Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[OH-:12].[Na+]>O>[Cl:1][C:2]1[NH:7][C:6](=[O:12])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: [OH-]
Reactant: CCc1nc(Cl)nc(Cl)c1F
Agent: [Na+]
Solvent: O
Product: CCc1nc(Cl)[nH]c(=O)c1F
Temperature: 80 °C

Procedure:
To the solution obtained as the product of part (iii) was added water (6 ml). The mixture was stirred at 80° C. and 4N sodium hydroxide (45 ml) was added slowly over 2 hours. At the end of this period the reaction was cooled and washed with dichloromethane (15 ml). The aqueous layer was then added to dichloromethane (60 ml) and the pH adjusted to 1 with concentrated hydrochloric acid. The organic layer was separated and the pH adjusted to 3 using concentrated aqueous ammonia solution. The precipitate of ammonium chloride was removed by filtration and the filtrate was then concentrated to a volume of 15 ml and diluted with ethyl acetate (150 ml). This solution was concentrated to a volume of 30 ml and the crystals of the title compound that formed were collected by filtration and dried (8 g), then characterised by 1H-NMR and mass spectrometry.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13]>[Cl-].[Zn+2].[Cl-]>[C:12]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:11]
Reactant: C=C(C)CC(C)(C)C
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C)CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
In a 2-liter reaction flask fitted with a condenser, nitrogen inlet, stirrer, thermometer and addition funnel is placed 272 grams (2.0 moles) of anhydrous zinc chloride. The flask is placed under a nitrogen atmosphere and 166 ml (2.0 moles) of concentrated (12N) hydrochloric acid is added over a 10-minute period with the temperature rising from 22° to 40° C. To this is then added 276 grams (2.0 moles) of o-nitroaniline over a 15-minute period to avoid the formation of lumps. The resulting thick red slurry is heated to 60° C. and then 474 grams (3.0 moles) of diisobutylene is added gradually over a 110-minute period with the temperature rising during this period from 60° to 90° C. The deep red fluid reaction mixture is heated for another 18 hours at reflux till only a trace of o-nitroaniline is observed by thin layer chromatography.
Reaction SMILES: C[C:2](C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:17]([C@@H:18]([CH2:42][CH3:43])[C@@H:19]([OH:41])[C@@H:20]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:21]3[CH2:22][C@@H:23]([OH:40])[C@@H:24]2[C@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:16]1.CO>CC(C)=O>[O:14]=[C:15]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:17]([C@@H:18]([CH2:42][CH3:43])[C:19](=[O:41])[C@@H:20]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:21]3[CH2:22][C:23](=[O:40])[C@@H:24]2[C@H:25]([CH3:30])[CH2:26][CH2:27][C:28]([O:3][CH3:2])=[O:29])[CH2:16]1
Reactant: CC(C)=O
Reactant: CC[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCCO)[C@H](O)C[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)C(=O)C[C@@H]23)[C@@]2(C)CCC(=O)C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Jones reagent (2 ml) was added dropwise to a stirred solution of the tetrol 7 (0.19 g, 0.45 mmol) in acetone (25 ml) at 0° C. and the mixture was stirred at room temperature for 1 h. Methanol (8 ml) was then added and the oxidized product was extracted with EtOAc (2×50 ml). The combined organic layers were dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (80 ml), pTSA was added and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduce pressure, the residue was dissolved in CHCl3 (50 ml), washed with a saturated aqueous solution of sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography using from 20 to 30% EtOAc in petroleum ether to afford the methyl ester 8 (0.115 g, 0.26 mmo, 58%1) as whitish solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[OH:14][C:15]1[C:20]2=[N:21][CH:22]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24](=[O:25])[N:19]2[CH:18]=[CH:17][CH:16]=1.P([O-])([O-])(O)=O.[K+].[K+].Br>C(O)(=O)C.CC(CC)=O>[BrH:1].[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:14][C:15]1[C:20]2=[N:21][CH:22]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:24](=[O:25])[N:19]2[CH:18]=[CH:17][CH:16]=1)([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cnc2c(O)cccn2c1=O
Reactant: CCOC(=O)c1ccccc1CBr
Agent: Br
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccccc1COc1cccn2c(=O)c(C(=O)OCC)cnc12

Procedure:
