Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=2[NH2:11])=[CH:5][CH:4]=1.[N:22]#[C:23]Br>CN(C=O)C.C(N(CC)CC)C>[NH2:22][C:23]1[N:8]([CH2:7][C:6]2[CH:20]=[CH:21][C:3]([Cl:2])=[CH:4][CH:5]=2)[C:9]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1cc(C(F)(F)F)ccc1NCc1ccc(Cl)cc1
Reactant: N#CBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc2cc(C(F)(F)F)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 2-(4-chlorobenzylamino)-5-trifluoromethylaniline hydrochloride (6.74 g, 20 mmol) in DMF (100 ml) and triethylamine (2.8 ml) was added cyanogen bromide (2.75 g, 26 mmol). The ice bath was removed after two hours and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and neutralized with an aqueous solution of sodium carbonate (5%). The product was filtered off and purified with activated charcoal and crystallization from ethanol. Yield 2.93 g (45%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:21][CH2:20][CH2:19]1)=[O:17])[CH3:14].[CH3:22][S:23]([O:26][C@H:27]([CH2:29][CH2:30]I)[CH3:28])(=[O:25])=[O:24]>C1COCC1>[CH3:22][S:23]([O:26][C@@H:27]([CH3:28])[CH2:29][CH2:30][C:18]1([C:16]([O:15][CH2:13][CH3:14])=[O:17])[CH2:21][CH2:20][CH2:19]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1CCC1
Reactant: C[C@@H](CCI)OS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(CC[C@H](C)OS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a solution of diisopropylamine (9.1 mL, 65 mmol) in 43 mL of THF was added n-BuLi (26 mL, 65 mmol) at 0° C. slowly (5 min). The mixture was stirred at 0˜5° C. for 30 min. After the mixture was cooled to −78° C. (10 min), Ethylcyclobutanecarboxylate (8 mL, 59.6 mmol, 1.1 eq.) was added dropwise and stirred at −78° C. for 30 min. The enolate was added into the solution of (S)-4-iodobutan-2-yl methanesulfonate 96 (15 g, 54 mmol) in 100 mL of THF at −78° C. Cooling bath was removed to allow the reaction to warm up to RT. After 30 min at RT, reaction was quenched by addition of water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4, filtered and concentrated down. The residue was purified by silica gel chromatography first with (5% to 30% EtOAc in hexanes) then 100% DCM to (98% DCM/2% EtOAc) to provide 5.3 g (36% isolated yield) of (S)-ethyl 1-(3-(methylsulfonyloxy)butyl)cyclobutanecarboxylate 97.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[N+:10]([O-:21])=[C:9]([NH:22][C:23](OCC(C)C)=[O:24])[N:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH-].[Na+]>O>[N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[N:10]3[O:21][C:23](=[O:24])[N:22]=[C:9]3[N:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(=O)Nc1nc(N2CC=CCC2)nc(NC(=O)OCC(C)C)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)COC(=O)Nc1nc(N2CC=CCC2)nc2nc(=O)on12
Reaction time: 1.25 h

Procedure:
8 g. of diisobutyl 6-[3,6-dihydro-1(2H)-pyridyl]-s-triazine-2,4-dicarbamate-3-oxide are dissolved in 300 ml. of methylene chloride and 1000 ml. of water and adjusted to pH 12.7 with concentrated sodium hydroxide. The mixture is stirred for 75 minutes, the organic phase is separated and the aqueous phase is adjusted to pH 4 with 3-N hydrochloric acid solution. The thus-obtained acidic aqueous solution is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated, there being obtained pure isobutyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate having a melting point of 210°-215° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([S:35](Cl)(=[O:37])=[O:36])[CH:33]=2)[NH:28][N:27]=1.C([O-])(O)=O.[Na+].CCCCCC>ClCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:35]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH3:25])(=[O:37])=[O:36])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2ccc(S(=O)(=O)Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1n[nH]c2ccc(S(=O)(=O)N(CC(C)C)CC(O)C(Cc3ccccc3)NC(=O)OC(C)(C)C)cc12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester 15 (60 mg, 0.18 mmol) and 3-methyl-1H-indazole-5-sulfonyl chloride (50 mg, 0.22 mmol) in 2 mL dichloromethane was added a 70 ul solution of a saturated NaHCO3 and 30 mg NaHCO3 and stirred overnight. The product was purified by preparative TLC using 1:1 ethyl acetate:hexane to give 95 mg product (99% yield). MS 531 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7].[N:20]1([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:24][CH2:25][N:20]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=3)[CH2:21][CH2:22]2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COC(=O)c1c(Cl)cccc1NC(=O)CCCCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(Cl)cccc1NC(=O)CCCCN1CCN(c2ccc3ccccc3n2)CC1
