Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(Cl)Cl.O>[CH2:33]([NH:35][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)N1CCC(C2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.10 g, 0.21 mmol, Preparation #K.1) and TEA (0.065 g, 0.64 mmol, Sd Fine Chem) in DCM (10 mL) was added ethyl isocyanate (0.018 g, 0.25 mmol, Lancaster). The reaction mixture was slowly warmed to RT and stirred for about 2 h. The reaction mixture was diluted with water (20 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 1% methanol in DCM. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-(5-(1-(ethylcarbamoyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 60 mg (56%): LC/MS (Table 1, Method c) Rt=1.83 min; MS m/z: 499.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:39])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:14][C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([NH2:32])=[O:31])[C:18]([C:33]([F:34])([F:36])[F:35])=[CH:17][N:16]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2F)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 2-(2-(2-(2-((2-fluoro-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (I62) (0.037 g, 0.074 mmol) in anhydrous methanol (3 mL) was added 37% aqueous formaldehyde (0.022 mL, 0.30 mmol) and sodium triacetoxyborohydride (0.081 g, 0.38 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure and the residue'taken up saturated aqueous NaHCO3 solution (25 mL). The resulting mixture was extracted with EtOAc (2×25 mL) then the combined organic layers were washed with brine (25 mL), dried (phase separation cartridge) and evaporated to dryness under reduced pressure. The residue was purified using silica gel column chromatography (0-50% MeOH/EtOAc with 1% 2 M ethanolic ammonia) to give the title compound (13) (0.020 g, 52%); 1H NMR (400 MHz, d6-Acetone+d4-MeOH) δ 8.54 (s, 1H), 7.88 (dd, J=8.5 Hz, 1H), 7.16 (m, 6H), 3.80 (s, 2H), 3.63 (s, 2H), 3.10 (m, 4H), 2.95 (m, 2H), 2.54 (m, 1H), 2.27 (s, 3H), 1.79 (m, 4H). LCMS Method C: rt 4.93 min; m/z 516.1 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([N:23]=[C:24]=[S:25])=[CH:18][C:17]=2[CH3:26])[CH:12]=[CH:13][CH:14]=1)([CH3:8])[CH3:7]>O1CCCC1>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([O:15][C:16]2[C:17]([CH3:26])=[CH:18][C:19]([NH:23][C:24](=[S:25])[N:3]([CH2:1][CH3:2])[CH3:4])=[C:20]([CH3:22])[CH:21]=2)[CH:12]=[CH:13][CH:14]=1)([CH3:5])[CH3:7]
Reactant: Cc1cc(Oc2cccc(C(C)(C)C)c2)c(C)cc1N=C=S
Reactant: CCNC
Solvent: C1CCOC1
Product: CCN(C)C(=S)Nc1cc(C)c(Oc2cccc(C(C)(C)C)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethylmethylamine (450 mg) is added dropwise to a solution of 1-{[3-(1,1-dimethylethyl)phenyl]oxy}-4-isothiocyanato-2,5-dimethylbenzene (1.9 g) in tetrahydrofuran (6 ml) at 0° C. The reaction mixture obtained is stirred at room temperature for 1 h and then concentrated and triturated with heptane. The title product is obtained in the form of a white precipitate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:24][CH:22]([CH3:23])[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[O:38])[CH2:9][CH2:10]2)[CH:15]=1)=[O:25]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3cccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-naphthyl isocyanate: ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12]>C(Cl)Cl.CCN(CC)CC>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COCC(=O)Cl
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@](C)(CO)C(=O)O
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Methoxy-acetyl chloride (7 mg, 30 μmol) was combined with a 0.4 mL solution of 0.075 M of (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (136 mg, 30 μmol) in DCM and Et3N (110 μL). The resulting mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (2.1 mg). MS m/z [M+H]+ calc'd for C22H26ClNO5, 420.15. found 420.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[N:12]([CH3:22])[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)O)[CH:6]=[CH:7][CH:8]=1)[CH3:2].CCN(CC)CC.CS([Cl:34])(=O)=O>C(Cl)Cl>[Cl:34][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1)[C:11]1[N:12]([CH3:22])[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1
Reactant: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cccc(C(Cl)c2nc(-c3ccccc3)nn2C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Intermediate 370.2 (350 mg, 1.2 mmol) was dissolved in CH2Cl2 (10 mL) and Et3N (0.50 mL, 3.6 mmol) and cooled to 0° C., MsCl (0.092 mL, 1.2 mmol) was added dropwise and the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with H2O, brine, dried (Na2SO4) and concentrated to yield 370 mg of Intermediate 370.3 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.15 (t, J=7.58 Hz, 3H) 2.56 (q, 2H) 3.71 (s, 3H) 6.30 (s, 1H) 7.09-7.16 (m, 1H) 7.21-7.29 (m, 2H) 7.28-7.43 (m, 3H) 7.99-8.05 (m, 2H).
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:12]=2[N+:25]([O-])=O)[CH2:7][CH2:6][N:5]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni]>[NH2:25][C:12]1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:9]1=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (26.3 g, 0.0526 mol) in THF (200 mL) and methanol (200 mL) was added Raney Nickel (in H2O, 4 g). The mixture was stirred under H2 (30 psi) at rt overnight. The mixture was filtered and concentrated under vacuum to give (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (24.7 g, 100% yield) as a yellow solid. The residue was used directly for the next step without further purification. LC-MS MS (ESI) m/z 414.0 [M−56+H]+, 492.0 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 7.77 (brs, 1H), 7.04 (s, 1H), 4.68-4.45 (m, 1H), 4.45-4.38 (m, 2H), 3.92 (s, 3H), 3.70-3.58 (m, 1H), 3.58-3.41 (m, 1H), 3.30 (s, 3H), 2.49-2.25 (m, 1H), 1.50 (s, 9H), 1.12 (d, J=6.9 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(CCn3cccn3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), pyrazole (2.04 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (80 ml) was stirred at 90° C. for 12 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1OCC2O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Under a nitrogen atmosphere 0.610 g (4.06 mmol) 7-methyl-2,3-dihydro-benzofuran-3-ol in 5 mL acetic acid were refluxed for 2 h with 770 μL (8.16 mmol) acetic anhydride. After cooling to RT, 60 mg palladium on charcoal (Pd/C 10%) were added and the mixture was hydrogenated for 3.5 h under a hydrogen atmosphere (3 bar). The catalyst was filtered off and the solvent was evaporated down.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.Cl.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: NCC(F)(F)F
Agent: Cl
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2,2,2-trifluoroethylamine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Fluorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[CH2:19][CH2:18][C:17]2[C:20](=O)[NH:21][C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[N:23][C:16]=2[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Cl-].C([N+](CC)(CC)CC)C.C(#N)CC>[CH2:6]([N:13]1[CH2:19][CH2:18][C:17]2[C:20]([Cl:3])=[N:21][C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)=[N:23][C:16]=2[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c(Cc2cccc(Cl)c2)nc2c1CCN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CCC#N
Product: Clc1cccc(Cc2nc(Cl)c3c(n2)CCN(Cc2ccccc2)CC3)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
Phosphoryl chloride (1.33 ml, 14.3 mmol) and tetra-ethyl ammonium chloride (472 mg, 2.85 mmol) were added to a solution of the product of Step A (361 mg, 0.95 mmol) in propionitrile (10 ml) and heated to 100° C. for 17 h. The reaction mixture was concentrated in vacuo then azeotroped with toluene then dichloromethane. The residue was partitioned between dichloromethane (30 ml) and water (20 ml), stirred for 30 min then the organic layer was separated, dried over magnesium sulphate and concentrated in vacuo to give the title compound as a foam in 87.7% yield, 332 mg.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:20])(=O)[C:17]#[CH:18].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:16](=[O:20])[C:17]#[CH:18])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
36 mL of a 1 molar DCC solution in dichloromethane is added dropwise at −10° C. to a solution of 4.9 g (70 mmol) of propynoic acid in 120 mL of dichloromethane and the mixture is stirred for 30 minutes. Then 7 g (34.37 mmol) 4′-chlorobiphenyl-4-ylamine, dissolved in dichloromethane, is slowly added dropwise and the mixture is stirred for 2 hours at −8° C. The reaction mixture is then filtered through CELITE®E filter aid, washed again with methanol, and the filtrate is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (6:1 to 2:1)). Yield: 7.6 g (95% of theory); C15H10ClN0 (M=255.70); calc.: molecular ion peak (M+H)+: 256/8 (Cl); found: molecular ion peak (M+H)+: 256/8 (Cl); Rf value: 0.2 (silica gel, cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C(#N)C>[CH3:1][N:2]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CNCCNC
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCN(C)c1ncccc1[N+](=O)[O-]

