Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:25])[C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C>C(O)(C)C.O=[Pt]=O>[CH:1]1([O:6][C:7](=[O:25])[C@@H:8]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC1CCCC1
Agent: O=[Pt]=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCC(O)CC1)C(=O)OC1CCCC1
Reaction time: 16 h
Yield: 76.4 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid cyclopentyl ester (Scheme 12) (2.35 g, 9.5 mmol) in isopropanol (40 ml) was placed in a glass insert (120 ml volume). PtO2 (0.47 g, 2.1 mmol) was added to the glass insert which was placed in a hydrogenation bomb. Acetic acid (3 ml) was placed in a glass vial in the bomb next to the glass insert. The bomb was sealed and the reaction stirred for 16 h under an atmosphere of hydrogen (5 bar pressure). The reaction mixture was filtered through celite and washed with isopropanol. The solvent was removed in vacuo and azeotroped with THF to remove excess isopropanol to furnish the 2.58 g (quantitative yield) of the desired product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]1.[ClH:22]>>[ClH:22].[ClH:22].[NH:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: Cl
Product: c1ccc2[nH]c(NC3CCNCC3)nc2c1

Procedure:
The product from step (i) (0.58 g) was heated under reflux with 5M hydrochloric acid (20 ml) for 24 h. The solvent was evaporated under reduced pressure, the residue azetroped with toluene, washed with ether. Yield 0.58 g as a solid.
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9](Cl)=[O:10])[CH:5]=1>C(Cl)Cl>[Cl:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([NH2:1])=[O:10])[CH:5]=1
Reactant: O=C(Cl)c1cc(CCl)on1
Reactant: N
Solvent: ClCCl
Product: NC(=O)c1cc(CCl)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Ammonia was passed for 1 hour at 10-15° C. into a solution of 10 g (55.56 mmol) of 5-chloromethylisoxazole-3-carboxylic acid chloride in 100 ml of methylene chloride and stirring was subsequently continued at room temperature for 1 hour. After the solution had cooled to 0° C., the precipitate was filtered off with suction and washed with a little cold methylene chloride, and the residue was extracted twice by stirring with water to remove the ammonium salts. Drying in vacuo resulted in 6.58 g of pure product as a pale powder (74% of theory)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCCC1CCOC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7](Cl)[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:13]1([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[C:24]2[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[C:24]2[CH:25]=[C:20]([OH:19])[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc2c(Br)c(-c3ccccc3)cnc12
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(-c2c(-c3ccccc3)cnc3c(-c4cccc(O)c4)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 1, substituting 4-bromo-8-chloro-3-phenyl-quinoline and 3-hydroxybenzeneboronic acid MS (ESI) m/z 390.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30]
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: COc1cccc(N=C=O)c1
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(dimethylaminomethyl)-aniline Rf value: 0.7 (aluminium oxide, ethyl acetate/ethanol=20:1) C27H27N3O3
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1O)=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:9]=[C:8]([O:22][CH3:23])[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:26])=O>C(#N)C>[Cl:26][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[CH:9][C:10]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC2CCN(C)CC2)c2c(O)c(C#N)cnc2c1
Solvent: CC#N
Product: COc1cc(OC2CCN(C)CC2)c2c(Cl)c(C#N)cnc2c1
Reaction time: 20 h

