOAc and quenched with NH4Cl (aqueous sat. solution) and Na2S2O3 (aqueous sat. solution). The organic layer was separated, washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in heptane 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-7 (7.8 g, 81%).