Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11]O>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-aminonicotinic acid (1.00 g, 7.24 mmol) in MeOH (20 ml) and MeCN (10 ml) was added 10% solution of trimethylsilyldiazolmethane in CH2Cl2 (25 ml) at room temperature. After stirring at room temperature for 0.5 h, the solvent was evaporated to give crude methyl 6-aminonicotinate as a yellow solid. Title compound was prepared from this crude methyl 6-aminonicotinate in 17% yield according to a procedure similar to that described in Preparation 6.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:27](=[O:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)[CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1CCCN(C(=O)C[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)C1

Procedure:
(2-methyl-1-(piperidin-3-yl)-1H-benzo[d]imidazole (0.486 mmoles, 0.160 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (4 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.486 mmoles, 0.140 g) and N-methylmorpholine (1.94 mmoles, 0.214 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.534 mmoles, 0.204 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (35-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-butyl 4-(3-(2-methyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (1354) as a clear oil. ESI-MS: raiz 527.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21]Cl)[CH3:17]>CN(C)C=O>[CH2:16]([O:18][CH:19]([O:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13])[CH3:17]
Reactant: CCOC(CCCl)OCC
Reactant: COc1ccc(CC#N)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CCC(C#N)c1ccc(OC)c(OC)c1)OCC
Reaction time: 1 h

Procedure:
An optionally substituted phenylacetonitrile is then alkylated with an ω-halopropionaldehyde acetal using a strong metallic base, in a polar, aprotic solvent. The desired phenylacetonitrile derivative is first deprotonated by adding about 1 eq of a strong metallic base, e.g., NaH, in a polar aprotic solvent at 15°-21° C. over 25-50 minutes. The resulting mixture is then stirred for 1-3 hours, and about 1 eq of 3-chloropropionaldehyde diethylacetal is added to yield a derivative of formula 5 (step 3). For example, 2-(3,4-dimethoxyphenyl)acetonitrile in dimethyl formamide (DMF) is added to NaH at 18°-20° C. over a 30 minute period, stirred for one hour, and then treated with 3-chloropropionaldehyde diethylacetal in DMF to yield 2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:7]1[CH:8]=[C:4]([NH2:1])[N:5]=[CH:6]1
Reactant: O=[N+]([O-])c1cn(-c2ccccn2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cn(-c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-nitro-imidazol-1-yl)-pyridine (150 mg, 0.79 mmol) in THF (12 ml) was added under inert gas atmosphere 10% Pd/C (28 mg, 0.026 mmol). Upon evacuation, the reaction vessel was charged with hydrogen and the reaction mixture was stirred at ambient temperature overnight. The catalyst was filtered off, the solvent volume was reduced and the amine was used without any further purification as ˜0.2 M THF solution for the next step.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:28][C:27]1[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: Nc1ccc(F)cc1
Product: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1c(F)cc(F)c(F)c1C