To a solution of 5.0 g of ethyl α-bromo-o-toluate, 4.7 g of 9-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-3-carboxylic acid, ethyl ester, and 200 ml of ethyl methyl ketone is added 3.9 g of anhydrous dipotassium hydrogen phosphate and the mixture stired and heated under reflux for 18 hours. The cooled mixture is filtered, and the filtrate is concentrated in vacuo to give a semi-solid product. To this product, 3.9 g, in 10 ml of acetic acid is added a solution of 0.81 g of hydrogen bromide in 4 ml of glacial acetic acid, dropwise, with agitation. The crystalline product that separates is filtered, washed with anhydrous ether, and recrystallized from acetonitrile to give the named product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.Cl.[CH2:12](O)[CH3:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[N:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc(Cl)n1

Procedure:
14.1 g (0.0895 mole) of 2-chloro-6-hydroxycarbonylpyridine in 133 ml of a solution of HCl in ethanol is heated for 8 hours under reflux. The solvent is evaporated off, ethyl acetate added and the mixture washed with a solution of bicarbonate. The solvent is further evaporated and the reaction product purified by flash chromatography (cyclohexane/ethyl acetate=7/3). The required product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].C(OCC)(=O)C.CO.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:42][CH2:41][CH2:40][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: NCCN1CCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCCNCCN2CCCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Yield: 63.5 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (8.462 g, 21.75 mmol) was dissolved in 2-pyrrolidin-1-yl-ethylamine (6.3 ml, 49.79) under stirring, the resulting solution was stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (200 ml) and a little methanol until a clear solution was obtained. The mixture was washed with water (30 ml×3), saturated brine (40 ml×2) and concentrated under reduced pressure to obtain light brown oil. The oil was purified by silica gel column chromatography to obtain the title compound 3-methyl-5-[3-(2-pyrrolidin-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 28a (4.488 g, yield 63.5%) as a yellow oil.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[Si:11]([O:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C)[CH:35]=[O:36]>C(OCC)C>[Si:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:35]=[O:36])=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cccc(O[Si](C)(C)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyllithium in pentane (1.7 M, 21.8 mL, 37.1 mmol, 2.40 equiv) was added to a solution of tert-butyl 3-{[tert-butyl(dimethyl)silyl]oxy}phenyl carbamate (12-3, 5.00 g, 15.5 mmol, 1 equiv) in ethyl ether (150 mL) at −40° C., and the resulting mixture was stirred at −40° C. for 2 h. N,N-Dimethylformamide (9.57 mL, 124 mmol, 8.00 equiv) was added, and the mixture was then warmed to 0° C. The reaction mixture was partitioned between water (500 mL) and ethyl ether (500 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (hexane, initially, grading to 20% hexane in EtOAc) to give tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylphenylcarbamate (12-4) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.54 (s, 1H), 7.76 (d, 1H, J=1.8 Hz), 7.26 (d, 1H, J=7.8 Hz), 6.35 (dd, 1H, J=7.8, 1.9 Hz), 1.37 (s, 9H), 0.78 (s, 9H), −0.02 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:19][CH:20]([CH2:24][CH3:25])[C:21](=[O:23])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[BH4-].[Na+]>C1COCC1.CO.C(O)(=O)C>[Br:1][C:2]1[C:3]([S:19][CH:20]([CH2:24][CH3:25])[CH:21]([OH:23])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
26 mg (0.058 mmol) of 5-[5-bromo-4-(1-ethyl-2-oxo-propylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide, dissolved in 1.5 ml of THF/MeOH 1:1, is mixed with 10 mg of sodium borohydride and stirred for 3 hours at room temperature. While being cooled, 2-3 drops of glacial acetic acid are added and concentrated by evaporation. Uptake in acetonitrile and suctioning-off yield 17 mg (65% of theory) of 5-[5-bromo-4-(1-ethyl-2-hydroxy-propylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[CH:9]=1
Reactant: CS(=O)(=O)c1cc(Cl)ccc1CBr
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: CS(=O)(=O)c1cc(Cl)ccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 100 °C
Reaction time: 14 h
Yield: 12.6 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 1-(bromomethyl)-4-chloro-2-(methylsulfonyl)benzene (0.37 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (50 mg).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.[OH-].[Li+]>C(#N)C>[NH3:11].[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:8]2[CH3:26]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1
