Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(=O)([O-])[O-].[Na+].[Na+]>[F:5][C:6]1[CH:15]=[C:14]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
With cooling with ice, fuming nitric acid (110 ml) was gradually added to methyl 2-fluoro-4-[(2-pyridinylcarbonyl)amino]benzoate (27.7 g), and stirred at room temperature for 1.5 hours. With cooling with ice, the reaction liquid was gradually added to an aqueous solution (2000 ml) of sodium carbonate (138 g), and the formed solid was taken out through filtration. After dried under reduced pressure, the entitled compound was obtained as a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([O:19]CC)=O.C(O)C.O1CCOCC1.O.[NH2:32][NH2:33]>O>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([NH:32][NH2:33])=[O:19]
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: NNC(=O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reaction time: 48 h

Procedure:
A mixture of ethyl anthraquinone-2-carboxylate (4.83 g), 25 ml of ethanol, 50 ml of dioxane and 7 ml of hydrazine hydrate is boiled under argon for 48 hours. It is poured into water and the product is isolated by filtration and dried at 60° C. in a vacuum oven. Crystallization of the crude product (4.05 g) from dimethylformamide/chloroform gives 3.01 g of product with a melting point (m.p.) of 250° C./decomposition.
Reaction SMILES: C(OC([NH:8][C:9]([CH2:31][CH3:32])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1)[CH2:10][OH:11])=O)(C)(C)C.[ClH:33]>O1CCCC1.O1CCOCC1>[ClH:33].[NH2:8][C:9]([CH2:31][CH3:32])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:16][CH:15]=1)[CH2:10][OH:11]
Reactant: CCC(CO)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCC(N)(CO)CCc1ccc(OCCCCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butanol (3.2 g) in tetrahydrofuran (10 ml) was added a solution of 4M hydrochloric acid in dioxane (10 ml) and the mixture was stirred for 3 hours. The solvent was distilled away to give the subject compound (3 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([C:9]2[CH:18]=[C:17]3[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:13]1[C:12]2[C:17](=[CH:18][C:9]([C:4]3[C:3]([C:2]([F:21])([F:20])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc(-c3ncccc3C(F)(F)F)ccc12
Product: FC(F)(F)c1cccnc1-c1ccc2c(Cl)ccnc2c1

Procedure:
Reflux 7-[3-(trifluoromethyl)pyridin-2-yl]quinolin-4-ol (145 mg) for 2 hours in POCl3 (2 mL). Evaporate the solvent, then carefully neutralize with saturated NaHCO3, and extract with EtOAc. Dry-over Na2SO4, concentrate under vacuum to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.O[N:14]1[C:18](=O)[CH2:17][CH2:16][C:15]1=O.[CH:21]1([N:27]=C=NC2CCCCC2)CCCC[CH2:22]1.NC(N)=O>C(OCC)C.C(#N)C>[CH2:15]([N:14]([CH2:22][CH2:21][NH:27][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12])[CH2:18][CH3:17])[CH3:16]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Agent: NC(N)=O
Solvent: CCOCC
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4.83 g indol-2-carboxylic acid and 3.8 g N-hydroxy-succinimide in 60 ml abs. acetonitrile is added at room temperature a solution of 6.8 g dicyclohexyl-carbodiimide in 30 ml abs. diethyl ether, whereby the temperature rises rapidly to 33°. The suspension goes into solution and urea precipitates. The mixture is stirred at room temperature for 3 hours, filtered and the filtrate washed with acetonitrile. The filtrate is treated dropwise with 8.5 ml (60 mM) diethyl-aminoethyl amine, whereby the temperature rises from 20° to 28°. The mixture is left overnight and then is partitioned between 1N aqueous sodium carbonate solution and CH2Cl2. The organic phase is evaporated to give the title compound, recrystallised from CH2Cl2 /hexane m.p. 133°-134°.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]2=[S:15].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[NH:4]1[CH:3]=[CH:2][N:1]=[C:10]1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)=[S:15]
Reactant: S=C1Nc2ccccc2Cc2nccn21
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 2.1 g of 11H-imidazo[1,2-c][1,3]benzodiazepine-5(6H)-thione, 23 ml of methylene chloride and 1.0 g of 1-methylpiperazine is stirred at room temperature for 15 hours. The crystalline product formed is filtered off and washed with methylene chloride, to yield 1-[2-(2-imidazolylmethyl)phenylthiocarbamoyl]-4-methylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[N:19]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([O:14][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]([F:29])([F:27])[F:28])=[CH:21][CH:22]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(C)c12
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a mixture of methyl(6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (150 mg) and THF (dry) (5 mL) were added (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (133 mg), tri-n-butylphosphine (0.204 mL) and ADDP (192 mg) at room temperature. The mixture was stirred at room temperature for 4 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (238 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]5[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=5[Cl:32])=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc(Cl)cc3Cl)cc2)C1
Temperature: 110 °C
Yield: 22.2 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), (2,4-dichlorophenyl)boronic acid (98 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was heated in an aluminum block at 110° C. for 2 h. The cooled reaction was diluted with ethanol then evaporated under reduced pressure to a yellow residue. The residue was triturated from methanol and the filtered methanol layer was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-70% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired product fractions were combined and evaporated in vacuo to a residue that was recrystallized from hexanes/ethyl acetate to afford the title compound as a white solid (26 mg, 21.8%). MS(ES)+ m/e 457.0, 459.2 [M+H]+, chlorine pattern.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29](NCC)[CH3:30].C(Br)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH2:29][CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCNCC
Reactant: COc1ccc(CCNCCCOc2noc(-c3ccccc3)n2)cc1OC
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCN(CCCOc1noc(-c2ccccc2)n1)CCc1ccc(OC)c(OC)c1
Temperature: 50 °C

