Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([OH:35])[CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([NH:8][C@H:9]([C:11]3[N:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15](=[O:23])[C:14]4=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]4[N:12]=3)[CH3:10])=[N:4][CH:5]=[N:6][CH:7]=2)[CH:32]=[C:33]([OH:35])[CH:34]=1
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncncc3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncncc3-c3cc(O)cc(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 54.8 %

Procedure:
(S)-2-(1-((5-Iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (115 mg, 0.24 mmol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (57 mg, 0.37 mmol), sodium carbonate (2M, 548 μl, 1.10 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 60 mg (54% yield) of the title compound. Purity 100%.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1.C(N(CC)CC)C>C(#N)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH:9]=1
Reactant: NCC(F)(F)F
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)CN=Cc1cccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of 2,2,2-Trifluoroethylamine hydrochloride (3.98 g, 29.4 mmol) in acetonitrile (9 mL) was added 3-pyridinecarboxaldehyde (Sigma-Aldrich) (2.1 g, 19.6 mmol) followed by triethylamine (4 ml, 29.43 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered and the solids washed with acetonitrile. The filtrate was then concentrated in vacuo. The residue was taken up in ethyl ether, filtered and concentrated to afford 3.12 g (84%) of the tile compound as a white foam. 1H NMR (300 MHz, DMSO-d6) δ4.40 (m, 2H), 7.52 (m, 1H), 8.18 (m, 1H), 8.61 (s, 1H), 8.70 (dd, J=1.8, 4.8 Hz, 1H), 8.92 (d, J=1.8, 1H). MS (ESI, [M+H] +), 189.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[C:40]([Cu])#[N:41].N1C=CC=CC=1>CC(N(C)C)=O>[C:40]([C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]1)#[N:41]
Reactant: N#C[Cu]
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)CCCC1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(C#N)c2)CCCC1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
To a 5 mL microwave vial were added methyl 1-{[1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]methyl}cyclopentanecarboxylate (94 mg, 0.16 mmol), CuCN (31 mg, 0.34 mmol), pyridine (0.5 mL) and DMA (1.5 mL). The vial was flushed with N2, then capped and irradiated in the microwave at 200° C. for 4 h. The resulting mixture was cooled to RT, poured into water (10 mL) and extracted with EtOAc. The organics were concentrated to dryness and the resulting residue was purified by FCC to provide 40 mg of the title compound. MS (ESI): mass calcd. for C33H30N4O3, 530.63; m/z found, 531.2 [M+H]+.
Reaction SMILES: ClC1C2C=CC(C(F)(F)F)=CC=2SC=1C([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=O.[Cl:29][C:30]1[C:31]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:32]=2[S:33][C:34]=1[C:35](Cl)=[O:36]>>[Cl:29][C:30]1[C:31]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:32]=2[S:33][C:34]=1[C:35]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:36]
Reactant: O=C(Cl)c1sc2cc(F)c(F)cc2c1Cl
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(F)c(F)cc2c1Cl

Procedure:
Following the 5a synthetic method, using 5-2 (66.77 mg, 0.25 mmol) instead of 5 gave 8a as a white powder; (91.63 mg, 92.6%). [α]D25: −15.9 (c=0.19, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 7.91 (s, 1H), 7.63-7.52 (m, 3H), 7.37-7.25 (m, 5H), 5.16-5.09 (m, 1H), 3.43-3.28 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 175.39, 160.02, 152.99, 151.92, 149.63, 148.61, 135.17, 133.75, 133.25, 129.45, 128.82, 127.53, 118.84, 110.98, 110.77, 110.50, 54.05, 37.28; HRMS (ESI): calcd for: C18H12ClF2NO3S [M−H]−=394.0122, obsd [M−H]−=394.0137.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][N:8]=1)=[O:6].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O.O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:2][CH2:3][NH:4][C:5]([C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[S:9][N:8]=4)=[O:6])[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: O=C(NCCCl)c1nsc2ccccc12
Reactant: Clc1ccc2c(N3CCCCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NCCC1CCN(c2noc3cc(Cl)ccc23)CC1)c1nsc2ccccc12
Temperature: 180 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
A mixture of N-(2-chloroethyl)-1,2-benzisothiazole-3-carboxamide (2.9 g) and 1-(6-chloro-1,2-benzisoxazol-3-yl)piperidine (3.48 g) in dry N-methylpyrrolidinone (125 ml) was heated to 180° C., with stirring, under nitrogen. After 5 hr, the reaction mixture was allowed to cool to room temperature, diluted with water, basified with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica using ether as the eluent. The appropriate fractions were collected and evaporated. The residue was triturated with dichloromethane/ether to give 2.38 g (44.6%) of product, mp 132°-134° C.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]1([C:19]2[NH:26][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][N:7]3[C:15](=[O:16])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]3=[O:17])[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccccc1
Reactant: O=C(CBr)CCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
To a solution of 2-(5-bromo-4-oxo-pentyl)-isoindole-1,3-dione [CAS 41306-64-3](12.4 g) in abs. DMF (50 ml) was added benzamidine 85% (5.65 g) and potassium carbonate (11.05 g). The reaction mixture was stirred at 80° C. for 4 h, concentrated under high vacuum, quenched with water and extracted with ethyl acetate. The organic phase was washed with ice/water and brine, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on silica gel using methylene chloride/methanol 2 and 5% as eluent. The product fractions were combined and evaporated to dryness to obtain 2-[3-(2-phenyl-1H-imidazol-4-yl)-propyl]-isoindole-1,3-dione (8.95 g) as a light yellow foam.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]2[N:3]=1.[CH3:25][NH2:26]>>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:26][CH3:25])=[N:3][C:4]4[N:5]([N:17]=[CH:18][C:19]=4[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CN
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Product: CCOC(=O)c1cnn2c1nc(NC)c1cnc3c(cnn3CC)c12