Product: N

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.11 g), acetonitrile (2.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 1 hour. The acetonitrile was removed under reduced pressure and the pH of the residue adjusted to 5 by the addition of saturated aqueous sodium dihydrogenphosphate solution. The resulting mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on a flash NH2 cartridge, eluting with methanol and then 2.0 M ammonia in methanol, gave title compound, 0.10 g.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].CO[CH2:23][CH2:24]OC>O>[CH:23]([C:2]1[C:3]([F:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2)=[CH2:24]
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1c(F)cnc2ccc(OC)nc12
Temperature: 85 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
To a solution of 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (2.0 g, 7.81 mmol), potassium carbonate (1.08 g, 7.81 mmol), tetrakis-triphenylphosphine (90 mg, 0.08 mmol) in DME (60 mL) and H2O (20 mL) was added 2,4,6-trivinylcycloborane-pyridine complex (0.94 g, 3.91 mmol). After stirring for 10 h at 85° C. the reaction contents were concentrated and the product purified by chromatography (silica, 25% EtOAc in hexane) to give a low melting solid (1.43 g, 90%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2
Reactant: Nc1ccc2ncccc2c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc4ncccc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 173.8 mg (1.2 mmol) of 6-aminoquinoline and 115.6 mg (1 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol was refluxed for 6 hr. The work up gave 212.5 mg (59.5%) of the product as a orange solid, m.p. 241-243° C., mass (electrospray, m/e): M+H 356.8. HRCIMS: calcd 356.127 for C20H17N5O2 (M+), obsd 356.1275.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35]Cl)=[CH:28][CH:27]=1)[CH3:23].[BrH:38]>[I-].[K+].C(O)(=O)C>[BrH:38].[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)=[CH:28][CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: Br
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 20 %

Procedure:
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]piperidine and 4-(3-chloropropoxy)benzoic acid ethyl ester were reacted using potassium iodide as catalyst to give the free base which was reacted with hydrogen bromide in glacial acetic acid. The oil was stripped to dryness and the solid obtained was recrystallized from isopropyl alcohol-diethyl ether to give the white salt in 20% yield, m.p. 142°-144° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[I:20]I>C1COCC1.CCCCC>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[I:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1I
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (pyridin-3-yl)-carbamic acid tert-butyl ester (prepared according to the procedure described in Tetrahedron Lett. 1994, 35, 9003) (2.2 g, 11.3 mmol) in 20 mL of THF at −78° C. is added dropwise t-BuLi (15.4 mL of a 1.7 M solution in pentane, 26 mmol). After 15 minutes, the solution is warmed to −10° C. for 3 hours. The mixture is cooled to −78° C. and a solution of iodine (5.7 g, 22.4 mmol) in 20 mL of THF is added via syringe. The resulting mixture is stirred at −78° C. for 1 hour, then allowed to warm to room temperature and quenched with saturated NH4Cl solution. The aqueous layer is extracted with EtOAc (2×). The combined organic layers are washed with 1 N HCl, water, dilute Na2S2O3, saturated NaHCO3 and saturated NaCl. The organic layer is then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc/CH2Cl2 to 20% EtOAc/CH2Cl2 to yield the title compound (1.3 g, 4.06 mmol) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](O)=[O:14])[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:34]2[N:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.CN1CCOCC1.NC1C=NC=CC=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:10]=[C:11]([C:13]([NH:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:14])[N:12]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (403 mg, 1.2 mmol) was dissolved in dichloromethane (5 mL) and treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (459 mg, 1.56 mmol) and N-methylmorpholine (NMM) (182 mg, 1.8 mmol). The mixture was stirred under argon for 15 minutes before 3-aminopyridine (349 mg, 3.6 mmol) was added. Stirring at rt was continued overnight. The reaction mixture was then adsorbed onto silica gel and chromatographed (2-3% MeOH in CH2Cl2) to afford 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(3-pyridinyl)-1H-imidazole-4-carboxamide (266 mg, 54% yield): LC-MS m/z 409.3, retention time 2.43 min (method 1).