Procedure:
To a solution of N,N'-dimethylethylenediamine (3.2 ml) and potassium carbonate (830 mg) in acetonitrile (15 ml) stirred at 20°-25° under a nitrogen atmosphere is added a solution of 2-chloro-3-nitropyridine (500 mg) in acetonitrile (10 ml) over one hour. The mixture is concentrated under reduced pressure and partitioned between methylene chloride (75 ml) and water (25 ml). The phases are separated and the aqueous phase is extracted with methylene chloride (25 ml) and the total organics are dried with saline and sodium sulfate. Concentration under reduced pressure gives the title compound, NMR (CDCl3) 8.29, 8.10, 6.69, 3.85, 2.90, 2.88 and 2.46δ.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: ClCc1ccccn1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccn2)cc1O
Reaction time: 11 h
Yield: 27 %

Procedure:
Separately, 13.8 g (100 mmol) of 2,4-dihydroxybenzaldehyde was dissolved in 250 mL of acetonitrile and 32.5 g (100 mmol) of cesium carbonate was added at room temperature. To this solution, the solution of 2-chloromethylpyridine in acetonitrile prepared in advance was added dropwise at 50° C. over 4 hours and the mixture was stirred for 11 hours. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to give 6.10 g (27% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15](=O)[NH:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=O)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].C([O-])(=O)C.[NH4+:32]>>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:32][C:18]([C:20]4[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=4)=[CH:17][N:16]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(=O)N2C(CCC2C(=O)NCC(=O)c2ccc(Br)cc2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Temperature: 130 °C
Yield: 60 %

