Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.CS([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[N:21]2[N:34]=[CH:35][N:36]=[C:20]2[N:19]=1)(=O)=O>O>[C:1]1([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[N:21]3[N:34]=[CH:35][N:36]=[C:20]3[N:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(-c2cc(-c3ccccc3)nc3ncnn23)nc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.2 mL of a phenyl magnesium bromide 3.0 M tetrahydrofuran solution was added at 0° C. to a tetrahydrofuran (dehydrated) 3 mL solution of 200 mg of 5-(methylsulfonyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, followed by stirring at 0° C. for 5 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to obtain 93 mg of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[CH3:35].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[S:12])=[CH:30][C:29]=1[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (65 mg, yield 83%).
Reaction SMILES: C(OC([C:8]([CH2:10][O:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:24][CH2:23]2)[CH:15]=1)=[O:9])=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>C(Cl)(Cl)Cl>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:13][NH:12][O:11][CH:10]=[C:8]=[O:9])[CH2:23][CH2:24]1
Reactant: COc1ccc(CNOCC(=O)C(=O)OC(C)(C)C)cc1N1CCN(Cc2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNOC=C=O)cc1N1CCN(Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
A mixture comprising 1.3 g of t-butyloxycarbonyl-3-[4-(2-quinolylmethyl)-piperazin-1-yl]-carbonylmethoxy-4-methoxybenzylamine, 14 ml of chloroform and 2.8 g of trifluoroacetic acid, was stirred at room temperature for one day. To the reaction solution, 50 ml of chloroform and 50 ml of 0.5N hydrochloric acid were added, and the mixture was reversely extracted. The aqueous layer was adjusted to pH 12 with an aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 850 mg of the above-identified compound as oily substance.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(N(CC)CC)C.[NH2:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>C(#N)C>[NH2:26][CH:27]1[CH2:31][CH2:30][N:29]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1
Reactant: NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21
Yield: 89.2 %

Procedure:
A mixture containing 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (2.7 g), triethylamine (1.01 g), 3-aminopyrrolidine (1.72 g), and acetonitrile (100 ml) was heated under reflux for 1.5 hours. After cooling the mixture, the resulting precipitate was collected and suspended in water (20 ml). The suspension was adjusted to pH 7.5-8.0 with acetic acid. The precipitate was collected, washed with water, and dried to yield 2.85 g of 7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 259°-262° C. (decomp.).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1>[N:11]1([CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCCN1CCCCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCN1CCCCC1
Reaction time: 1.5 h

Procedure:
Diketene (2.40 mL, 31.1 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(3-aminopropyl)piperidine (2.95 g, 20.7 mmol, 1.0 equiv, Bates, R. J.; Cymerman-Craig, J.; Moyie, M.; Yong, R. J. J. Chem. Soc. 1956, 388) in anhydrous THF (40 mL) under argon, and stirring was continued at room temperature for 1.5 hours. The mixture was concentrated to give 4.8 g (100%) of light brown oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[N:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cn3)CC2)c(C)c1
Yield: 59.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 21 and oxazolidin-2-one (174 mg), the title compound (449 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Reactant: C1CCNC1
Solvent: CO
Product: COc1cc(CCN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 75 %

