Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CS(O[CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Reactant: OC[C@H]1OC(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOCCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reaction time: 8 h
Yield: 0.1 %

Procedure:
(3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D) (30 mg, 78.7 mmol), 2-(2-(tert-butoxycarbonylamino)ethoxy)ethyl methanesulfonate (26.8 mg, 94.5 mmol) and Cs2CO3 (30.8 mg, 94.5 mmol) were dissolved in DMF (3 ml) at room temperature and stirred overnight. The mixture was then extracted with EtOAc, washed with NH4Cl and NaCl, dried over Na2SO4, and evaporated to get the crude product, tert-butyl 2-(2-(4-(2-chloro-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethoxy)ethylcarbamate (intermediate U) (40 mg), which was used for the next step without further purification. The crude intermediate U was dissolved in MeOH (0.5 mL), MeSO3H (6 μL) was added, and the mixture was stirred overnight at room temperature. Then the reaction was quenched with NaHCO3, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, concentrated, and separated by preparative HPLC to obtain compound V (11.6 mg). 1H NMR (CD3OD): δ 7.40˜7.27 (m, 3H), 7.14˜7.10 (m, 2 H), 6.87˜6.85 (m, 2 H), 4.54 (d, J=16, 1H), 4.19˜4.18 (m, 1H), 4.16˜4.14 (m, 2H), 4.05˜4.01 (m, 4 H), 3.94˜3.93 (m, 1H), 3.88˜3.86 (m, 2H), 3.83˜3.76 (m, 3H), 3.67˜3.57 (m, 1H), 3.16˜3.13 (m, 2 H); MS ESI (m/z): 468 (M+H)+, calc. 467.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].Cl.[NH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:17])[C:6]([C:18]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:19])=[C:5]2[OH:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)C1=C(O)c2cc(F)ccc2C2(CCOCC2)C1=O
Temperature: 95 °C
Reaction time: 13 h
Yield: 17.2 %

Procedure:
A mixture of ethyl 6-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.5 g, 2 mmol), tert-butyl 2-aminoacetate hydrochloride (0.4 g, 2 mmol) in 5 mL dioxane was treated with N-ethyl-N-isopropylpropan-2-amine (0.6 g, 5 mmol). The mixture was warmed to 95° C. and stirred for 13 hours, M−1=404. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane and further purified by HPLC to give 0.12 g of the title compound as a pale yellow solid. MS (m/z)=406 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30]Cl)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:38]1[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]1>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[CH2:30][N:38]3[CH2:43][CH2:42][CH:41]([OH:44])[CH2:40][CH2:39]3)[CH:8]=2)[N:3]=1
Reactant: OC1CCNCC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CCl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3CN3CCC(O)CC3)ccc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of [2-amino-6-(2-chloromethyl-5-fluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 5 ml of acetonitrile. 301 mg of caesium carbonate and 57 μl of piperidin-4-ol are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[N:14][C:15]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[C:10]2[CH:9]=[N:8]1.Cl.CCO.C(=O)([O-])[O-]>CO>[NH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:17]([NH:16][C:15]2[N:14]=[CH:13][N:12]=[C:11]3[NH:7][N:8]=[CH:9][C:10]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCCC(Nc2ncnc3c2cnn3COCC[Si](C)(C)C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCO
Product: c1nc(NC2CCCCNC2)c2cn[nH]c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Tert-butyl 3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)azepane-1-carboxylate (0.5 g, 1.1 mmol) was dissolved conc HCl:EtOH (1:3, 10 mL) and the solution was heated to 60° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in MeOH and treated with solid supported carbonate resin to neutralize the solution. The reaction mixture stirred for 2 h and filtered off slurry, washed solid with MeOH (2×20 mL). The filtrate was concentrated in vacua to afford the titled intermediate (200 mg, 80%), which was used in the next step without further purification. LCMS: m/z [M+1]=233.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14]>C(O)C.[C].[Pd]>[NH2:8][C:6]1[C:5]([F:11])=[CH:4][C:3]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(C)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)c1cc(F)c(N)cc1F
Yield: 76.7 %

Procedure:
To a solution of compound (28a) (5.2 g, 21.2 mmol) in ethanol (96 mL), 10% palladium-carbon (0.52 g, 10% w/w) was added and treated under hydrogen gas flow in the same manner as in (d) in Production Example 1 to give 3.5 g (83%) of compound (29a) as red oil.
Reaction SMILES: [OH:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:8](=[O:27])[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:38]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:39]=[CH:40][C:41]([C:44]([O:1][C:2]2[CH:37]=[CH:36][C:5]([CH2:6][N:7]([CH2:28][C:29]([OH:31])=[O:30])[C:8](=[O:27])[C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:26])[CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)=[CH:4][CH:3]=2)=[O:45])=[CH:42][CH:43]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(OC(=O)c4ccc(-c5ccccc5)cc4)cc3)cc2)cc1
Reaction time: 18 h
Yield: 25 %