Reaction SMILES: Cl.[C:2]([OH:10])(=[O:9])[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].Cl>O.ClCCl>[CH2:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C:3]([C:2]([OH:10])=[O:9])=[CH:4][CH2:5]1)=[O:19])[CH:22]=[CH2:23]
Reactant: O=C(O)C1=CCNCC1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)N1CC=C(C(=O)O)CC1
Reaction time: 5 h
Yield: 102.4 %

Procedure:
1,2,5,6-Tetrahydroisonicotinic acid hydrochloride (150 g, 0.92 mol) is added to an aqueous solution of sodium carbonate (194 g, 1.83 mol) in water (920 ml), and thereto is added dropwise 2-propenyl chloroformate (116 g, 0.96 mol) under ice-cooling over a period of one hour. After the addition, the mixture is further stirred under icecooling for five hours. Separately, conc. hydrochloric acid (191 g) and dichloromethane (1000 ml) are cooled, and thereto is added dropwise the above reaction mixture in portions. The mixture is separated, and the aqueous layer is extracted twice with dichloromethane. The organic layers are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to give 1-(2-propenyloxycarbonyl)-1,2,5,6-tetrahydro-isonicotinic acid (198.9 g, quant.) as a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O[CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15].CS(C)=[O:24]>O>[OH:24][CH2:15][CH2:14][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CS(C)=O
Reactant: CC(O)N1CCNCC1
Solvent: O
Product: O=Cc1ccc(N2CCN(CCO)CC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
4-Fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol), 1-hydroxyethylpiperazin (0.80 mL, 6.5 mmol) and DMSO (3.5 mL) were added and stirred at 100° C. for 1.5 hours. The reaction mixture was added with water and was washed with hexane/ethyl acetate=4/1 to remove impurities. After removing impurities, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 4-[4-(2-hydroxyethyl)piperazin-1-yl]-2-nitrobenzaldehyde (0.34 g, 100%).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[CH:8][C:7]=1[OH:23])(=[O:5])[CH3:4].[H][H].I[CH3:27].Cl>O1CCCC1>[C:3]([C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[CH:8][C:7]=1[O:23][CH3:27])(=[O:5])[CH3:4]
Reactant: CI
Reactant: CC(=O)c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1O
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OCc2cccc([N+](=O)[O-])c2)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a degreased suspension of sodium hydride (23 g) in tetrahydrofuran at ice temperature is slowly added (under nitrogen) a solution of 3-[(4-acetyl-3-hydroxyphenoxy)methyl]nitrobenzene (13.6 g, prepared as in Example 1A) in tetrahydrofuran (100 ml). When hydrogen evolution ceases, the mixture is allowed to warm to room temperature and is stirred for 2 hours. To this slurry is added iodomethane (6.7 g, neat) and the mixture is stirred 15 hours at room temperature. Another 6.7 g of iodomethane is then added and the mixture is refluxed 6 hours. After cooling to room temperature, the reaction mixture is poured into 10% HCl and extracted with ether. The extracts are washed with saturated brine, then dried over MgSO4 and concentrated. Recrystallization from acetone gives 9.1 g (64% yield) of product, m.p. 111°-114° C.