Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][NH:27][C:26]4=[O:30])=[CH:21][C:18]=3[C:19]#[N:20])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][N:27]([CH2:32][CH2:33][O:34][CH3:35])[C:26]4=[O:30])=[CH:21][C:18]=3[C:19]#[N:20])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COCCBr
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3C#N)CC2)c(C)c1
Product: COCCN1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(C#N)c2)C1=O
Yield: 73.9 %

Procedure:
Using 2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxoimidazolidin-1-yl)benzonitrile (399 mg) described in Example 434 and 1-bromo-2-methoxyethane (165 mg) and by the reaction and treatment in the same manner as in Example 36, the title compound (337 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CN1CCN(c2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CN1CCN(c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide and 1-(6-bromopyridin-2-yl)-4-methylpiperazine as the starting materials.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:28])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN(CCCCC(=O)O)c2cc(C)c(Br)cc2C=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1cc(C)c(Br)cc1C=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 5-((4-bromo-2-formyl-5-methylphenyl)(4-methoxybenzyl)amino)pentanoic acid (3.5 g) and potassium carbonate (1.34 g) DMF in (30 ml) was added dropwise a solution of iodomethane (1.6 g) in DMF (10 ml) under nitrogen atmosphere at 0° C. After returning to room temperature, the reaction mixture was stirred for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water five times and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 5-((4-bromo-2-formyl-5-methylphenyl)(4-methoxybenzyl)amino)pentanoate (3.5 g) as a brown oily material.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:1].[ClH:1].[N:13]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: ClCc1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: c1cnc2ccc(Cn3ccnc3)cc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A mixture of 12.3 parts of 6-(chloromethyl)quinoline, 9.5 parts of 1H-imidazole, 19.2 parts of potassium carbonate and 135 parts of N,N-dimethylformamide was stirred for 3 hours at 80° C. After evaporation to dry, the residue was taken up in water and further purified according to similar procedures as described in example 12, yielding 10 parts (48%) of 6-(1H-imidazol-1-ylmethyl)quinoline dihydrochloride; mp. 254.6° C. (compound 19).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CO.Cl.[C:17](=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1c(F)cc(C(=O)O)c(Cl)c1N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(F)c(C)c(N)c1Cl

Procedure:
12 g of 3-amino-2-chloro-5-fluoro-4-methylbenzoic acid are initially introduced into 60 ml of MeOH. HCl gas is passed in for 20 minutes and is then boiled under reflux for 5 hours. Thereafter, the mixture is poured into water and rendered alkaline with sodium carbonate and the product is isolated. Yield: 8 g, melting point: 51°-52°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5](O)=[CH:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])[CH3:2].Cl.[NH2:37]O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:11][C:10]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:37]=1)=[O:35])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(O)=CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 25 °C

Procedure:
4-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (1 eq) was dissolved in ethanol with stirring. Hydroxylamine hydrochloride (1.2 eq) was added and the solution was heated to reflux for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between brine and dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][NH2:31])=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][NH:31][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][N:17]=[CH:18][C:10]=3[NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NNc1ccnc2cc(Cl)ccc12)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N′-(7-chloroquinolin-4-yl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotino-hydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.50 mmol of 7-chloroquinolin-4-yl-hydrazine. LC/MS [7.69 min; 534 (M+1)]
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH3:23].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH3:23])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 96.8 %

Procedure:
Following the procedure of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (525 mg, 2.02 mmol), 1-bromobutan-2-one (428 mg, 2.83 mmol), and triethylamine (0.480 mL, 3.44 mmol) were reacted in ethanol (20 mL) to provide N-(3-(benzyloxy)pyridin-2-yl)-4-ethylthiazol-2-amine (609 mg) as a yellow oil. The HCl salt was prepared according to Example 3, Step C, to provide N-(3-(benzyloxy)pyridin-2-yl)-4-ethylthiazol-2-amine hydrochloride (585 mg, 83%) as a white powder. 1H NMR (d6-DMSO) δ 7.97 (d, 1H), 7.59-7.61 (m, 3H), 7.35-7.42 (m, 3H), 7.12 (m, 1H), 6.86 (s, 1H), 5.34 (s, 2H), 2.67 (q, 2H), 1.23 (t, 3H). Mass spectrum (apci) m/z=312 (100) (M+H-HCl).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>C(Cl)Cl.O>[C:22]([O:14][CH2:13][C:3]1[C:4]([F:12])=[C:5]([CH:9]=[C:10]([F:11])[C:2]=1[Br:1])[C:6]([OH:8])=[O:7])(=[O:24])[CH3:23]
Reactant: O=C(O)c1cc(F)c(Br)c(CO)c1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1c(F)c(C(=O)O)cc(F)c1Br
Reaction time: 1 h

