Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.[Cl-].[Na+].O>[CH3:17][O:15][C:14]([CH:9]1[CH:10]([OH:13])[CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1C(O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution containing 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60, 16 g, 71 mmol. See: Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0° C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90° C. for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14.8 g (87%) of 3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (61) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:3]=1[CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:20][C:3]1[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1C
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1C
Yield: 86.8 %

Procedure:
Methyl 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (1.1 g), phenylboronic acid (487 mg), sodium carbonate (488 mg) and tetrakis(triphenylphosphine)palladium (355 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), and the mixture was reacted in a microwave reactor (Emrys Optimizer, Personal Chemistry, 140° C., 4 min). The reaction mixture was filtered through celite, water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 947 mg, 87%).
Reaction SMILES: [CH2:1]([N:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:8](=[O:27])[C@H:9]([CH3:26])[N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25])C(OC(C)(C)C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:27])[C@H:9]([CH3:26])[NH:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCN(CCCCCC)C(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN(CCCCCC)C(=O)[C@H](C)Nc1ccccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
To a solution of 0.98 g of N-t-butoxycarbonyl-(2-cyanophenyl)alanine dihexylamide in 1.7 ml of dichloromethane was added 1.7 ml of trifluoroacetic acid, followed by stirring at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added an aqueous sodium bicarbonate solution, followed by extracting with dichloromethane. The extract was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give 0.76 g of a crude (2-cyanophenyl)alanine dihexylamide, which was then used for the next step without purification.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:4].CCN(CC)CC.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>CN(C=O)C.O>[CH3:1][N:2]([C@@H:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:4])[C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: CN[C@H](C)c1oc2ccccc2c1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)N(C)[C@H](C)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To an ice cold mixture of (R)-methyl-[1-(3-methyl-benzofuran-2-yl)-ethyl]amine (7.5 mL of a 0.46 M solution in DMF, 3.5 mmol) and Et3N (0.6 mL, 4.1 mmol) was added acryloyl chloride (0.3 mL, 3.8 mmol) drop-wise. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was diluted with H2O and extracted with Et2O (3×). The combined organics were washed with H2O and satd NaCl, dried (Na2SO4) and concentrated. Purification by column chromatography (silica gel, 7:3 hexanes/EtOAc) gave the title compound (630 mg, 75%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) 7.50-7.47 (m, 1H), 7.44-7.41 (m, 1H), 7.30-7.20 (m, 2H), 6.81-6.52 (m, 1H), 6.40-6.25 (m, 2H), 5.74-5.70 (m, 1H), 2.99-2.90 (m, 3H), 2.23 (s, 3H), 1.69-1.58 (m, 3H).
Reaction SMILES: CO[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]([S:17][CH3:18])=[C:15]3[C:10]([N:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12](=[O:21])[N:13]([CH3:20])[C:14]3=[O:19])=[N:9]2)=[CH:5][CH:4]=1.BrCC1C=CC([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=CC=1>>[N:37]1([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][N:8]3[C:16]([S:17][CH3:18])=[C:15]4[C:10]([N:11]([CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:12](=[O:21])[N:13]([CH3:20])[C:14]4=[O:19])=[N:9]3)=[CH:27][CH:28]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COc1ccc(Cn2nc3c(c2SC)c(=O)n(C)c(=O)n3CC(C)(C)C)cc1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cccn2)cc1