Procedure:
Prepared using General Procedures 2 and 8: To a stirring solution of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7 (40 mg, 0.079 mmol) and TEA (0.022 mL, 0.159 mmol) in DCM (1 mL) were added [1,1′-biphenyl]-4-carbonyl chloride (26 mg, 0.119 mmol). The reaction was stirred for 18 h then TFA (1 mL) was added. After stirring for 2 h, the solvent was concentrated and the product was purified by preparative HPLC to afford 12.5 mg (25%) of 2-(N-(4-(([1,1′-biphenyl]-4-carbonyl)oxy)benzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 32. LCMS-ESI (m/z) calculated for C38H32N2O7: 629; found 628 [M−H]−, tR=7.83 min (Method 4). NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.21 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.4 Hz, 3H), 7.79 (d, J=7.7 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 7.58-7.41 (m, 4H), 7.41-7.17 (m, 6H), 6.88 (d, J=8.2 Hz, 2H), 4.64 (d, J=36.7 Hz, 2H), 3.95 (d, J=33.6 Hz, 2H), 3.72 (s, 3H), 3.57 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccco1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
The product of Example 255a (1.00 g, 2.89 mmol) was dissolved in DMF to which K2CO3 (801 mg, 5.79 mmol), and 4-mercapto-phenol (366 mg, 2.89 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.00 g, 99%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc12

Procedure:
5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and 1-bromomethyl-4-methanesulfonyl-benzene are processed according to the method described in Example 11 to give 5-chloro-1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, MeOD) δ ppm 2.29 (s, 3H), 3.09 (s, 3H), 5.46 (s, 2H), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.53-7.57 (m, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.79-7.84 (m, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H), 8.52 (dd, J=2.3, 1.0 Hz, 1H), 8.61 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI) m/z 411.0927 [(M+H)+ Calcd for C22H20N2O2SCl: 411.0934].
Reaction SMILES: [K+].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:24][CH:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([O-])=[O:27])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:40][CH2:41][C:42]#[N:43]>>[C:42]([CH2:41][NH:40][C:26]([CH:25]([O:24][CH:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])[CH2:14][CH2:13]2)=[O:16])=[CH:22][CH:21]=1)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])#[N:43]
Reactant: N#CCN
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N

Procedure:
Using the same procedure as described in step 3, 2-[(4-{[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}phenyl)(phenyl)methoxy]-4-methylpentanoic acid potassium salt from step 4 (0.55 g, 1.1 mmol) was coupled with amino acetonitrile HCl salt. The crude product was chromatographed on silica gel using 5% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][NH2:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][C:25]([I:31])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[I:31][C:25]1[CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:22]([NH:20][CH2:19][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:23][CH:24]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: COc1ccc(COc2ccc(CN)cc2OC)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(CNc3ncc(I)cc3[N+](=O)[O-])cc2OC)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a stirred solution of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (9.11 g, 33.21 mmol) in acetonitrile (150 mL) was added 2-chloro-5-iodo-3-nitropyridine (9.90 g, 34.81 mmol) and N,N-diisopropylethylamine (6.44 g, 49.81 mmol). The yellow solution was heated to reflux and stirred. After 3 h, the red-brown mixture was cooled to 0° C. resulting in the formation of a precipitate. The precipitate was isolated by filtration and washed with acetonitrile (50 mL) and water (200 mL). The moist solids were dissolved in dichloromethane, and a small amount of water separated and was removed. The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 14.67 g (85%) of 5-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine as a yellow-brown solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
2-Furoyl chloride (118 μL, 1.2 mmol) was added to a stirred solution of Compound 26 (287 mg, 0.8 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried and recrystallized by hexane and ether to yield 340 mg (90%) of white solids. M.P. 146° C. 1H NMR (DMSO-d6): δ 2.36 (s, 3H), 3.69 (m, 4H), 3.97 (m, 4H), 5.47 (s, 2H), 6.66 (t, J=2.5 Hz, 1H), 7.09 (d, J=3.4 Hz, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.23 (d, J=7.4 Hz, 1H), 7.29–7.33 (m, 3H), 7.44 (d, J=1.3, 8.7 Hz, 1H), 7.71 (s, 1H), 7.89 (s, 1H). EIMS m/z 475 (M+23). Anal. (C27H24N4O3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[CH3:11][C@H:12]1[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:15][C:14](=[O:23])[NH:13]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][N:13]1[C@@H:12]([CH3:11])[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:15][C:14]1=[O:23]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(F)ccc1Br

Procedure:
Prepared according to the procedure described in Example 1, Step 3, using the following starting materials: 2-bromo-5-fluorobenzyl bromide and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N([C:16]1[NH:17][CH2:18][CH2:19][CH2:20][N:21]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[NH:21]1[CH2:20][CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])NC1=NCCCN1
Reactant: NCCC(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: OC(CCNC1=NCCCN1)c1ccccc1