Procedure:
In 18 ml of methylene chloride was suspended 1.80 g of 4-bromo-2,5-difluoro-3-hydroxymethylbenzoic acid and to the suspension were added 1.64 g of triethylamine and 0.84 g of acetic anhydride with ice-cooling, after which the suspension was stirred for one hour. The temperature of the suspension was then elevated to room temperature, at which the mixture was stirred for a further 12 hours. The reaction mixture was added to a mixed solvent of 20 ml of methylene chloride and 50 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluent: chloroform:ethanol=9:1), to obtain a colorless, oily 3-acetoxymethyl-4-bromo-2,5-difluorobenzoic acid. The oily product obtained was dissolved in 42 ml of anhydrous tetrahydrofuran, and 1.64 g of N,N'-carbonyldiimidazole was added to the solution with ice-cooling. The resulting mixture was stirred at room temperature for one hour. Subsequently, 1.45 g of magnesium ethoxycarbonylacetate was added thereto and the resulting mixture was stirred at the same temperature for 20 hours. The reaction mixture was added to a mixed solvent of 80 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=20:1), to obtain 1.32 g of colorless, crystalline ethyl 3-acetoxymethyl-4-bromo-2,5-difluorobenzoylacetate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1.O>O1CCCC1>[Si:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][N:26]=2)=[CH:5][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCOc2ncnc3ccccc23)cc1

Procedure:
2-hydroxyethyl-4-(4-tert-butyldimethylsilyloxybutyl)benzene (0.3 g, 0.97 mmol)is dissolved in dry tetrahydrofuran and to it is added sodium hydride (24 mg, 1 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.164 g, 1 mmol) is added to the above solution. The solution is then stirred for 6 hours after which water is added to the mixture. The solution is then extracted in dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the product.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([Mg]Br)[CH2:9][CH:10]([CH3:12])[CH3:11].[Mg].C(Br)CC(C)C>CCOCC.[Cu]I>[CH3:3][C:2]([CH3:5])([C:1](=[O:6])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)CC[Mg]Br
Agent: [Cu]I
Agent: [Mg]
Solvent: CC(C)CCBr
Solvent: CCOCC
Product: CC(C)CCC(=O)C(C)(C)C
Reaction time: 16 h

Procedure:
To a stirred mixture of pivaloyl chloride (6.02 g, 0.05 m) and copper (I) iodide (0.10 g, 0.6 mm) in dry ether (50 mls) at -60° C. under nitrogen was added dropwise isoamyl magnesium bromide [prepared from magnesium turnings (1.8 g, 0.075 m) and isoamyl bromide (7.55 g, 0.05 m) in dry ether (70 mls]. The cooling bath was removed and the reaction mixture stirred for 16 hours then poured cautiously into ice-cold dilute hydrochloric acid and extracted with ether. The combined ethereal extracts were washed with saturated aqueous sodium hydrogen carbonate solution, brine, dried (anhydrous MgSO4) and evaporated. The residue was chromatographed on silica using gradient elution (dichloromethane (0-30%) in petrol) to give the ketone as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:19].[CH3:20][N:21]([CH:23]=O)C>>[CH:20]1[C:11]2[C:10](=[C:9]([NH:19][C:15](=[O:17])/[CH:14]=[C:13](/[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)\[CH3:18])[CH:8]=[CH:7][CH:12]=2)[CH:13]=[CH:23][N:21]=1
Reactant: CN(C)C=O
Reactant: N
Reactant: C/C(=C\C(=O)O)c1ccc(N2CCCCC2)cc1
Product: C/C(=C\C(=O)Nc1cccc2cnccc12)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound was prepared using the procedure described in 142D using the product from Example 147A instead of the product from Example 142C. 1H NMR (300 MHz, d6-DMSO) 10.50 (s, 1H), 9.82 (s, 1H), 8.71 (d, 1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.26 (d, 1H), 7.95 (m, 2H), 7.62 (m, 2H), 6.80 (s, 1H), 3.20 (m, 4H), 2.58 (s, 3H), 1.90-1.56 (m, 6H); MS (DCI/NH3) m/e 372 (M+H)+; Anal. Calcd. For C24H25N3O.2.0HCl.2.0H2O.0.3 DMF: C, 59.24; H, 6.69; N, 9.27. Found: C, 59.44; H, 6.83; N, 9.24.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.CCOC(C)=O>[N:17]([C@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)COC(=O)[C@@H]1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (10 g) in DCM (10 mL) was added tetra-n-butylammonium azide (11.1 g). The reaction mixture was stirred at rt for 16 hr. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, citric acid, water, and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 3.87-4.02 (3H, m), 1.17 (3H, s), 1.02 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][Br:13]
Reactant: COC(=O)c1cccc(F)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc(F)c1CBr