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 5 wherein 2-(4-methoxybenzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 2-(4-methoxybenzyl)-5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and 1-(4-(bromomethyl)phenyl)-1H-pyrazole is used instead of 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. MS (ESI) m/z 439.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][N:31]=[CH:30]2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([CH3:26])=[CH:35][CH:34]=4)[CH:30]=[N:31]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1ccc2[nH]ncc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 328 μmol), 5-methyl-1H-indazole (41.7 mg, 316 μmol) in dioxane (2 mL) was added sodium tert-butoxide (66.8 mg, 695 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.1 mg, 31.6 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-methyl-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.34 (s, 1H), 8.20 (d, J=0.8 Hz, 1H), 7.95-8.07 (m, 1H), 7.78 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 5.71 (s, 2H), 3.55-3.60 (m, 2H), 2.53 (s, 3H), 1.63 (s, 9H), 0.92-0.98 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)=[O:4].[CH3:26][C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([C:8]2[S:7][C:6]([NH:5][C:3]([C:2]([NH:1][C:30]([C:27]3([CH3:26])[CH2:29][CH2:28]3)=[O:31])([CH3:25])[CH3:24])=[O:4])=[N:10][C:9]=2[C:11]([F:13])([F:14])[F:12])=[O:23])=[CH:17][CH:18]=1
Reactant: CC(C)(N)C(=O)Nc1nc(C(F)(F)F)c(C(=O)c2ccc(F)cc2)s1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CC1(C(=O)NC(C)(C)C(=O)Nc2nc(C(F)(F)F)c(C(=O)c3ccc(F)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-Amino-N-[5-(4-fluoro-benzoyl)-4-trifluoromethyl-thiazol-2-yl]-2-methyl-propionamide (150 mg, 0.400 mmol), 1-methylcyclopropyl carboxylic acid (80 mg, 0.80 mmol), triethylamine (140 uL, 1.00 mmol) and HBTU (300 mg, 0.809 mmol) was stirred at RT for 18 h, partitioned between ethyl acetate and, sequentially, 3 M HCl and aqueous KOH. The organic extract was dried over MgSO4, concentrated and purified by HPLC to give the title compound. m/z 458.3 (MH+). 1H NMR (CDCl3) δ 7.91 (dd, J=8, 4 Hz, 2H), 7.16 (t, J=8 Hz, 2H), 6.04 (br s, 1H), 1.63 (s, 6H), 1.38 (s, 3H), 1.30-1.25 (m, 2H), 0.70-0.65 (m, 2H), retention time 1.42 min (method A).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:23]=[CH:22][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)O1.Br[C:26]1[N:31]2[N:32]=[C:33]([NH2:35])[N:34]=[C:30]2[CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O>[O:21]=[S:17]1(=[O:20])[CH2:16][CH2:15][N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:26]3[N:31]4[N:32]=[C:33]([NH2:35])[N:34]=[C:30]4[CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:22]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2ccc(CN3CCS(=O)(=O)CC3)cc2)OC1(C)C
Reactant: Nc1nc2cccc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc2cccc(-c3ccc(CN4CCS(=O)(=O)CC4)cc3)n2n1
Temperature: 90 °C

Procedure:
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (4:1). K2CO3 (2 eq.) and PdCl2dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N2. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhydrous MgSO4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[CH:16][CH:15]=2)=[O:13])[CH2:9][OH:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12](=[O:13])[C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(C(=O)N[C@@H](CO)c3ccc(F)cc3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1ccc(F)cc1)c1ccc([C@H]2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 2-(4-((R)-1-(4-fluorophenyl)-2-hydroxyethylcarbamoyl)phenyl)morpholine-4-carboxylate (44 mg, 0.099 mmol) was dissolved in dichloromethane (0.3 ml) and trifluoracetic acid (447 mg, 0.3 ml, 3.92 mmol) was added. The reaction mixture was stirred at room temperature for 60 min. The solvent and excess of trifluoracetic acid were evaporated. The residue was dissolved in dichloromethane (3 ml) and extracted with odium bicarbonate saturated solution (2 ml). The organic layer was dried over MgSO4 and evaporated. The crude product was directly used for the next step.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].C(N(CC)C(C)C)(C)C.[CH2:31]([NH:33][C:34](=[O:49])[NH:35][C:36]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:37]=1[C:38](O)=[O:39])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:38]([C:37]3[CH:41]=[C:42]([C:45]([F:47])([F:48])[F:46])[CH:43]=[CH:44][C:36]=3[NH:35][C:34]([NH:33][CH2:31][CH3:32])=[O:49])=[O:39])[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17]
Reactant: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)NCC)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (77 mg, 0.26 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.32 mL), 2-(3-ethylureido)-5-(trifluoromethyl)benzoic acid (80 mg) and HATU (129 mg). The reaction was stirred at RT for 14 h, diluted with water, filtered, and purified by RP-HPLC to afford 1-{2-[((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl]-4-(trifluoromethyl)phenyl}-3-ethylurea. MS found: (M+H)+=554.4. [Note: for larger scale preparations, the reaction was frequently run with CH2Cl2 as a co-solvent, and the following aqueous workup was used before RP-HPLC purification. Volatiles were removed and the residue was dissolved in EtOAc. The organic phase was washed with sat. NaHCO3, water, 1N HCl, sat. NaCl, and then dried (MgSO4), filtered, and concentrated in vacuo.]
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]#[N:19])[C:15]([OH:20])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH:32][NH2:33])=O)=[CH:25][CH:24]=1>>[O:21]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]2[NH:19][C:30]([CH2:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[N:32][N:33]=2)[C:15]([OH:20])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: N#Cc1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Reactant: NNC(=O)Cc1ccc(F)cc1
Product: O=S1(=O)CCCCN1c1nc(-c2nnc(Cc3ccc(F)cc3)[nH]2)c(O)c2ncccc12