Yield: 63.5 %

Procedure:
A mixture of 1.29 g of methyl 2-(5-bromopentanoylamino)-6-chloro-benzoate as synthesized in above Step 7-18-B, 800 mg of 2-piperazin-1-ylquinoline as synthesized in Step 7-1-A, 400 mg of triethylamine and 20 ml of toluene was heated under reflux for 3 hours. After cooling, the solution was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:methanol=15:1) to provide 1.13 g (64%) of methyl 2-chloro-6-[5-(4-quinolin-2-ylpiperazin-1-yl)pentanoylamino]benzoate.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-n2ccnc2)c1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
90 mg of 1-(3-hydroxymethylphenyl)imidazole was dissolved in 10 ml of chloroform, and 100 microliters of thionyl chloride was added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl ether and water. The organic layer was separated, washed successively with a 5% aqueous solution of sodium hydrogen carbonate and then with water, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration and then ethyl ether was evaporated to give 1-(3-chloromethylphenyl)imidazole as a pale yellow oily product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.CCN(CC)CC.[Cl:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([C:46]([NH:48][C:49]3[C:50]([OH:56])=[N:51][CH:52]=[CH:53][C:54]=3[OH:55])=O)[CH:40]=[CH:41][CH:42]=2)[N:37]=1>C(Cl)Cl>[Cl:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[C:39]([C:46]3[O:55][C:54]4[CH:53]=[CH:52][NH:51][C:50](=[O:56])[C:49]=4[N:48]=3)[CH:40]=[CH:41][CH:42]=2)[N:37]=1
Reactant: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Cl)nc12
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]ccc2oc(-c3cccc4ccc(Cl)nc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of triphenylphosphine (381 mg, 1.454 mmol), perchloroethane (287 mg, 1.212 mmol), and Et3N (540 μl, 3.88 mmol) in DCM (4846 μl) was stirred at RT for 1 h. The yellow solution was transferred to a flask containing solid 2-chloro-N-(2,4-dihydroxypyridin-3-yl)quinoline-8-carboxamide (153 mg, 0.485 mmol); this was stirred at RT for 1 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(2-chloroquinolin-8-yl)oxazolo[4,5-c]pyridin-4(5H)-one (181, >99% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, J=7.04 Hz, 1H) 7.53 (t, J=6.65 Hz, 1H) 7.77 (d, J=8.61 Hz, 1H) 7.84-7.90 (m, 1H) 8.35 (dd, J=8.22, 1.37 Hz, 1H) 8.43 (dd, J=7.24, 1.37 Hz, 1H) 8.64 (d, J=8.61 Hz, 1H) 11.89 (br. s., 1H). MS (ESI, pos. ion) m/z: 298.1 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C[O-].[Na+].Cl>CO.CCOC(C)=O>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:14][C:13](=[O:15])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C=CC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-carbomethoxybenzaldehyde (79 mg, 0.48 mmol) and acetophenone (56 μL, 0.48 mmol) in anhydrous methanol (1.6 mL), was added neat sodium methoxide (26 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then heated to reflux for 1 hour, cooled down to room temperature and added HCl 1N and EtOAc. The layers were separated and the organic layer dried over anhydrous MgSO4 and filtered. The solvent was evaporated under vacuum to afford a yellow solid, which was recrystallized from acetonitrile/water to give a pale yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirred solution of 5-chloro-N-{2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (0.30 g, 0.66 mmol) in CH2Cl2 (10 mL) at −780C was added a solution of boron tribromide (1.0 M, 0.99 mL, 0.99 mmol) dropwise. After 4 h at −78° C. and 18 h at room temperature, another 1.5 eq BBr3 (0.99 mL) was added at −78° C. The reaction mixture was gradually warmed to room temperature and stirred for 18 h. The reaction mixture was slowly poured into H2O and extracted with CH2Cl2 (3 x's), dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude solid was purified by column chromatography (SiO2, EtOAc/hexane, 2:3), then precipitated with Et2O/hexane to yield a white solid in 34% yield.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([NH:11][C:12](SC)=[C:13]([C:16]#[N:17])[C:14]#[N:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CS>CO>[NH2:15][C:14]1[NH:3][N:2]=[C:12]([NH:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:13]=1[C:16]#[N:17]
Reactant: CSC(NCc1ccccc1)=C(C#N)C#N
Reactant: NN
Agent: CS
Solvent: CO
Solvent: O
Product: N#Cc1c(NCc2ccccc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