Procedure:
3.5 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester (0.01 mol) and 3.5 g of methylamine are heated in 50 ml of alcohol in an autoclave for 10 hours at 100°. The solvent is removed in vacuo and the residue treated with water, filtered off and recrystallized from butyl alcohol, yield 2.9 g (86%); m.p. 321°-322°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 3.00 g of 5-{4-(6-bromo-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-tri-phenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 60) and 40 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.75 g of the title compound, melting at 204°-205° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[F-:16].[K+].[F-].[F-].[Ca+2]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([F:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: [F-]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: [Ca+2]
Agent: [K+]
Product: CC#CCOc1ccc(S(=O)(=O)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of 4-but-2-ynyloxybenzenesulfonyl chloride (prepared from Example 30, step 4) (2.0 g, 8.18 mmol) in acetonitrle (10 ml) was added KF-CaF2 (2.85 g, 16.3 mmol) and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was filtered and the filterate was concentrated. The crude product was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed to obtain 1.5 g (80%) of the product as solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]3[CH2:15][O:14]3)[O:11][C:10]([CH3:17])([CH3:16])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CO>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([OH:14])[CH2:15][NH:28][CH:25]3[CH2:27][CH2:26]3)[O:11][C:10]([CH3:17])([CH3:16])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C2CO2)OC1(C)C
Reactant: NC1CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CNC2CC2)OC1(C)C
Reaction time: 8 h

Procedure:
A mixture of 733 mg (2.16 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-5-[(RS)-2-oxiranyl]-3-oxazolidinecarboxylate (WO 88/4664) and 2 ml of cyclopropylamine in 15 ml of methanol is stirred at 50° overnight under argon. Thereafter, the reaction mixture is evaporated and, for purification and separation of the epimers, the residue is chromatographed on 100 g of silica gel using a 98:2 mixture of chloroform and methanol as the eluent. There are obtained 185 mg of the less polar tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 397 (M+H)+, and 341 mg of the more polar tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 397 (M+H)+, each as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24](=[S:26])[NH2:25])[CH2:23][CH2:22]1.Cl[CH2:28][CH:29]=O>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24]2[S:26][CH:28]=[CH:29][N:25]=2)[CH2:23][CH2:22]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(C(N)=S)CC1
Reactant: O=CCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(c2nccs2)CC1
Temperature: 25 °C
Yield: 9.4 %

Procedure:
A mixture of Example 119 (100 mg, 0.24 mmol) and chloroacetaldehyde (22 mg, 0.28 mmol) in N,N-dimethylformamide (2 ml) was heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (×3). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomenex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [50:50 to 98:2]. The appropriate fractions were concentrated in vacuo to give the titled compound (10 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1([CH3:20])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([OH:17])[C:12]=2[CH3:16])[O:7]1)=[O:5])[CH3:2].[O:21]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH2:1]([NH:3][C:4](=[O:5])[C:6]([OH:21])([CH3:20])[CH2:15][CH2:14][C:13]1[C:8](=[O:7])[C:9]([CH3:19])=[C:10]([CH3:18])[C:11](=[O:17])[C:12]=1[CH3:16])[CH3:2]
Reactant: CCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CCNC(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 91.1 %