Procedure:
A mixture of 3-cyano-4-hydroxy-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (313 mg) and phosphoryl chloride (1.8 ml) in acetonitrile (10 ml) was refluxed and stirred for 20 hours. After cooling, the solution was evaporated to dryness. The flask containing the residue was filled with ice chips and excess concentrated aqueous ammonia (25 ml) was added. This mixture was allowed to warm up while stirring overnight. The product was filtered off and dried under high vacuum overnight. The title compound was obtained as a white solid (225 mg, 68%); NMR spectrum: (DMSOd6) 1.80 (m, 2H), 1.98 (m, 2H), 2.18 (s, 3H), 2.27 (m, 2H), 2.58 (m, 2H), 3.94 (s, 3H), 4.72 (m, 1H), 6.92 (d, 1H), 7.09 (d, 1H), 8.93 (s, 1H); Mass spectrum: M+H+ 332.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.Cl[C:38]([O:40][CH2:41][CH2:42][Cl:43])=[O:39]>>[Cl:43][CH2:42][CH2:41][O:40][C:38](=[O:39])[NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(Cl)OCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCCCl)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (0.5000 g, 1.365 mmol) and N,N-Diisopropylethylamine (0.2383 mL, 1.365 mmol) in 1 mL of was added dropwise, 2-Chloroethyl chloroformate (0.1951 g, 1.365 mmol). The reaction mixture was stirred overnight at ambient temperature. Ethanol was removed under vacuum and the crude was purified by preparative LCMS (m/z=472). The proper fractions were collected and lyophilized to afford the title compound as an off-white solid in 38% yield. LCMS m/z (%)=472 (M+H 35Cl, 100), 474 (M+H 37Cl, 40). 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.71 (d, J=2.16 Hz, 1H), 7.68 (d, J=2.01 Hz, 1H), 7.45-7.34 (m, 3H), 7.08 (d, J=8.08 Hz, 1H), 6.98 (d, J=8.08 Hz, 1H), 6.31 (bs, 1H), 7.19-7.13, (m, 2H), 5.18 (bt, J=5.80 Hz, 1H), 4.28 (t, J=6.01 Hz, 2H), 4.03 (t, J=4.80 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.65 (t, J1=5.80 Hz, 2H), 3.45 (q, J=11.10 Hz, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]2)=[CH:17][CH:16]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CCCCc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1ccc(S(=O)(=O)N(CC(=O)OCC)c2ccc(N3CCC(=O)CC3)cc2)cc1

Procedure:
A solution of 0.12 g of 4-butyl-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 247), 0.038 mL of ethyl bromoacetate and 0.047 g of potassium carbonate in 10 mL acetonitrile was refluxed overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography (8:1 Hexanes: EtOAc-1:1 Hexanes: EtOAc) to give 0.107 g of the title compound as a yellow gum; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J=7.26 Hz, 3H), 1.19-1.26 (m, 3H), 1.31-1.43 (m, 2H), 1.57-1.66 (m, 2H), 2.52 (t, J=6.03 Hz, 4H), 2.67 (t, J-7.56 Hz, 2H), 3.60 (t, J=6.00 Hz, 4H), 4.14 (q, J=7.14 Hz, 2H), 4.35 (s, 2H), 6.80-6.85 (m, 2H), 7.06-7.12 (m, 2H), 7.24 (m, 2H), 7.59 (d, J=8.28 Hz, 2H); MS (ES) m/z: 473.0 (MH+); HRMS found for C25H32N2O5S: 472.2028.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](S(C)(=O)=O)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1.[C-:24]#[N:25].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([C:24]#[N:25])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(S(C)(=O)=O)nc21
Agent: [Na+]
Solvent: CS(C)=O
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(C#N)nc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the product from step (iv) (0.13 g) and sodium cyanide (0.054 g) in dimethylsulphoxide (3 ml) was stirred at room temperature for 72 h then partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), evaporated under reduced pressure and the residue purified by chromatography on silica eluting with 2:1 ethyl acetate in isohexane. Yield 0.035 g
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[C-:12]#[N:13].[Na+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 55.1 %

Procedure:
A solution of 1-(bromomethyl)-3-nitrobenzene (30 g, 0.14 mol) in DMF (200 mL) was heated to 70° C., then sodium cyanide (17 g, 0.21 mol) was added slowly. The reaction mixture was stirred at 70° C. for 5 hours. The reaction was terminated by addition of water. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 2-(3-nitrophenyl)acetonitrile (12.5 g, yield 33%). 1H NMR: 400 MHz CDCl3 δ 8.15-8.14 (m, 2H), 7.66-7.64 (m, 1H), 7.56-7.52 (m, 1H), 3.82 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[B:9](OC)([O:12]C)[O:10]C.Cl>C1COCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:9]([OH:12])[OH:10]
Reactant: Oc1ccccc1Br
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1ccccc1O
Temperature: 0 °C
Yield: 95.3 %