24 ml (0.48 mol) of hydrazine hydrate are added dropwise to a solution of 92 g (0.4 mol) of 3-benzylamino-3-methylmercapto-2-cyano-acrylonitrile in 400 ml of methanol, during which the temperature rises to 40° C. The reaction mixture is heated slowly to boiling (→ evolution of MeSH!), boiled for 2 hours, cooled to RT and concentrated by evaporation to a residual volume of ≈200 ml. Dilution with diethyl ether, filtering and washing with diethyl ether yield 5-amino-3-benzylamino-1H-pyrazole-4-carbonitrile [Spectrochimica Acta, 47A, 1635 (1991)]; m.p. 150-152° C.; TLC: Rf =0.41 (ethyl acetate).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1)[C:14]([CH3:16])=[O:15].O[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:23][N:25]2[C:29](=[O:30])[C:28]3[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]2=[O:35])[CH2:19][CH2:18]1)[C:14]([CH3:16])=[O:15]
Reactant: CC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)CC1
Reaction time: 6 h

Procedure:
A solution of 39.5 ml (0.2413 mol) of diethyl azodicarboxylate (95%) in 300 ml of tetrahydrofuran is added dropwise to a mixture of 36.13 g (0.2298 mol) of cis-4-acetaminocyclohexanol [Ber. Dtsch. Chem. Ges. 72, 995 (1939)], 37.49 g (0.2298 mol) of N-hydroxyphthalimide, 60.28 g of triphenylphosphine and 1500 ml of tetrahydrofuran at 20°-30° C., while stirring. After stirring at room temperature for 14 hours, in each case 20% of the amount of triphenylphosphine and diethyl azodicarboxylate originally employed is again added to the reaction mixture, stirring is continued for 6 hours and the reaction mixture is left to stand at room temperature for 2.5 days. The crystalline precipitate formed is filtered off and washed with tetrahydrofuran. The title compound thus obtained melts at 210°-213° C. The yield can be increased by further recrystallization or chromatography of the mother liquor.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2.CS(C)=O.[C-:15]#[N:16].[Na+]>CC(OC)(C)C>[C:15]([CH2:2][CH2:3][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2)#[N:16]
Reactant: [C-]#N
Reactant: ClCCC12C=CC(CC1)C2
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: N#CCCC12C=CC(CC1)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 1 L, 4 neck RBF was equipped with a thermowell, condenser with a nitrogen inlet, stopper and mechanical stirrer. The RBF was charged with chloroethylnorbornene (100 g, 0.64 mol), 300 mL DMSO and solid NaCN (43.8 g, 0.89 mol). An extra 20 mL DMSO was added to rinse in the NaCN. The reaction mixture was stirred at ˜80° C. for 2 hours. GC analysis of an aliquot indicated all starting material had been consumed and the reaction was completed. The reaction mixture was cooled to room temperature. Approximately 200 mL water was poured into the flask and diluted with 100 mL MTBE. The organic phase was separated and the aqueous layer was re-extracted with (3×200 mL) MTBE. The organic phases were combined and washed with (3×500 mL) tap water until the aqueous wash reached pH=6. The MTBE solution was dried over anhydrous sodium sulfate overnight, filtered, and rotary evaporated to give 93.5 g (99.5% yield) with 99.3% purity by GC. NMR analysis indicated the material contained ˜1% MTBE. The crude product was used for the next reaction without further purification. Data: GC analysis done on a DB5 Column, 30 meters, 0.32 mm ID, 0.25 μm film, 75° C. to 300° C. at 25° C./min., hold for 2 min at 300° C., Injector temperature: 275° C., Detector temperature: 350° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([N:34]1[C:38](=[O:39])[C:37](=[C:40]2[N:44]([CH3:45])[C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[S:41]2)[S:36][CH2+:35]1SC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N:13]=[C:35]2[N:34]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:38](=[O:39])[C:37](=[C:40]3[N:44]([CH3:45])[C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=4[S:41]3)[S:36]2)[CH:6]=1)(=[O:12])[CH3:11]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCOc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCOc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethoxy-3′-nitroacetophenone was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.77 (1H, dd), 7.64–7.68 (2H, m), 7.61 (1H, d), 7.48 (1H, m), 7.25–7.36 (4H, m), 7.15 (1H, m), 6.99 (1H, d), 6.98 (1H, d), 5.20 (2H, s), 4.11 (2H, q), 3.69 (3H, s), 2.57 (3H, s), 1.43 (3H, t); MS(ESI): 516 