Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13].O=P(Cl)(Cl)[Cl:17]>CC#N.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:17][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=[O:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)c1cc(O)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: CC(C)c1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
To a suspension of 4-hydroxy-6-isopropyl-3-nitro-1H-pyridin-2-one (3.02 g, 15.2 mmol) in CH3CN (60 mL) at room temperature is added benzyltriethylammonium chloride (13.88 g, 61.0 mmol). The mixture is stirred at room temperature for 5-10 min, and then POCl3 (6.25 mL, 67.1 mmol) is added. The reaction mixture is stirred at room temperature for 15 min and then at reflux for 1 h. After cooling, the reaction mixture is concentrated in vacuo. The flask is then placed in an ice bath, and the residue treated with H2O (˜60 mL). The mixture is stirred for 4 h while slowly warming to rt. The solid that forms over this period of time is collected by filtration and then washed with H2O and a small amount of hexanes. 4-Chloro-6-isopropyl-3-nitro-1H-pyridin-2-one is obtained as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 13.13 (br s, 1H), 6.24 (s, 1H), 2.89 (sept, J=6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:12]=1[C:38](=[O:40])[CH3:39].[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:33][CH2:34][N:35]([S:47]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)(=[O:49])=[O:48])[CH2:36][CH2:37]2)[C:12]=1[C:38](=[O:40])[CH3:39]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1c(C2CCN(S(=O)(=O)N3CCOCC3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DIEA (121 mg, 0.94 mmoL) was added to at 0° C. a mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (64.3 mg, 0.15 mmoL) and morpholine-4-sulfonyl chloride (28.9 mg, 0.15 mmol) in DMF (3 mL). After stirring at 0° C. for 0.5 h and then room temperature for 2 h, the mixture was purified by prep-LC to afford 1-(7-amino-5-(1-(morpholinosulfonyl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, LCMS tR=3.83 Min (5 min run, UV254nm). Mass calculated for, M+ 561.66, observed LC/MS m/z 567.66 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3C(CN4C(=O)C5=CC=CC=C5C4=O)=CN=[C:10]3[CH2:9][N:8]=[C:7]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[C:6]=2[CH:35]=1.O.[NH2:37]N.[CH2:39](O)[CH3:40]>>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[C:7]1[N:8]2[C:40]3[CH:39]=[CH:35][CH:2]=[CH:3][C:4]=3[CH:5]=[N:11][CH2:10][C:9]2=[N:37][CH:6]=1
Reactant: NN
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Solvent: O
Product: Fc1cccc(F)c1-c1cnc2n1-c1ccccc1C=NC2

Procedure:
In the manner given in Example 28, 8-chloro-1-(phthalimidomethyl)-6-(2,6-difluorophenyl)-4H-imidazo-[1,2-a][1,4]benzodiazepine is reacted at room temperature with hydrazine hydrate, dissolved in ethanol, to give 8-chloro-1-(aminomethyl)-6-(2,6-difluorophenyl-4H-imidazo-[1,2-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[H][H].[CH2:14]=O>O>[CH3:14][NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9]
Reactant: C=O
Reactant: COC(=O)c1ccccc1N
Reactant: [H][H]
Solvent: O
Product: CNc1ccccc1C(=O)OC

Procedure:
A mixture of methyl anthranilate, dissolved in a water-miscible solvent, with a solution of formaldehyde is reduced in a hydrogen atmosphere in the presence of a hyrogenation catalyst at moderate temperatures and pressures to yield methyl N-methylanthranilate. The invention provides a process which is feasible towards producing the compound in commercial quantities in high purity and good yield.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][S:16][C:17]1[NH:26][C:20]2[C:21](=O)[NH:22][CH:23]=[CH:24][C:19]=2[N:18]=1>CN(C)C=O.O>[CH2:7]([N:26]1[C:20]2[C:1](=[O:4])[N:22]([CH2:21][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[S:16][CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc2cc[nH]c(=O)c2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccn(Cc3ccccc3)c(=O)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
553 mg (4.0 mmol) of potassium carbonate and 0.48 ml (4.0 mmol) of benzyl bromide were added to a solution of 362 mg (2.0 mmol) of 2-methylmercapto-3,5-dihydro-imidazo[4,5-c]pyridin-4-one in 5.0 ml of dimethylformamide and this mixture was stirred for three hours at ambient temperature. Then it was diluted with 10 ml of water and extracted three times with 10 ml of ethyl acetate. The organic extracts were dried and evaporated down, the crude product thus obtained was purified by column chromatography (silica gel, eluant:dichloromethane with 0–3% ethanol).