Procedure:
2-Bromophenol (10.0 g, 57.8 mmol) was dissolved in dry THF (100 ml) in a dry 250 ml flask flushed with nitrogen. The mixture was chilled in a dry ice/2-propanol bath, n-butyl lithium (51 ml of a 2.5M solution in hexanes, 127.2 mmol) was added, then the cooling bath was exchanged for an ice-water bath. The reaction was stirred for an hour at 0° C. then trimethyl borate (6.9 ml , 60.7 mmol) was added to the slurry which became homogeneous after a few minutes. The mixture was stirred at room temperature overnight, then treated with 2N aqueous HCl to pH 3, mixed well for 30 minutes and extracted with ether (3×25 ml). The organic materials were combined, dried (MgSO4), then concentrated under reduced pressure which gave 7.6 g (91%) of 2-hydroxybenzene boronic acid as a white solid, m.p. 156°-158° C.
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([O:45]C(C)(C)C)=[O:44])=[CH:41][C:40]=4[CH3:52])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[CH:51]=[CH:50][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=4[CH3:52])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a 0° C. solution of tert-butyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 95 mg, 0.131 mmol) in dichloromethane (0.700 mL) was added TFA (0.700 mL). The ice bath was removed, and the reaction mixture was stirred for 1 hour. Upon completion, the solvent was removed under reduced pressure, and the resultant residue was dissolved in acetonitrile:water (1:1) for direct purification by reverse phase HPLC (C18) followed by lyophilization of appropriate fractions to yield 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoic acid (62 mg, 0.078 mmol) as a white fluffy solid. LCMS (M+H)+: 670.2. 1H NMR (500 MHz, CD3OD): δ 8.22 (m, 2H), 7.98 (s, 1H), 7.91 (d, 1H, J=8.7 Hz), 7.70 (s, 1H), 7.50 (m, 2H), 7.40 (m, 2H), 5.76 (d, 1H, J=8.7 Hz), 5.54 (br s, 0.5H), 5.43 (br s, 0.5H), 4.62 (d, 1H, J=17.1 Hz), 4.50 (m, 2H), 4.40 (m, 1H), 4.24 (m, 2H), 4.14 (d, 1H, J=17.0 Hz), 4.02 (s, 3H), 2.39 (s, 3H), 0.75 (d, 3H, J=6.5 Hz). RTA IC50: 12 nM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:29]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[OH:37])[CH2:30]1>>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:34]1[CH2:35][CH2:36][C:31]2([CH2:30][CH2:29]2)[C@H:32]([OH:37])[CH2:33]1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2cccc(OC(F)(F)F)c2)CCC1=O
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(OC(F)(F)F)c2)CCC1=O
Yield: 60 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-[7-oxo-4-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 60% yield as light yellow viscous oil. MS: 500.3 (MH+).
Reaction SMILES: F[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9].[NH2:19][C:20]([NH2:22])=[O:21].O>CN(C)C=O>[NH:19]([C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:15])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH2:11])[C:7]=1[N+:8]([O-:10])=[O:9])[C:20]([NH2:22])=[O:21]
Reactant: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(F)c1[N+](=O)[O-]
Reactant: NC(N)=O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]
Yield: 92.4 %

Procedure:
A solution of 5-fluoro-1,3-diamino-2,4,6trinitrobenzene (1.57 g, 6 mmol) and urea (1.80 g, 30 mmol) in 30 ml of dry dimethylformamide (DMF) was heated for 1 hour at 90° C. A yellow precipitate formed after about 5 minutes. The mixture was cooled, poured into 150 ml of cold H2O and the solid filtered. Trituration of the solid with warm DMF-H2O (1:1, 100 ml), filtration and drying gave 5-ureido-1,3-diamino-2,4,6-trinitrobenzene (1.67 g, 92.3%): mp 350° C. dec; IR (KBr) 1730 cm-1 (C=O); mass spectrum (CI, CH4) m/z 259 (M+1-HNCO, 100).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:32][O:33][C:34]1[CH:55]=[CH:54][C:37]([C:38](Cl)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:36][CH:35]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:23])[CH3:22])[C@@H:16]([O:17][C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:37]2[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:55][CH:54]=2)[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(O[C@H]2C[C@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)O[C@@H]2CO[Si](C)(C)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 40 °C
Yield: 698.5 %