Procedure:
A mixture of 6-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), ammonium acetate (193 mg, 2.5 mmol) and xylenes (8 mL) was heated to 130° C. After 1 hour the mixture was cooled and the xylenes were removed under reduced pressure. Dichloromethane was added to the resulting residue and the mixture was filtered. The solvent was removed under reduced pressure from the filtrate and the resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol, 60%). C18H0BrN4O3 calculated 418.1 observed [M+1]+ 419.1; rt=1.50 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[C].[Pd]>[F:14][C:13]([F:15])([F:16])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([NH2:10])[CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(N)cc(C(F)(F)F)c1
Yield: 101.8 %

Procedure:
In a mixed solvent of 10 mL of ethyl acetate and 1 mL of methanol, 500 mg (2.12 mmol) of 3,5-dinitrobenzotrifluoride was dissolved, and 20 mg of 10% palladium carbon was added thereto, and the mixture solution was stirred at room temperature for 20 hours in a hydrogen atmosphere at normal pressures. The catalyst was removed by filtration, and the filtrate was concentrated and dried to obtain 380 mg (100%) of a brown oily target product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:18])[CH2:14][N:15]=[N+:16]=[N-:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]([O:18][CH:13]([CH2:12][O:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:14][N:15]=[N+:16]=[N-:17])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCC(O)CN=[N+]=[N-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
3-Azido-2-hydroxypropyl 4-methylbenzenesulfonate 14 (1.83 g, 6.70 mmol) was dissolved in CH2Cl2 (15 mL) and treated with TEA (1.4 mL, 10.00 mmol), a catalytic amount of DMAP and acetic anhydride (0.95 mL, 10.00 mmol) at room temperature. After stirring for 1 hr, silica was added to the reaction mixture, the solvent was evaporated and the residue was purified on silica gel using 50% EtOAc/hexanes as the eluent to afford 2.07 g of 15 (98.8% yield) as a thick, clear, colorless oil. 1H NMR (CDCl3, 400 MHz) δ: 7.79 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 5.02-5.07 (m, 1H), 4.09-4.21 (m, 2H), 3.43-3.53 (m, 2H), 2.46 (s, 3H), 2.05 (s, 3H). Mass Spec (lo-res): Calc'd for C12H15N3O5S: 313.07. found: 314.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[N:4][C:5]([Cl:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:27][NH2:28]>C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:28][NH:27][C:13](=[O:14])[C:6]=2[C:5]([Cl:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccc(N)cc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(Cl)c3c(=O)[nH][nH]c(=O)c3c2N)cc1
Temperature: 90 °C

Procedure:
To 0.30 g of 3-amino-6-chloro-4,5-diethoxycarbonyl-2-(4-aminophenyl)pyridine was added 6 ml of hydrazine monohydrate, and the mixture was heated at 90° C. for 30 minutes. The reaction mixture was poured into 150 ml of ice-water and the mixture was adjusted to pH 6 with acetic acid. The resultant precipitate was collected by filtration, and washed with water, followed by reprecipitation from DMSO/H2O, whereby 0.21 g of the title compound was obtained as orange powder.
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]([F:28])([F:27])[C:8]([NH:10][C@@H:11]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([CH3:21])[O:14][C@H:13](Br)[C@@H:12]1OC(=O)C)=[O:9]>[Zn].C(O)(=O)C>[F:28][C:7]([F:6])([F:27])[C:8]([NH:10][C@@H:11]1[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([CH3:21])[O:14][CH:13]=[CH:12]1)=[O:9]
Reactant: CC(=O)O[C@@H]1[C@H](NC(=O)C(F)(F)F)[C@H](OC(C)=O)[C@H](C)O[C@@H]1Br
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@@H](NC(=O)C(F)(F)F)C=CO[C@H]1C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a mixture of 18 g. of zinc dust and 1.8 g. of cupric sulfate in 60 ml. of 50% aqueous acetic acid containing 25 g. of sodium acetate, 10 g. of the product of Examples 10 and 11 in 10 ml. of acetic acid is added dropwise at -10° C. The reaction is continued for 4 hours at -10° C., after which the zinc dust and copper are removed by filtration, 50 g. of ice is added to the filtrate, and the filtrate is extracted three times with chloroform. The combined extracts are washed with water, a cold saturated sodium hydrogen carbonate solution, and water. After the chloroform solution is dried over anhydrous magnesium sulfate, it is evaporated in vacuo to a heavy syrup. The syrupy residue is crystallized from a mixture of ether-petroleum ether to give 4.7 g. (77% yield) of 3-trifluoroacetamido-4-O-acetyl-1,2,3,6-tetradeoxy-L-lyxo-hex-1-enepyranose.