Procedure:
A mixture of 8 parts of α(2-aminoethyl)benzylalcohol, 7.2 parts of 2-(nitramino)- 1,4,5,6-tetrahydropyrimidine and 40 parts of xylene is stirred and refluxed for 48 hours with waterseparator. Upon cooling the reaction mixture, the product is separated as an oil. The xylene is decanted and the oily product is triturated in diisopropylether. The solid product is filtered off and crystallized from acetone, yielding α-[2-(1,4,5,6-tetrahydro-2-pyrimidinylamino)ethyl]benzylalcohol; m.p. 130°-135°C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C:3]1[C:4]([CH3:9])=[N+:5]([O-:18])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 90 h
Yield: 89.6 %

Procedure:
First, 3-ethyl-2-methylpyridine (7.25 g, 59.8 mmol) was dissolved in dichloromethane (dehydrated) (100 ml) and 3-chloroperbenzoic acid (19.0 g, 71.6 mmol, as the content was regarded as 65%) was added in a nitrogen atmosphere at ice-cooling temperature. The mixture was stirred at room temperature for 90 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added. The aqueous layer was extracted twice with dichloromethane and three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was purified by silica gel column chromatography (silica gel: 100 g, elution solvent: heptane, ethyl acetate/methanol=10/1) to obtain the title compound (7.35 g, yield: 89.6%) as a reddish solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][O:11][C@@H:12]([CH:17]=[CH2:18])[C:13]([F:16])([F:15])[F:14].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:21][OH:22])[CH2:10][O:11][C@@H:12]([CH:17]=[CH2:18])[C:13]([F:16])([F:15])[F:14]
Reactant: NO
Reactant: C=C[C@H](OCC(=O)c1cccc(F)c1F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@H](OCC(=NO)c1cccc(F)c1F)C(F)(F)F
Temperature: 50 °C

Procedure:
(S)-1-(2,3-difluorophenyl)-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)ethanone (3.91 g) was dissolved in anhydrous methanol (40 mL) and hydroxylamine hydrochloride (1.25 g) and sodium acetate (1.68 g) were added. The reaction mixture was heated to 50° C. for 90 min, then cooled to RT, concentrated in vacuo and the residue purified by silica gel chromatography (2% to 20% EtOAc in hexanes) to afford the title compound as a mixture of geometric isomers (4.10 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.04-4.26 (m 1 H), 4.43-4.55 (m, 0.4 H) 4.80-4.89 (m, 1.6 H) 5.39-5.55 (m, 2 H) 5.64-5.80 (m, 1 H) 7.05-7.30 (m, 3 H), 7.76 (br s, 0.2 H), 8.30 (br s, 0.8 H).
Reaction SMILES: [Br-].[Li+].[CH2:3]([Mg]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](Cl)=[O:30])[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:28][C:29](=[O:30])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(=O)Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
To a suspension of copper(I) bromide-dimethyl sulfide complex (2.6 g, 12.72 mmol, 1.2 eq.) in dry THF was added a solution of lithium bromide (2.2 g, 25.44 mmol, 2.4 eq.) in dry THF. The mixture was stirred at room temperature (RT) for 20 min, and then was cooled to −78° C. A solution of benzyl magnesium chloride (13 mL, 12.72 mmol, 1.2 eq.) followed by a solution of (S)-methyl 2-(benzyloxycarbonylamino)-4-chloro-4-oxobutanoate (3.16 g, 10.6 mmol, 1 eq.) in dry THF were added. The mixture was stirred at −78° C. for 30 min and then was quenched with sat. ammonium chloride. The mixture was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash column (1:1 ethyl acetate:hexane) to give 2 g of (S)-methyl 2-(benzyloxycarbonylamino)-4-oxo-5-phenylpentanoate.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[C:16]([F:32])[C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=2)=[N:18][CH:19]=1>[Na].C(O)C>[OH:5][C:3]1[CH:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[C:16]([F:32])=[CH:15][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:19][N:18]=3)=[CH:26][CH:25]=2)[CH2:28][C:29](=[O:31])[CH:30]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1C(O)=CC(=O)CC1c1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 1.0 liter flask was dissolved 2.4 g (0.104 mol) of freshly cut sodium metal in 10 mL of absolute ethanol. To this solution was added a solution of 15.6 g (0.0975 mol) of diethyl malonate in 25 mL of absolute ethanol followed by a solution of 30.2 g (0.0928 mol) of 1-(4-(5-(trifluoromethyl)-3-fluoro-2-pyridyloxy)phenyl)but-1-en-3-one in 75 mL of absolute ethanol. The mixture was stirred at ambient temperature for 6 hours and a cream colored solid precipitated from the solution. The mixture was then diluted with 250 mL of water and the solid slowly dissolved therein. To this solution was slowly added 12 mL of concentrated HCl and the desired product crystallized out of the solution. The product was recovered by filtration, thoroughly washed with water and dried in vacuo. The product melted at 161°-163° C., with decomposition; Rf -0.32 (silica gel, 10:90 MeOH:CHCl3), 1H NMR (CDCl3): δ 1.0 (t, 3H, CH3CH2 --), 2.3-3.1 (m, 2H, ring protons), 3.4-3.75 (m, 2H, ring protons), 3.96 (q, 2H, CH3CH2 --), 5.39 (s, 1H, vinyl), 7.10-8.2 (m, 6H, aromatic), 9.0-11.7 (b, 1H, --OH).