Procedure:
2 g of 3-{3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propyloxy}-5-phenyl-1,2,4-oxadiazole (for preparation, see Example 69) were dissolved in 20 ml dimethylformamide. 0.9 ml of diethylamine and 0.6 g ethyl bromide were added to the solution and the reaction mixture was heated at 50° C. for 3.5 hours. For workup, the reaction mixture was then concentrated to dryness and the residue dissolved in dichloromethane. A sufficient quantity of water was added to the solution for a clear phase separation to occur. The mixture was shaken and the organic phase separated out, dried with sodium sulfate, filtered, and concentrated. The crude oily title compound obtained was refined by medium-pressure chromatography on fine-grained silica gel using ethyl acetate/methanol/concentrated aqueous ammonia solution, ratio 9:1:0.05, as the eluent. 1.3 g of the title compound were obtained as a yellow oil.
Reaction SMILES: CC(C)CC(O)C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([C:20](=[O:22])[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>[Cl-].[Cl-].[Zn+2].OCC(CO)O>[F:8][C:9]([F:23])([F:24])[C:10]1[CH:11]=[C:12]([C@@H:20]([OH:22])[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)CC(C)O
Solvent: OCC(O)CO
Product: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 24 h

Procedure:
For the conversion, a mixture of 1 mL of a buffer (100 mM TEA, pH=7, 10% glycerol, 1 mM ZnCl2), 3 ml 4-methyl-2-pentanol, 1 ml 1-[3,5 bis-(trifluoro-methyl)phenyl]ethane-1-one, 2 mg NAD and 0.7 kU recombinant oxidoreductase from Microbacterium spec. DSMZ 20028 was incubated at room temperature for 24 h with constant thorough mixing. After 24 h, more than 90% of the 1-[3,5 bis-(trifluoro-methyl)phenyl]ethane-1-one used had been reduced to (1S)-1[3,5-bis(trifluoromethyephenyl)ethane-1-ol. Subsequently, the 4-methyl2-pentanol phase containing the product was separated from the aqueous phase, filtered, and the product (1S)-1[3,5-bis(trifluoromethyl)phenyl]ethane-1-ol was obtained by distillation. The crude product (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethane-1-one obtained in this manner exhibited an enantiomeric excess of >99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8](=O)[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[C:14]([OH:18])[CH:13]=[C:12]([CH3:19])[CH:11]=3)=[CH:4][CH:3]=1.O.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:8]1[C:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:16]([CH3:17])[C:15]2[C:14]([OH:18])=[CH:13][C:12]([CH3:19])=[CH:11][C:10]=2[N:9]=1
Reactant: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(Cl)nc2c1