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1>CS(C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCN(c2cc(Cl)nc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of N-methyl piperazine (0.604 g, 6.04 mmol) in dry DMSO (6 mL) was prepared and NaH (0.2637 g, 10.98 mmol) was added. The resulting mixture was stirred for 30 minutes at 0° C., after which time 2,4,6-trichloropyridine (1.0 g) was added. The reaction mixture was stirred at 20 to 40° C. for 4 hours. In the reaction mixture ice cold water was added and extracted with ethyl acetate giving 3-4 times water washing. The organic layer was dried and concentrated. The residue was purified by column chromatography using 100-200 mesh silica gel. Elution of the column with 20% acetone in hexanes gave the pure product as a colorless solid. Yield: 26%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[CH2:17]O)=[CH:3][N:2]=1.P(Br)(Br)[Br:20].O>ClCCl>[Br:20][CH2:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: OCc1ccc(C(F)(F)F)cc1-c1ccnnc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(CBr)c(-c2ccnnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[2-Pyridazin-4-yl-4-(trifluoromethyl)phenyl]methanol (Preparation 32, 46 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. Phosphorus tribromide (1.0 M in dichloromethane, 199 μL, 0.20 mmol) was added and the reaction stirred for 30 minutes. Water (2 mL) was added dropwise to the reaction at 0° C. before the organics were separated and dried using a phase separation cartridge. The organics were concentrated in vacuo to afford the title compound as a residue which was re-dissolved in THF (1 mL) and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([O:15]C(C)C)[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)=[C:4]([OH:15])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1nnn(-c2cc([N+](=O)[O-])c(F)cc2O)c1=O
Temperature: 25 °C
Yield: 82.9 %

Procedure:
A solution of 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 13.9 mmol, 1 equiv) in H2SO4 (35 mL) was cooled in ice/water bath. To the cooled solution, was added HNO3 (fuming>90%; 715 uL, 15.3 mmol, 1.1 equiv) dropwise, and the cooled reaction mixture was allowed to warm to RT over 2 h. The reaction mixture was quenched with ice, and extracted with EtOAc 3×. The organic layer was then extracted with saturated NaHCO3 3×. The basic aqueous layer was acidified to pH<3 with 6N HCl. Then, the acidic layer was extracted with EtOAc 3×, and the organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-hydroxy-5-nitrophenyl)-4-methyl-1H-tetrazol-5(4H)-one (2.94 g, 83%) as brown solid that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 12.5 (bs, 1H), 8.41-8.44 (d, 1H, J=8.7 Hz), 7.04-7.08 (d, 1H, J=13 Hz), 3.59 (s, 3H); 19F NMR (282 MHz; d6-DMSO) δ −111.3 (q); m/z=256 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[F:24][C:25]([F:44])([F:43])[C:26]1[CH:27]=[C:28]([C@@H:36]2[O:40][C:39](=[O:41])[NH:38][C@@H:37]2[CH3:42])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:38]2[C@H:37]([CH3:42])[C@H:36]([C:28]3[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:26]([C:25]([F:24])([F:43])[F:44])[CH:27]=3)[O:40][C:39]2=[O:41])[CH:6]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[N:10](C)[CH:9]1[C:15]([CH3:18])(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C@H]1CNCCN1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:18][C@@H:15]1[NH:10][CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)C1C(C)(C)C
Agent: C[C@H]1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-2-tert-butyl-3-methyl-4-imidazolidinone (2 g, 8,3 mmol) (BOC-ON) in chloroform (15 ml) was added (2S)-2-methylpiperazine (5 g, 50 mmol), a compound of formula (6), and triethylamine (1.25 g, 12.5 mmol) in chloroform. The mixture was stirred for about 15 hours at room temperature, and then washed with water, the solvent removed from the organic layer under reduced pressure, and the residue purified using column chromatography, to give tert-butyl (3S)-3-methylpiperazinecarboxylate, a compound of formula (7).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(Oc2ccc(NC(=O)c3ccccc3)c(Oc3cccc(C#N)c3)n2)c1
Reaction time: 3 h

Procedure:
To 3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (1.0 g, 2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirring for 3 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3) as eluent gave N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]benzamide; NMR (CDCl3) 8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.