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and p-fluoroaniline (0.39 g), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-(4-fluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride (0.15 g) as in Reference Example 9 to give ethyl 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylate (0.64 g), as white crystals (recrystallized from ethanol), m.p. 256°-259° C.
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1.[Cl:21][C:22]1[C:23]([Cl:31])=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27](O)=O>>[Cl:21][C:22]1[CH:30]=[C:26]([C:27]2[O:20][N:19]=[C:2]([C:3]3[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:5]([F:18])[CH:4]=3)[N:1]=2)[CH:25]=[N:24][C:23]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)COc1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 49 (995.01 mg; 3.50 mmol) and 5,6-dichloronicotinic acid (806.4 mg; 4.2 mmol). The reaction mixture was evaporated. The crude product was dissolved in EtOAc and washed with NH4Cl sat, NaHCO3 sat, brine and dried over MgSO4. After evaporation of the solvents, the resulting solid was suspended in MeCN and filtrated, affording the title compound as an off-white solid. LC/MS (Method B): 420.3 (M−H)−. HPLC (Method A) Rt 5.72 min (Purity: 99.4%).
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]1[C:17]([OH:18])=[C:16]2[C:12]([CH:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[O:14][CH2:15]2)=[CH:11][N:10]=1.[N+:26]([O:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])([O-:28])=[O:27].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[N+:26]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:18][C:17]1[C:16]2[CH2:15][O:14][C@H:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[C:12]=2[CH:11]=[N:10][C:9]=1[CH3:8])=[O:34])([O-:28])=[O:27]
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Reactant: O=C(O)CCCO[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ncc2c(c1OC(=O)CCCO[N+](=O)[O-])CO[C@@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methylmorpholine (90 μL, 0.82 mmol) was added to a stirred solution of (R)-(−)-cicletanine (48 mg, 0.18 mmol), 4-(nitrooxy)butanoic acid (27 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol), and 4-dimethylaminopyridine (9 mg, 0.07 mmol) in dichloromethane (1.8 mL). The solution was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by HPLC reverse phase (C-18) cluting with acetonitrile/water with 0.05% TFA to afford the title compound as a colorless oil. LC-MS: m/z 392.9 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:39])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 160, 100 mg, 0.13 mmol) in THF (3 mL), which was cooled in an ice/CH3OH bath to approximately −15° C. The mixture was stirred for 1 h and allowed to warm to −0° C. The mixture was then diluted with CH2Cl2 (50 mL) and the resulting solution was washed with sat. NaHCO3 (50 mL). The aqueous solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo onto silica. Patrial purification by FCC, eluting with 0-3.5% 7N methanolic ammonia in CH2Cl2 provided some of the title compound. Further purification by FCC, eluting with 0-1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (33 mg, 49%) as a yellow solid; 1H NMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d), 2.39-2.48 (1H, m), 2.87 (1H, s), 3.11-3.20 (1H, m), 3.33-3.42 (2H, m), 3.81 (3H, s), 4.26-4.34 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H, dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03 (1H, s), 8.08 (1H, s), 8.30 (1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m), 9.41 (1H, s); m/z: ES+ MH+ 511.16.
Reaction SMILES: [O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12](=[O:15])[CH2:13][CH2:14][N:3]1[C:4]=23.[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13][CH2:14][N:3]1[C:4]=23
Reactant: OCCO
Reactant: O=C1CCN2C(=O)OCc3cccc1c32
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1OCc2cccc3c2N1CCC31OCCO1

Procedure:
A solution of 6,7-dihydro-3,7-dioxo-1H,3H,5H-pyrido [3,2,1-ij][3,1]benzoxazine (2 g), ethylene glycol (2.2 ml) and p-toluenesulfonic acid (catalytic amount) in toluene (60 ml) was refluxed by use of Dean-Stark apparatus for 3 hours. After washing the reaction mixture with a saturated aqueous solution of sodium hydrocarbonate, the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 6,7-dihydro-3-oxo-7,7-ethylenedioxy-1H,3H,5H-pyrido[3,2,1-ij][3,1]benzoxazine (2.1 g).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[K+].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH:21]1([NH:27][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:19][CH:18]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: O=C([O-])c1ccc(Cn2cnc3ccccc32)cc1
Agent: [K+]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A stirred suspension of crude potassium 4-(1H-benzimidazylmethyl)benzoate (0.49 g, 1.7 mmol) in dry DMF (10 ml) under argon was treated with cyclohexylamine (0.2 g, 2.0 mmol) and triethylamine (0.34 g, 3.4 mmol). The solution was cooled to -5° C. and DPPA (0.53 g, 1.9 mmol) in DMF (10 ml) was added. The solution was allowed to warm to room temperature, stirred overnight and concentrated to give the crude product. Chromatography (silica gel, ethyl acetate) followed by crystallisation from toluene gave N-cyclohexyl 4-(1H-benzimidazylmethyl)benzamide (91 mg, 16%) as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([O:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-3-nitrobenzoic acid (36.6 g) in N,N-dimethylformamide (500 mL) were added benzyl bromide (50.0 mL) and potassium carbonate (66.3 g), and the mixture was stirred overnight at 60° C. The reaction mixture was poured into water and the resulting mixture was extracted with a mixture of ethyl acetate and n-hexane (1:1). The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixture of tetrahydrofuran (100 mL) and methanol (200 mL), and the resulting mixture was stirred for 30 minutes at 50° C. The reaction mixture was concentrated and the residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from isopropanol (50 mL)/n-hexane (200 mL) to give the title compound (31.99 g) having the following physical data.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Br:10]Br>[Fe]>[Br:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1ccccc1
Reactant: BrBr
Agent: [Fe]
Product: CCCc1ccccc1Br
Yield: 88.7 %