Procedure:
The title compound was prepared in a similar manner to that described in example 3 from 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carbonitrile (12 mg, 0.04 mmol) and 2-(4-fluorophenyl)acetic hydrazide (33 mg, 0.20 mmol) to give a white solid (6 mg, 31%). 1H NMR (CDCl3/CD3OD): δ 9.13 (m, 1 H), 8.56 (d, J=8.4 Hz, 1 H), 7.63 (dd, J=8.4, 4.0 Hz, 1 H), 7.32 (dd, J=8.4, 5.6 Hz, 2 H), 6.99 (t, J=8.4 Hz, 2 H), 4.17 (s, 2 H), 3.90 (m, 1 H), 3.77 (m, 1 H), 3.52 (m, 1 H), 3.32 (m, 1 H), 2.44-1.89 (m, 4 H); 19F NMR (CDCl3/CD3OD): δ −116.86; MS m/z 455 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[NH2:6].[C:23]([S:26][CH2:27][CH:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](O)=[O:30])(=[O:25])[CH3:24]>CO>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[NH:6][C:29](=[O:30])[CH:28]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:27][S:26][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React O-benzyl-L-tyrosine methyl ester hydrochloride (2.,7 g) and 3-acetylthio-2-benzylpropionic acid (2.05 g) in a manner similar to that described in Example 1, Step 1 to give a yellow-orange oil. Chromatograph this oil on a column of silica gel (2.5L) and elute with CH2Cl2 :ethyl acetate 98:2 to give Isomer A, a white solid (0.84 g) m.p. 108°-109°; [α]D26 =-39.8° (MeOH); overlap Isomer A and Isomer B (0.80 g); and Isomer B, white solid (0.45 g), m.p. 92°-93°, [α]D26 =+19.2° (MeOH).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:17])([S:15][CH3:16])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:41][C:42]1[N:46]2[C:47](=[O:56])[N:48]([CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:49][C:45]2=[CH:44][N:43]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:14][C:13]([S:15][CH3:16])([CH3:17])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:53]1[CH2:52][CH2:51][CH:50]([N:48]2[CH2:49][C:45]3=[CH:44][N:43]=[C:42]([CH3:41])[N:46]3[C:47]2=[O:56])[CH2:55][CH2:54]1)=[O:12]
Reactant: CSC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSC(C)(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 74.9 %