Procedure:
Oxidation as described in protocol B, using 100 mg (0.360 mmol) of N-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide and 415 mg CAN (0.757 mmol) yielded 96.2 mg of N-ethyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:20])[C:18]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:20])[C:18]=1[N:8]1[CH2:7][CH2:6][CH:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[CH2:10][CH2:9]1
Reactant: CN(C)C(=O)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 80.9 %

Procedure:
General procedure C was followed using N,N-dimethylpiperidine-4-carboxamide 6 (43 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (66 mg, 80%), m.p. 120-122° C.; umax (CHCl3)/cm−1 3026, 2850, 1631, 1559, 1140, 1092, 934; m/z (ESI) C13H18Cl2N3O requires 302.0821, found [M+H]+ 302.0823.
Reaction SMILES: [F:1][C:2]1([CH2:26]O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:34])CC>COCCOCCOC>[F:1][C:2]1([CH2:26][F:34])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CO)CC3)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: COCCOCCOC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CF)CC3)c(F)c2)C(=O)O1
Yield: 24 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-fluoro-4-hydroxymethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with DAST (1.25 mmol) in diglyme (10 ml) at a temperature 0° C. for two hours and by purifying the compound by silica gel column chromatography in 24% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C(C)C)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Reaction time: 20 h
Yield: 89685.9 %

Procedure:
To a solution of methyl (E)-3-[5-(4-isopropylphenyl)thiophen-2-yl]acrylate (0.75 mg) in THF/ethanol (10/10 ml) was added at room temperature 2N sodium hydroxide solution (2.0 ml), and the mixture was stirred for 20 hours. Under reduced pressure, the mixture was concentrated, and to the residue was added 1N hydrochloric acid (10 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated. The resulting crystals were collected by filtration to give pale yellow crystals of (E)-3-[5-(4-isopropylphenyl)thiophen-2-yl]acrylic acid (639.7 mg).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33].C([O:37][B:38](OC(C)C)[O:39]C(C)C)(C)C>C1COCC1>[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:22]([B:38]([OH:39])[OH:37])=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33]
Reactant: Cn1c(=O)c2cn(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (1.26M, 28.4 mL, 35.8 mmol) was added dropwise to a solution of diisopropylamine (3.63 g, 35.8 mmol) in THF (20 mL) at −78° C., keeping the internal temperature below −40° C. Once the addition was complete, the contents of the flask were allowed to warm to −5° C., then were re-cooled to −78° C. The resulting mixture was cannulated over a period of about 30 minutes into a suspension of 1,3-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (6.93 g, 22.4 mmol) in THF (75 mL) at −78° C. The mixture was stirred at −78° C. for 30 minutes, then triisopropylborate (8.3 mL, 35.8 mmol) was added dropwise. The solution was stirred at −78° C. for 1.5 hours, then was quenched by carefully adding sat ammonium chloride (200 mL). The mixture was allowed to reach room temperature and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried with magnesium sulfate and the solvent was removed under vacuum. The crude material was triturated with ether/hexane and dried under vacuum at 50° C. The solid was recombined with the mother liquor which was reduced under vacuum. The resultant semi-solid material was triturated with iso-hexane and dried under vacuum at 50° C. to afford the title compound;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: NCc1ccncc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCc2ccncc2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 4-aminomethylpyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]4[C:12](=[O:33])[NH:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][N:23]([C:30]=3[CH:31]=4)[C:24]=2[C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C1COCC1.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]4[C:12](=[O:33])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][N:23]([C:30]=3[CH:31]=4)[C:24]=2[C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cn2c(-c3ccoc3)c(C3CCCCC3)c3ccc(cc32)C(=O)NCCC=CCCN1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Cn2c(-c3ccoc3)c(C3CCCCC3)c3ccc(cc32)C(=O)NCCCCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 1 (30 mg, 0.067 mmol) and 10% Pd/C (20 mg) in methanol (10 mL) and THF (10 mL) was shaken in a hydrogenation apparatus under 55 psi pressure at room temperature for 1 h. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated to dryness. Filtration on silica gel afforded 24 mg (80%) of the target product 2: m/z=448 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH2:21][O:22][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(2S,4R)-4-(Tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 53, 51.4 g, 155 mmol) dissolved in 500 ml of dichloromethane was cooled to 0° C., then p-nitrobenzoic acid (28.5 g, 171 mmol), N,N′-dicyclohexylcarbodiimide (35.2 g, 171 mmol) and 4-dimethylaminopyridine (1.90 g, 1.60 mmol) were added. The mixture was maintained under stirring at room temperature for 18 hours, then filtrated; the filtrate was concentrated to obtain crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 15/1 to 10/1). (2S,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(4-nitro-benzoyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as white solid (70 g, yield: 94%).