Procedure:
N2-isobutyryl-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (19.8 g) was dissolved in 100 ml of anhydrous pyridine. 4,4′-dimethoxytrityl chloride (1.66 g) was added to the resultant solution and 140 ml of anhydrous pyridine was further added, follow by stirring at 40° C. After the reaction completed, the reaction mixture was neutralized by sodium hydrogen carbonate and pyridine was distilled off. Extraction using chloroform was carried out and the extract was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. The extract was concentrated and purified by column chromatography (ethyl acetate/hexane) to obtain 25.8 g of the titled compound (yield: 78%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].B(F)(F)F.CCOCC.[C:21]1(C)[CH:26]=CC=C[CH:22]=1>CC(C)=O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]2[O:11][C:21]([CH3:26])([CH3:22])[S:1][C:2]=2[CH:3]=1)([OH:7])=[O:6]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(O)c(S)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(C(=O)O)cc2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16 g of 3-mercapto-4-hydroxybenzoic acid (III) was dissolved in a mixture of 300 ml of toluene and 50 ml of acetone. 50 ml of boron trifluoride etherate was added and the mixture was stirred at room temperature for 4 hours. Ice (50 g) was added and the mixture was stirred for a further 1 hour. The organic layer was separated, washed with brine, dried with magnesium sulfate and evaporated to leave a solid residue. The residue was recrystallized from aqueous methanol to yield 15 g of 5-carboxy-2,2-dimethyl-1,3-benzoxathiole (IV), m.p. 124°-125° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH:22]=[O:23])[CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[O:24]>C1COCC1>[CH:1]1([CH:22]([OH:23])[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:13]2[CH:14]=[CH:15][C:10]3[O:9][C:8](=[O:24])[N:7]([CH3:6])[C:11]=3[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: Cn1c(=O)oc2ccc(-c3cnccc3C=O)cc21
Solvent: C1CCOC1
Product: Cn1c(=O)oc2ccc(-c3cnccc3C(O)C3CC3)cc21
Reaction time: 3 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M in THF, 3.5 mL, 1.8 mmol) was added dropwise to a solution of 3-(3-Methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-pyridine-4-carbaldehyde (150 mg, 0.58 mmol) in THF (1.6 mL) at −36′C. The resulting mixture was stirred at this temperature for 3 h, and the reaction was quenched by the addition of saturated NH4Cl solution. The mixture was diluted with ethyl acetate and water. The organic layer was separated and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (MeOH/DCM, v/v, 0-4%) to give the title compound. (67 mg, 39%); ESI-MS m/z 297.2 [M+1]+, Retention time 1.00 min; 1HNMR (CDCl3, 400.342 MHz) δ ppm −0.27-0 (m, 1H), 0.36-0.45 (m, 2H), 0.52-0.57 (m, 1H), 0.96-1.02 (m, 1H), 3.47 (s, 3H), 4.52 (d, J=7.6 Hz, 1H), 7.14 (dd, J=8, 1.6 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.33 (d, J=: 8 Hz, 1H), 8.18 (d, J=6 Hz, 1H), 8.47 (s, 1H), 8.63 (d, J=6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12](OCC)(=[O:18])[C:13]([O:15]CC)=[O:14].CC(C)([O-])C.[K+].O>C(O)C>[CH3:11][C:3]1[C:2]([CH2:1][C:12](=[O:18])[C:13]([OH:15])=[O:14])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
A solution of 15.1 g (0.10 mol) of 2-methyl-3-nitrotoluene and 14.6 g (0.10 mol) of diethyl oxalate in 10 ml of ethanol was added to a solution of 11.2 g (0.10 mol) of potassium tert-butoxide in 50 ml of ethanol. After stirring at room temperature for 1.5 hour, the reaction mixture was refluxed for 1.5 hour. After 60 ml of water was added to the reaction mixture, the mixture was refluxed for further an hour. After cooling, ice water was poured onto the reaction mixture followed by washing twice with ethyl acetate. The aqueous layer was acidified with conc. hydrochloric acid and then extracted three times with chloroform. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 10.4 g (46.6%) of the desired 6-methyl-2-nitrophenylpyruvic acid.