Procedure:
3-Fluoro-2-methyl-benzoic acid methyl ester (4.3 g, 26 mmol), N-bromosuccinimide (5.0 g, 28 mmol) and AIBN (2,2′-azobisisobutyronitril) (420 mg, 2.6 mmol) were stirred at 80° C. for 10 hours in carbon tetrachloride (45 ml). The reaction solution was mixed with water and chloroform, washed with saturated sodium bicarbonate aqueous solution and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the extract under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 5.1 g (21 mmol, 81% in yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
8.4 g (54.8 mmol) of 4-methoxymethyloxyaniline and 7.5 g (49 mmol) of 2-chloro-3-nitropyridine were dissolved in 35 ml of dimethylformamide. 7.6 g (55 mmol) of anhydrous potassium carbonate was added to the solution. The resulting solution was heated under stirring at 100° C. for 4 h. The reaction liquid was cooled to room temperature and an insoluble matter thus formed was removed by filtration. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous citric acid solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol to obtain 9.68 g of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:6]([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH3:7].[C:17]1([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C(Cl)Cl>ClC(Cl)C>[CH2:6]([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13](=[O:15])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:25][CH:26]=1)[CH3:7]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CCCC(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
93 g aluminium chloride are added over 15 minutes at -10° C. to a solution of 52.0 g glutaric acid monoethyl ester chloride [Cl--CO--(CH2)3 --COOC2H5 ]. The mixture is stirred for 15 mins. at 0° to 10° C. and then added portion-wise over a period of 20 mins. at -5° to 10° C. to a pre-prepared solution of 50.0 g diphenylether in 150 ml dichloroethane. The reaction mixture is allowed to rise slowly to room temperature and is then stirred for 12 hours, poured onto ice and shaken well with H2O/methylene chloride. The organic phase is washed thouroughly with H2O and saturated NaHCO3 solution, dried over MgSO4 and the solvent evaporated off. The obtained light yellow oil is crystallised from hexane/ethyl ether on an ice bath: m.p.=61°-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[CH2:14]1[S:16][CH2:15]1>O>[CH3:9][S:10]([O-:13])(=[O:12])=[O:11].[SH:16][CH2:15][CH2:14][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccnc1
Reactant: CS(=O)(=O)O
Reactant: C1CS1
Solvent: O
Product: COc1ccc[n+](CCS)c1
Product: CS(=O)(=O)[O-]
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 7.6 %

Procedure:
To precooled (5° C.) 3-methoxypyridine (698 mg, 6.4 mmol) was added dropwise methanesulfonic acid (0.216 mL, 3.05 mmol) and ethylene sulfide (0.19 mL, 3.2 mmol). The mixture was then heated at 60° C. for 18 h, cooled to 20° C., diluted with water (10 mL) and washed with ether (3×10 mL). The aqueous phase was pumped under high vacuum for 15 min and poured on a C18 reverse phase column. The title compound was eluted with water. The appropriate fractions were combined and evaporated under high vacuum to give the desired thiol (61.6 mg, yield 76.3%); ir (CH2Cl2) νmax :2550 (w, SH) and 1620, 1600, 1585 cm-1 (m, aromatic); 1Hmr (DMSO d6) δ: 8.90-7.90 (4H, m, aromatic C-H), 4.72 (2H, t, J=6.6 Hz, CH2N+), 4.01 (3H, s, OCH3), 3.5-3.0 (m, hidden CH2S), 2.66 (1H, dd, J=9.6 Hz, J=7.5 Hz, SH) and 2.31 ppm (3H, s, CH3SO3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>O>[N:1]1([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a mixture of imidazole (5.13 g, 75.35 mmol), K2CO3 (11.45 g) and DMSO (50 ml) at room temperature was added to 4-fluorobenzonitrile (10.04 g) in one portion. The reaction mixture was stirred at room temperature for 1 hour, and then was warmed on a steam for 2 hours. The reaction mixture was cooled to room temperature, and poured into cold water. A precipitate formed which was collected by filtration and washed with water and recrystallized from CHCl3 /hexane to afford 4.07 g of 4-(1-imidazolyl)benzonitrile, m.p. 146-148° C.
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>CO>[C:2]1([C:1]2[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:19][N:18]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: O
Solvent: CO
Product: c1ccc(C2=NNC(c3ccccc3)C2)cc1

Procedure:
Benzalacetophenone (12.5 parts) is reacted with hydrazine hydrate (3.1 parts by volume) in methanol to form 3,5-diphenyl-2-pyrazoline. Panasol AN-2 (30 ml), nitrobenzene (7.4 parts) and 5% palladium on carbon catalyst (2 parts) are then added and the mixture heated. Following the distillation of methanol and water from the reaction mixture, the temperature is raised to 200° C. and held at that temperature for 24 hours. The mixture is then cooled to 50° C., filtered, and the catalyst bearing cake of 3,5-diphenylpyrazole is 79.5%, m.p. 194° to 199° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CCCCCN
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 67.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and amylamine (0.016 g, 0.184 mmol) gives the title compound (0.0426 g, 67.5%) TOFMS ES+ 344.2 (M+H)+, HRMS calcd for C19H26N3O3 344.1974 (M+H)+, found 344.1963time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.1 min, 100% purity.