Procedure:
A solution of 3-(4-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1H-quinolin-2-one (1.8 g) in phosphorus oxychloride (9.0 mL) was heated at 180° C. in a microwave reactor for 15 minutes. The solution was poured onto a mixture of ice and water and the resulting precipitate collected by filtration, washed with water and then dried to afford title compound, 2.3 g.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=1.CCN(CC)CC.O>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)C1CC1)c1cc(Br)ccn1
Yield: 98.8 %

Procedure:
Add cyclopropanecarbonyl chloride (1.42 g, 13.68 mmol) slowly to a solution of tert-butyl N-(4-bromo-2-pyridyl)carbamate (1.24 g, 4.6 mmol), Et3N (1.38 g, 13.68 mmol) in DCM (15 mL) at 0° C. After addition, stir the reaction at room temperature for 2 hrs. Pour the reaction mixture to water (50 mL), extract with EtOAc (15 mL×3), combine the organic layers and wash with brine (100 mL). Dry over anhydrous Na2SO4; concentrate under reduced pressure to give the crude product (1.55 g) which is used without further purification. MS: (M+1): 241.0
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].C(Br)C=C.[Cl:10][C:11]1[S:15][C:14]([CH2:16]Cl)=[CH:13][CH:12]=1>CCOCC>[Cl:10][C:11]1[S:15][C:14]([CH2:16][CH2:3][CH:2]=[CH2:1])=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCCc1ccc(Cl)s1
Temperature: 0 °C
Yield: 195.9 %

Procedure:
A solution of allyl magnesium bromide (from 14.6 g of magnesium and 24.2 g (0.2 M) of allyl bromide) in 100 ml ether is added dropwise with stirring to 29.9 g of 5-chloro-2-chloromethylthiophene in 10 ml ether over half an hour and the resulting mixture heated under reflux overnight. The mixture is then poured into 300 ml ice cold dilute sulfuric acid, the ether layer separated and the aqueous phase extracted with 200 ml of ether. The combined ethereal solutions are washed with aqueous potassium carbonate, dried over MgSO4 and evaporated to give crude 4-(5-chloro-2-thienyl)-1-butene as a yellow oil (34 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1.Cl.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=[S:17])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(c2cccc(Br)n2)COCC(=O)N1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(Br)n2)COCC(=S)N1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 5-(6-bromo-pyridin-2-yl)-5-methyl-morpholin-3-one (4.65 g, 17.15 mmol) and P2S5 (4.57 g, 20.58 mmol) in pyridine (60 ml) was stirred at 80° C. under N2 for 6 h. The reaction mixture was cooled to rt and diluted with 0.5N aq. HCl and EtOAc. The phases were separated and the aq. phase was twice extracted with EtOAc. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was obtained as a pale yellow solid after flash chromatography on silica gel (cyclohexane/EtOAc 100:0 to 75:25). HPLC RtH4=0.89 min; ESIMS: 287, 289 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 11.15 (s, 1H), 7.86-7.82 (m, 1H), 7.61 (dd, 1H), 7.39 (dd, 1H), 4.44-4.34 (d, 2H), 4.13 (d, 1H), 3.74 (d, 1H), 1.52 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH:14]=[C:10]([Cl:9])[N:11]=[CH:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Clc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2cnc(Cl)c2)ncn1
Yield: 54.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.8 g, 12 mmol), 4-chloro-1H-imidazole (1.23 g, 12.00 mmol), and cesium carbonate (3.91 g, 12.00 mmol) was stirred in DMF (8 mL) at room temperature for 18 h. The reaction was diluted into water and extracted with EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 120 g silica gel cartridge with 0 to 40% ethyl acetate in hexane to yield 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (1.41 g, 54.6% yield). The positive identification of the 4-chloroimidazole regioisomer was accomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.86 (1H, d, J=0.76 Hz), 8.33 (1H, d, J=1.51 Hz), 7.54 (1H, d, J=1.76 Hz), 7.30 (1H, d, J=0.76 Hz). LCMS: RT=0.81 min, MH+=215.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[N:19]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][N:43]([CH2:50][C@H:51]1[CH2:56][CH2:55][C@H:54](N)[CH2:53][CH2:52]1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:42][N:43]([CH2:50][C:51]1([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]([NH2:19])=[O:17])[S:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2sc(C=CC(N)=O)cc2C2(CN(C)C3CCOCC3)CCCCC2)cc1
Reaction time: 2 h
Yield: 66.4 %