Procedure:
3.07 g (17.17 mmol) of the product prepared in step 24.1 and 7.13 mL (85.84 mL) of pyrrolidine in 60 mL of anhydrous methanol are placed in a sealed tube. The mixture is heated under pressure at 100°C. for 4 hours. After cooling to room temperature, it is evaporated to dryness. The residue obtained is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (100/0 to 90/10). 3.22 g of the expected product are obtained in the form of a yellow solid. Yield=75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)([CH3:19])[C:17]#[N:18]>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:16]([C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)([CH3:19])[C:17]#[N:18]
Reactant: CC(C#N)(c1ccc(F)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C#N)(c1ccc(F)cc1)c1ccc(N2NCC(=O)NC2=O)cc1Cl
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a stirred and refluxed mixture of 1.5 parts of 2-chloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl) -α-(4-fluorophenyl)-α-methylbenzeneacetonitrile and 75 parts of acetic acid were added portionwise 3 parts of zinc during a period of 30 minutes. Upon complete addition, stirring was continued for 3 hours at reflux. The reaction mixture was filtered while hot and the filtrate was concentrated in vacuo to 10 parts of its volume. Water was added to the concentrate. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and eluent was evaporated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.8 parts (53.6%) of 2-chloro-α-(4-fluorophenyl)-α-methyl-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile; mp. 122.5° C. (compound 2).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH:20]=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:23][O:24][NH2:25]>>[CH3:23][O:24][N:25]=[CH:20][CH2:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: CON
Reactant: O=CCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: Cl
Product: CON=CCCc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
The process described in Method A was followed. 3-(4,5-Diphenyl-1,3-oxazol-2-yl)propanal (554 mg, 2.0 mmol, see Pridgen L. N. et al in Tetrahedron Lett., 25(27), 2835 (1984)) and methoxyamine hydrochloride (222 mg, 2.66 mmol) were used to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=2.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[C:10]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2
Reactant: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (R)-methyl 3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (66 mg, 0.18 mmol, 1.00 equiv) in methanol (15 mL). A solution of sodium hydroxide (35 mg, 0.88 mmol, 5.00 equiv) in water (2 mL) was added. The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted in 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 25 mg (39%) of (R)-3-(2-(methoxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:47]([Si:51](Cl)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:50])([CH3:49])[CH3:48].O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O)CC3)n2n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 1.387 mmol) in DMF (10 mL) at 0° C. was added imidazole (142 mg, 2.081 mmol) followed by tert-butylchlorodiphenylsilane (0.533 mL, 2.081 mmol) and the resulting mixture was stirred at room temp for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (2×25 mL). Ether layer was then washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified via Biotage (0-10% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 1.227 mmol, 88% yield) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J=8.0, 1.5 Hz, 4H), 7.47-7.28 (m, 6H), 7.01 (s, 1H), 5.82 (br. s., 1H), 4.50-4.38 (m, 2H), 4.31-4.07 (m, 2H), 3.94-3.77 (m, 1H), 3.41-3.24 (m, 3H), 2.61 (s, 3H), 1.88 (br. s., 2H), 1.67 (br. s., 1H), 1.54 (br. s., 1H), 1.51-1.39 (m, 5H), 1.30 (s, 3H), 1.26-1.23 (m, 6H), 1.22 (s, 9H), 1.08 (s, 3H), 1.06 (s, 9H). 4 missing piperidine hydrogens. LCMS (M+H)=816.4.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C@H:27]2[CH2:32][C@H:31]([N:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([NH:42][C:43]4[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:50])=[O:41])[CH2:35][CH2:34]3)[CH2:30][CH2:29][NH:28]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:28]1[CH2:29][CH2:30][C@@H:31]([N:33]2[CH2:34][CH2:35][N:36]([CH2:39][C:40]([NH:42][C:43]3[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:44]=3[CH3:50])=[O:41])[CH2:37][CH2:38]2)[CH2:32][C@@H:27]1[CH2:26][C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)=[O:7]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 0.08 h
Yield: 43.9 %

Procedure:
3,5 di(trifluormethyl)benzoyl chloride (0.0011 mol) was added to a mixture of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.001 mol) in DCM (20ml). The mixture was stirred for 5 minutes. Triethylamine (2ml) was added. The mixture was stirred at RT for 3 hours, washed with a diluted NaOH solution and with water, and then dried. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.32 g (44%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 139).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.N#C[Br:20]>ClCCl>[Br:20][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CBr
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: Brc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 26 h
Yield: 81.4 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (5.0 g, 20.2 mmole) and cyanogen bromide (4.28 g, 40.4 mmole) in 100 mL of dichloromethane was stirred at room temperature for 26 h. The precipitate was filtered and washed with dichloromethane to yield 4.18 g (81%) of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole as a white powder: mp 189-190° C.; 1H NMR (CDCl3)δ 8.23 (d, 1H), 7.82 (d, 1H), 7.52 (t, 1H), 7.42 (d, 1H) ppm; 13C NMR (1:1 CDCl3 :DMSO-d6):δ 162.78, 149.67, 129.22, 125.53, 122.25, 119.48, 117.25, 111.27 ppm; IR (KBr):ν 3025, 2925, 1601, 1493, 1451, 1028, 757, 701 cm-1 ; HRMS calcd for C8H4N3SBr 252.9309, found 252.9307. Anal. Calcd for C8H4N3SBr: C, 37.81;H, 1.59; N, 16.54. Found: C, 37.44; H, 1.33; N. 16.57.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCC>[Br:14][CH2:13][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[C:11]=1[Cl:12]
Reactant: COC(=O)c1ccc(C)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Cl)c1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 40 g (0.183 mol) of methyl 2,3-dichloro-4-methylbenzoate, 34.17 g (0.192 mol) of N-bromosuccinimide, 0.4 g (0.0017 mol) of benzoylperoxide, and 640 mL of carbon tetrachloride was stirred at room temperature while being irradiated with a 150 watt flood lamp for 2.5 hours. Concentration of the filtered reaction mixture under vacuum gave 54 g of material which on trituration with pentane followed by storage of the slurry at 5° C. for 18 hours gave 34.6 g (63.5%) of product; mp 57°-61° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[O:3][CH2:2]1.[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[C:9]=2[N:10]=1)[CH3:12]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: Nc1cccc2c1OCO2
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3