Reaction SMILES: [C:1]([CH2:5][C:6]1[N:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:8]2[S:9][CH:10]=1)([O:3][CH3:4])=[O:2].CN(C)[CH:22]=[O:23].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.C(N(CC)CC)C>[C:1]([CH2:5][C:6]1[N:7]2[C:13]([CH:22]=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:8]2[S:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1csc2cc(-c3ccccc3)cn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1csc2cc(-c3ccccc3)c(C=O)n12
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 200 mg. of 3-carbomethoxymethyl-6-phenylpyrrolo[2,1-b] thiazole in 2 ml. of dimethylformamide is cooled to -40°, and 500 mg of a 1:2 mixture of phosphorous oxychloride:dimethylformamide is added. The temperature of the reaction is maintained at -40° C. for 30 minutes, then 2 ml of triethylamine are added and the mixture allowed to warm to room temperature. After 2 hours, 2 ml of 10% sodium hydroxide solution are added; the reaction mixture is diluted with water and extracted four times with ether. The combined ether extracts are diluted with hexane and washed with water. After drying and evaporation, the residue is chromatographed on 10 g of silica gel. Elution with chloroform initially gives 3-carbomethoxy-5-phenylthiacycl[2.2.2]azine as a brilliant yellow material, intensely fluorescent under long wavelength ultra-violet light, which may be crystallized from hexane, m.p. 118°-120°. Continued elution with chloroform affords 3-carbomethoxymethyl-5-formyl-6-phenylpyrrolo[2,1-b] thiazole, δ 3.70(3H), 4.42(2H), 6.40(1H), 6.61(1H), 0.93(1H) ppm. 150 Mg. of this aldehyde is refluxed in 100 ml of tetrahydrofuran with 0.5 ml. of triethylamine, 5 mg. of p-toluenesulfonic acid, and 20 ml of pentamethylsilazane to give an additional amount of 3-carbomethoxy-5-phenylthiacyl[2.2.2] azine.
Reaction SMILES: CN([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]2[N:18]([CH3:31])[C:19]3[C:24]([C:25]=2[CH:26]=[CH:27][C:28](O)=[O:29])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1.Cl.[CH3:35][N:36](C)[CH2:37]CCN=C=NCC>C(Cl)Cl>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([O:15][CH2:16][C:17]2[N:18]([CH3:31])[C:19]3[C:24]([C:25]=2[CH:26]=[CH:27][C:28]([N:4]2[CH2:5][CH2:6][CH:7]([N:36]([CH3:37])[CH3:35])[CH2:8][CH2:9]2)=[O:29])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C=CC(=O)O)c2ccccc21
Reactant: CN(C)N1CCCCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)C=Cc2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere dimethylaminopiperidine was dissolved in 3.0 ml of methylene chloride. To this solution were added 3-(2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indol-3-yl]prop-2-enoic acid (0.050 g, 0.1462 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0356 g, 0.278 mmol). The resulting mixture was stirred at room temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:36])[CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=O)[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:43]([C:47]1[CH:48]=[C:49]([NH2:54])[C:50]([NH2:53])=[CH:51][CH:52]=1)([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:54][C:49]1[CH:48]=[C:47]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:52]=[CH:51][C:50]=1[NH:53][C:33](=[O:35])[CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH3:36])[CH2:31]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A solution of 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)acetic acid and 4-tert-butylbenzene-1,2-diamine (89.4 mg, 0.545 mmol) in N,N-dimethylformamide (4.5 mL) was treated with N,N-diisopropylethylamine (0.261 mL, 1.50 mmol) dropwise followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (259 mg, 0.681 mmol). The solution was allowed to stir at room temperature for 18 h during which time LCMS indicated the starting material had been consumed. The reaction mixture was concentrated under high vac. The residue was taken up in 30 mL ethyl acetate and 20 mL 1/1 H2O/sat NaHCO3 solution. The mixture was extracted and the aqueous phase was washed with 35 mL ethyl acetate. The combined organic phase was washed with two 20 mL portions of H2O, and 20 mL brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield a tannish brown glass/stiff foam. The crude material was purified by flash chromatography (35 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (272 mg, 82%) as a light tan glass/stiff foam which was a mixture of regioisomeric amides: MS (ESI+) for C41H53N7O6 m/z 728.8 (M+H)+; MS (ESI−) for C41H53N7O6 m/z 726.9 (M−H)−; HPLC purity >95%, (ret. time, 3.14, 3.17 min) two peaks observed due to amide regioisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:5]([N:7]([CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:9][C:10](O)=[O:11])=[O:6].