Procedure:
Into a 250-mL round-bottom flask was placed propylbenzene (20 g, 166.40 mmol, 1.00 equiv) and Fe (10 g, 178.57 mmol, 1.07 equiv). This was followed by the addition of Br2 (26.6 g, 166.45 mmol, 1.00 equiv) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 100 mL of NaHSO3 (aq.). The mixture was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. Purification afforded 29.4 g (crude) of 1-bromo-2-propylbenzene as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].C[N:20]([CH3:23])C=O>>[C:23]([C:3]1[CH:2]=[CH:9][C:6]([CH2:7][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:20]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C=O)c2)cc1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a stirred solution of 10.0 g (59.8 mmol) of 5-hydroxy-2-nitrobenzaldehyde and 12.3 g (62.8 mmol) of a-bromo-p-tolylnitrile in 50 ml of dry dimethyl-formamide was added 9.10 g (65.8 g) of anhydrous potassium carbonate. The mixture was warmed to 50° C. for 2 h and partitioned between water and ethyl acetate. The organic phase was washed with 1N sodium bicarbonate, water, brine, and dried over anhydrous magnesium sulfate. Concentration gave 13.8 g (82%) of 5-(4-cyanobenzyloxy)-2-nitrobenzaldehyde. 1H NMR (300 MHz, d6 -acetone) d 10.39 (1H, s, Ar-CHO), 8.23 (1H, d, J=9.0 Hz, O-Ar-H), 7.85 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.77 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.48 (1H, dd, J=9.0, 2.9 Hz, O-Ar-H), 7.43 (1H, d, J=2.9 Hz, O-Ar-H), 5.50 (2H, s, ArCH2O).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccc(OCCBr)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(OCCBr)cc1
Yield: 86 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11 H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2 H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES-MS (m/z) 458 [M+H]+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH:19]=O)=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:19][C:18]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[N:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:16][C:17]=1[CH:21]([CH3:23])[CH3:22]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
A solution of carbon tetrabromide (2.866 gm, 8.64 mmol) in CH2 Cl2 (8 ml) was added over a 10 minute period to a cold (-10° C.) solution of 2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.840 gm, 5.76 mmol) (the preparation of which is described in Example 3) and triphenylphosphine (4.590 gm, 17.5 mmol) in CH2Cl2 (30 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 2X with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed (flash, Merck, SiO2, 1:1 CH2Cl2 :hexane) to give 3-(2,2-Dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine as a white solid (2.701 gm, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][NH2:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25](O)=[O:26].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([NH:17][CH2:16][C:15]([NH:14][CH2:13][CH:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:18])=[O:26]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{(glycylamino)methyl)piperidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0.15 mL) was treated with 3-bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 15 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CHCl3 1:1 (12 mL) and CH3OH (12 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(3-bromo-4-methylbenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)piperidine (Compound No. 1113) (16.1 mg, 65%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 494.0 (C23H27BrClN3O2).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.N1CCCC[CH2:14]1.CC(O)=O>CO>[C:1]1([C:7](=[CH2:14])[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: C=C(C(C)=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1-Phenyl-propan-2-one (40.8 g) was dissolved in 200 ml of MeOH. Formaline (37%) (79 mL), piperidine (4 ml) and HOAc (4 ml) where added and de reaction was stirred for 3 h at 60° C. The reaction mixture was evaporated to dryness under reduced pressure. The residue was taken up in diethyl ether, and extracted with water. The organic layer was washed with 1M HCl, dried over MgSO4 and evaporated under reduced pressure to yield 36.3 g of a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 5.87 (s, 1H), 6.18 (s, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][C:36]1[S:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1>CN(C=O)C>[CH3:35][C:36]1[S:37][C:38]([S:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[C:17]=3[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]2)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)s1

Procedure:
Compound A32 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (20 μL), 2,4-dimethyl-thiazole-5-sulfonyl chloride (10 mg, 0.047 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.09 (m, 4H), 2.67 (s, 3H), 2.75 (s,3H), 3.08 (s, 3H), 3.21 (m, 2H), 3.50 (m, 2H), 5.58 (m, 1H), 7.85 (d, 2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C21H24N6O7S3 568.09, found 569.4 (MH+).