Procedure:
To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-3-methyl-3-(methylthio)butanoic acid (T. Fukami et al., J. Med. Chem., 39, 2313 (1996); 1.3 g) and HOBt (1.14 g) in acetonitrile (30 ml) was added WSC (1.42 g), and the reaction mixture was mixed at room temperature for 15 minutes. Then, a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (1.43 g), DBU (1.47 ml) and triethylamine (2.2 ml) in acetonitrile (10 ml) was added thereto. The reaction mixture was mixed at room temperature for 15 hours, the solvent was then distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) to obtain the title compound as colorless powder (1.7 g, 71%).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=[CH2:8])[CH2:4][CH2:3]1.[O-:10]S([O-])(=S)=O.[Na+].[Na+].Cl.[OH2:18]>O=[Os](=O)(=O)=O>[F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5]([CH2:8][OH:10])([OH:18])[CH2:4][CH2:3]1
Reactant: O=S([O-])([O-])=S
Reactant: O
Reactant: C=C1CCC(F)(F)CC1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: [Na+]
Product: OCC1(O)CCC(F)(F)CC1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
To the solution from EXAMPLE 490A was added water (75 mL), then N-metthylmorpholine-N-oxide (6.4 mL, 50% solution in water) and OsO4 (14.2 g, 2.5 wt % solution in tert-butanol) were added, and the reaction was stirred for 96 hours at 50° C. The solution was cooled to room temperature, treated with saturated aqueous Na2S2O3 solution (100 mL) for 30 minutes, and then acidified with concentrated aqueous HCl. The solution was then extracted three times with ethyl acetate, and the organic layers were combined, washed with 1M aqueous HCl, and brine, and concentrated. The crude mixture was chromatographed on silica gel using 10-100% ethyl acetate in hexanes, and then 5% methanol in ethyl acetate to give the product.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[Cl:15])(=[O:5])[CH3:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:3](=[O:5])[CH3:4])=[C:7]1[Cl:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1c(Cl)n(Cc2ccccc2)c2ccccc12
Reaction time: 72 h

Procedure:
To a slurry of 400 mg of NaH in 20 ml THF was added 1 g of (75), and then 770 μl of benzyl bromide. The reaction was left with stirring for 3 days. Water was added, and the product extracted with diethylether, dried, and the solvent evaporated off to give 1.52 g of a redbrown powder, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[C:7]([CH2:8][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: BrCc1cccnc1Br
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ncccc1Cn1ccnc1

Procedure:
Synthesized from 5a (891 mg, 2.78 mmol), imidazole (658 mg, 5.56 mmol) and K2CO3 (1.92 g, 13.9 mmol) according to Method B. Yield: 375 mg, 1.41 mmol, 51%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.23 (s, 2H), 6.96 (t, J=1.3 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H) 7.15 (t, J=1.3 Hz, 1H), 7.24 (dd, J=7.6, 4.7 Hz, 1H), 7.66 (brs, 1H), 8.32 (dd, J=4.7, 1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=49.7, 119.3, 123.4, 130.0, 133.4, 136.6, 137.6, 142.0, 149.7; MS (ESI): m/z=239.10 [M+H]+.
Reaction SMILES: [C:1]([N:12]1[C@@H:16]([CH3:17])[C:15](=[O:18])OC1=O)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.CN1CCOCC1>O1CCCC1>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:15](=[O:18])[C@H:16]([CH3:17])[NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:27])=[CH:22][CH:21]=1
Reactant: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Reactant: Cc1ccc([C@H](C)N)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@@H](C)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
(S)-3-Decanoyl-4-methyl-2,5-oxazolidinedione (N-decanoyl-L-alanine-NCA) (100 mg, 0.37 mmol) was dissolved in tetrahydrofuran (3 mL), and at 0° C., (S)-1-(p-tolyl)ethylamine (49 mg, 0.36 mmol) and N-methylmorpholine (37 mg, 0.36 mmol) were added, followed by stirring for 30 minutes. The reaction mixture was treated in a similar manner as in Example 19 to afford the title compound (103 mg, 77%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19](Cl)[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:26]=[S:27]1(=[O:36])[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:33]([CH:30]3[CH2:31][CH2:32][S:27](=[O:36])(=[O:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCS(=O)(=O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCS(=O)(=O)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1,1-dioxo-hexahydro-1λ6-thiopyran-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 509.1 [M]+.