[CH3:21][N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:5]([N:7]([CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:9][C:10](=[O:11])[NH:22][CH3:21])=[O:6]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(Cl)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a stirred solution of 3-[(3-chloro-5-methoxy-benzoyl)-isopropyl-amino]-propionic acid (0.600 g), TBTU (1.28 g) in DMF (10 ml) was added DIPEA (0.696 ml) followed a 2M solution of methylamine in THF (8.0 ml) after 10 min. The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (0.575 g).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:47]=[CH:46][C:25]([O:26][CH2:27][C:28](=[O:45])[CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:34][CH:33]=2)[CH3:30])=[CH:24][CH:23]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28](=[O:45])[CH:29]([O:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:36][CH:37]=2)[CH3:30])=[CH:46][CH:47]=1
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO)cc1
Temperature: 70 °C
Yield: 91.6 %

Procedure:
A solution of (3R and 3S)-1-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (2.82 g, 4.32 mmol) in tetrahydrofuran (70 ml) was treated with acetic acid (1.5 ml) followed by 1M tetrabutylammonium fluoride in tetrahydrofuran (10 ml, 10.0 mmol). The mixture was then heated at 70° C. for 3.5 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 1.64 g (91%) of the title material as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-])=O.C.[H][H]>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=[N+]([O-])c1ccc(-n2cnnc2)cc1C(F)(F)F
Reactant: [H][H]
Product: Nc1ccc(-n2cnnc2)cc1C(F)(F)F

Procedure:
The following compound, m.p. 196°-8°, was prepared similarly to the previous Preparation using 4-(4-nitro-3-trifluoromethylphenyl)-1,2,4-triazole and 5% palladised charcoal/H2 as the starting materials: ##STR137##
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[CH2:9]([O:11][C:12](=[O:15])[CH2:13][Br:14])[CH3:10]>ClCCl>[Br-:14].[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N+:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:10]
Reactant: CCN1CCCCC1
Reactant: CCOC(=O)CBr
Solvent: ClCCl
Product: CCOC(=O)C[N+]1(CC)CCCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 1-ethylpiperidine (2.5 g, 22.1 mmol) in dichloromethane (4 mL) was added ethylbromoacetate (3.7 g, 22.1 mmol) via a syringe. The mixture was stirred at room temperature overnight. The resulting white precipitate was washed with hexane and ethylacetate to give 6.1 g, 98.6% yield of the product as a white solid. Positive mode ESI/MS: m/z=200.4 (M+, minus Br); confirmed by 1H NMR.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([OH:21])[C:12]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:28]1([S:38](Cl)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>ClCCl>[C:28]1([S:38]([O:21][C:13]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=2)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(O)c2-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(OS(=O)(=O)c3cccc4ccccc34)c2-c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ol (0.1 g, 0.25 mmol, prepared according to the procedure described in PCT/IB03/01289) in dichloromethane (10 ml) was added naphthalene-1-sulfonyl chloride (0.086 g, 0.37 mmol) in dichloromethane (4 ml) at 0° C. and the mixture was stirred for 10 minutes. Subsequently pyridine (0.04 ml, 0.5 mmol) was added under stirring and the stirring was continued further for 6 hours at 37° C. Dichloromethane was removed under vacuo and the resultant mixture was diluted with water:ethyl acetate (1:1, 100 ml) and then extracted with ethyl acetate (3×25 ml). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulphate and evaporated to afford the title compound (0.096 g, yield 67%); m.p. 204-206° C. 1H-NMR (CDCl3) δ: 2.99 (s, 3H), 7.12-7.14 (d, 2H), 7.26-7.29 (dd, 3H), 7.37-7.39 (m, 2H), 7.48-7.50 (m, 2H), 7.61-7.64 (m, 3H), 7.77-7.79 (d, 2H), 7.84-7.86 (d, 2H), 7.94-7.96 (d, 2H); MS m/z: 585.1 (M++1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:16]([N+:17]([O-])=O)=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:4][CH2:3]1>CO.O1CCOCC1.