Procedure:
Into a suspension of (E)-3-[5-(4-methylphenyl)-thiophen-2-yl]acrylic acid (200 mg) and 1-hydroxybenzotriazole (166 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (235 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (368 mg), triethylamine (0.23 ml) and 1,8-diazabicyclo[5,4,0]-7-undecene (374 mg) in acetonitrile (10 ml), and the resulting mixture was stirred further for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethanol/ethyl acetate) to obtain trans-(E)-N-[4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethylcyclohexyl]-3-[5-(4-methylphenyl)thiophen-2-yl]acrylamide (compound 71) (246 mg) as yellow crystals.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C([C:41](=[O:60])[N:42]([C:51]7[S:52][C:53]8[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=8[N:55]=7)[CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[OH:92][CH2:93][CH2:94][CH2:95][C:96]1[C:97]([C:132]([O:134][C:135]([CH3:138])([CH3:137])[CH3:136])=[O:133])=[N:98][C:99]([N:102]2[CH2:111][CH2:110][C:109]3[C:104](=[C:105](C(=O)/N=C4\SC5C=CC=CC=5N\4COCC[Si](C)(C)C)[CH:106]=[CH:107][CH:108]=3)[CH2:103]2)=[CH:100][CH:101]=1.[CH3:139][N:140]([CH3:157])[CH2:141][CH2:142][O:143][C:144]1[CH:145]=[CH:146][C:147]([C:150]2[CH:155]=[CH:154][C:153](O)=[CH:152][CH:151]=2)=[N:148][CH:149]=1>>[S:52]1[C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=[C:51]1[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:48])[CH3:49])[C:41]([C:105]1[CH:106]=[CH:107][CH:108]=[C:109]2[C:104]=1[CH2:103][N:102]([C:99]1[N:98]=[C:97]([C:132]([O:134][C:135]([CH3:138])([CH3:137])[CH3:136])=[O:133])[C:96]([CH2:95][CH2:94][CH2:93][O:92][C:153]3[CH:152]=[CH:151][C:150]([C:147]4[CH:146]=[CH:145][C:144]([O:143][CH2:142][CH2:141][N:140]([CH3:157])[CH3:139])=[CH:149][N:148]=4)=[CH:155][CH:154]=3)=[CH:101][CH:100]=1)[CH2:111][CH2:110]2)=[O:60]
Reactant: CN(C)CCOc1ccc(-c2ccc(O)cc2)nc1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCCO
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN(C)CCOc1ccc(-c2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)N(COCC[Si](C)(C)C)c6nc7ccccc7s6)c5C4)nc3C(=O)OC(C)(C)C)cc2)nc1

Procedure:
Compound 95A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 94F and compound 90B, respectively: ESI (+)LC/MS: 915 (M+H2O—NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=1.[CH:20]1(N(C2C=CC(N)=CN=2)C)CCCCC1>>[CH3:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[N:1]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][N:12]=1)[CH3:20]
Reactant: CN(c1ccc(N)cn1)C1CCCCC1
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Cc1ccc(N(C)c2ccc(N)cn2)c(C)c1

Procedure:
2-(N-(2,4-dimethylphenyl)-N-methylamino)-5-amino-pyridine was prepared from 1-amino-2,4-dimethylbenzene and 2-chloro-5-nitropyridine in the same manner as 2-(N-Cyclohexyl-N-methylamino)-5-amino-pyridine was prepared.