Procedure:
The title compound (14) was prepared from benzo[1,3]dioxol-4-ylamine following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=566 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8]([CH2:10][CH2:11][NH2:12])=[O:9].[C:13](=[S:15])=[S:14]>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8]([CH2:10][CH2:11][NH:12][C:13](=[S:14])[SH:15])=[O:9]
Reactant: Cc1[nH]cnc1CS(=O)CCN
Reactant: S=C=S
Product: Cc1[nH]cnc1CS(=O)CCNC(=S)S

Procedure:
Oxidation of 5-methyl-4-(2-aminoethylthio)methylimidazole with one equivalent of sodium metaperiodate yields 5-methyl-4-(2-aminoethylsulphinyl)methylimidazole and reaction of this compound with carbon disulphide gives N-[2-((5-methyl-4-imidazolyl)methylsulphinyl)ethyl]dithiocarbamic acid which, on treatment with methyl iodide may be converted into S-methyl-N-[2-((5-methyl-4-imidazolyl)methylsulphinyl) ethyl]dithiocarbamate hydriodide.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>>[F:24][C:19]1[CH:18]=[C:17]([CH3:16])[CH:23]=[CH:22][C:20]=1[NH:21][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccc(N)c(F)c1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(C)cc1F
Yield: 53.5 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 4-methyl-2-fluoroaniline (6.04 g, 48.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (4.05 g, 53%) was obtained.
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:7]([O:9][P:10]([CH2:5][CH:4]=[CH:3][CH2:2][Br:1])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8]
Reactant: CCOP(OCC)OCC
Reactant: BrCC=CCBr
Product: CCOP(=O)(CC=CCBr)OCC
Yield: 55.2 %

Procedure:
A solution of 1,4-dibromo-2-butene (20 g, 93.5 mmol) and triethylphosphite (23.7 g, 142.6 mmol) is heated at 85° C. under reduced pressure for four hours. The reaction mixture is purified directly on silica gel using ethyl acetate as eluant to give 14 g of a clear oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>O>[CH2:28]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CC(=NO)c1ccc(NC(=O)NCC(=O)OC(C)(C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of the N-[4-(1-hydroxyiminoethyl)phenyl]-N'-tertbutoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the product N-[4-(1-allyloxyiminoethyl)phenyl]-N'-tert-butoxycarbonylmethylurea.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:5]([CH3:27])[NH:4][N:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:6]4[C:5]([CH3:27])=[N:4][N:3]([S:29]([CH3:28])(=[O:31])=[O:30])[C:2]=4[CH3:1])[CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1
Reactant: Cc1n[nH]c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nn(S(C)(=O)=O)c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a solution of 4-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.250 g, 0.7 mmol, 1 eq) add methanesulfonyl chloride (63 μL, 0.8 mmol) followed by pyridine (2 mL). Stir at room temperature for 3 hr. then add a further portion of methanesulfonyl chloride (100 μL, 1.4 mmol, 2 eq). Stir for 2 hr. at room temperature then add yet a further portion of methanesulfonyl chloride (63 μL, 0.8 mmol, 1.2 eq) and then stir at room temperature overnight. Add water (10 mL) and ethyl acetate (10 mL), separate and extract the aqueous layer twice with ethyl acetate (10 mL), dry the combined organic extracts (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with a gradient of 0:100 to 10:90 methanol:DCM), to give the title compound (207 mg, 66%). MS (ES): m/z=445.1 [M+H]+.