[Pd]>[NH2:17][C:16]1[C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]2)=[N:10][CH:11]=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(trans-4-Hydroxycyclohexylamino)-5-nitronicotinonitrile (3.35 g) was dissolved in a mixture of methanol (17 ml) and 1,4-dioxane (17 ml), and 10% palladium on carbon (383 mg) was added to the solution under nitrogen atmosphere. The mixture was shaken at ambient temperature for 3 hours under hydrogen atmosphere (3 atm). The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give 5-amino-6-(trans-4-hydroxycyclohexylamino)nicotinonitrile (3.15 g) as a brown amorphous.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15][OH:16])=[CH:11][CH:10]=2)[O:3]1.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33](C)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[C:30]1([S:27]([O:16][CH2:15][CH2:14][O:13][C:12]2[CH:17]=[CH:18][C:9]([B:4]3[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)(=[O:29])=[O:28])[CH:36]=[CH:35][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(OCCOS(=O)(=O)c3ccccc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Into dichloromethane 100 ml, 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanol (4.4 g, 16.7 mmol) synthesized in Example 2 (2b) was dissolved, to which triethylamine (4.6 ml, 33.2 mmol), 4-dimethylaminopyridine (400 mg, 3.3 mmol), tosyl chloride (4.8 g, 25.2 mmol) were sequentially added while cooling with ice. The resulting mixture was warmed back to room temperature, followed by further stirring for two hours. The resulting reaction liquid was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-70:30, V/V) to give the desired title compound (6.1 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]([NH:20][NH2:21])=O)=[CH:4][CH:3]=1.[N:22]([CH3:25])=[C:23]=[S:24]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[S:24][C:23]([NH:22][CH3:25])=[N:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: CN=C=S
Reactant: NNC(=O)Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Solvent: CCO
Product: CNc1nnc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(2-(4-chlorophenyl)imidazo[1,2-α]pyridin-3-yl)acetohydrazide (0.1 g, 0.33 mmol) in EtOH (1 mL) was treated with isothiocyanatomethane (0.023 mL, 0.33 mmol) and refluxed for 3 h. The precipitated thiosemicarbazide was filtered and dissolved in concentrated sulfuric acid. The reaction mixture was stirred for 30 min at rt. The mixture was poured into cold water and the precipitated product was filtered in vacuo and washed with ditilled water. The crude product was recrystallized in EtOH to provide the title product as a yellow solid. M/e+ 356 for C17H15ClN5S (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.22 (m, 2H), 6.84 (t, J=6.6 Hz, 1H), 4.65 (s, 2H), 2.98 (s, 3H) ppm.
Reaction SMILES: C(OC([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.C(OC([NH:37][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:37][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([Br:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Br)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Br)c23)C1
Product: Cl

Procedure:
Intermediate 24a was used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>N1CCCCC1.C(O)(=O)C.C1(C)C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[C:17]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:18](=[O:20])[CH3:19])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: CC(=O)Cc1ccncc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)C(=CC=Cc1ccccc1)c1ccncc1
Yield: 17 %

Procedure:
Trans-cinnamaldehyde (1.84 ml, 14.8 mmol), five drops of piperidine and five drops of acetic acid were added to a solution of 4-pyridyl acetone (2.0 g, 14.8 mmol) in toluene (25 ml). The mixture was heated to reflux for 48 hours with a Dean-Stark trap to remove water. The mixture was concentrated to give a black oil. The oil was purified by silica gel chromatography (eluted with 1:1 hexane/ethyl acetate). The desired fractions were collected, combined and concentrated to give 6-phenyl-3-(4-pyridinyl)hexa-3,5-dien-2-one (628 mg). The ketone was further purified by an additional column chromatography on silica gel (eluting with hexane-ethyl acetate-methylene chloride-methanol (1:1:2:0.12)) (380 mg, 27.3%): Anal. Calc'd for C17H15NO 0.4 H2O: C, 79.91; H, 5.84; N, 5.48. Found: C, 79.72; H, 5.91; N, 5.25. MS (M+H+) : 250.