Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:11][C:12]#[N:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[OH:15][N:14]=[C:11]([C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:12]#[N:13]
Reactant: O=N[O-]
Reactant: N#CCC(=O)C=Cc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=NO)C(=O)C=Cc1ccccc1
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
Cinnamoyl acetonitrile (5.1 g; 0.03 mol) is dissolved in 50 ml of acetic acid. 10 ml of H2O are added and the mixture is cooled to 3° C. in an ice/salt bath. Partial precipitation occurs, but the mixture remains well stirrable. Sodium nitrite (4.14 g; 0.06 mol) is added by portions over 10 min, keeping the temperature between 3 and 5° C. Complete solution is observed during addition, but precipitation occurs again towards the end. The mixture is then stirred at 0° C. for 1.5 h. The mixture is diluted with 100 ml of iced water with stirring, the light ochre precipitate is filtered, and washed with ca 100 ml of water. The humid cake is redissolved in ether (100 ml), washed with water, brine and dried over magnesium sulfate. Rotary evaporation and drying affords 2-hydroxyimino-3-oxo-5-phenyl-pent-4-enenitrile (4.7 g; 78%) as a dark yellow solid (mp 144-145° C. dec) which is used without further purification in the next reaction step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.Cl>CN(C=O)C.O>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(C3C(=O)Nc4ccc(C#N)cc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
A solution of 5-cyanooxindole (213 mg, 1.35 mmol), (Tet. Lett., 1987, 28, 4027), in DMF (3 ml) was added dropwise to a suspension of sodium hydride (54 mg, 1.35 mmol, prewashed with hexane) in DMF (2 ml). The mixture was stirred for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (152 mg, 0.45 mmol), (prepared as described for the starting material in Example 5), was added and the mixture was heated at 70° C. for 1 hour. The mixture was allowed to cool and then was diluted with water and adjusted to pH1 with 2M hydrochloric acid. The solution was washed with ether and then basified with aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration, washed with water, ether and dried under vacuum. The solid was purified by flash chromatography eluting with methylene chloride/methanol (90/10 followed by 80/20). The purified solid was dissolved in methylene chloride/methanol and 5M methanolic hydrogen chloride (0.5 ml) was added. The solution was concentrated by evaporation to a total volume of 2 ml and ether (15 ml) was added. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(5-cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (120 mg, 50%).
Reaction SMILES: CS([C:4]1[C:5]2[CH:28]=[CH:27][NH:26][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:9]=1)=O.[NH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:4]2[C:5]3[CH:28]=[CH:27][NH:26][C:6]=3[N:7]=[C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:32][CH2:31]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(S(C)=O)c4cc[nH]c4n3)cc2)CC1
Reactant: NC1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc(Nc3nc(NC4CCC(N)CC4)c4cc[nH]c4n3)cc2)CC1
Temperature: 116 °C
Yield: 13.1 %

Procedure:
To a solution of 1-(4-(4-(4-(methylsulfinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (34 mg, 0.085 mmol) in DMSO (1 mL), 1,4-diaminocyclohexane (cis and trans mixture, 35 mg, 0.31 mmol) and diisopropylethylamine (0.060 mL, 0.35 mmol) were added. The mixture was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (5 mg). MS 449.3 (M+H); UV 208.5, 265.1, 305.5 nm.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCOC(C)(C)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(C2CNC2)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A mixture of 3-(2,2-dimethylmorpholin-4-yl)azetidine-1-carboxylic acid tert-butyl ester (492 mg, 1.82 mmol) and TFA (5 mL) in DCM (10 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-2,2-dimethylmorpholine as a white solid (302 mg, 97%). 1H NMR (CDCl3, 300 MHz): δ 3.73 (t, J=4.8 Hz, 2H); 3.64-3.51 (m, 4H); 3.18-3.11 (m, 1H); 2.23 (t, J=4.8 Hz, 2H); 2.23-2.07 (m, 1H); 2.06 (s, 2H); 1.25 (s, 6H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccccc1Cl
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and 2-chlorobenzylamine (228 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200˜300 mesh, eluting with dichloromethane:methanol, 30:1˜10:1) to afford the crude product (90 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford (2-chloro-benzyl)-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine; hydrochloride. (Yield 25 mg, 14.3%). 1H NMR (300 MHz, CD3OD): δ 8.62 (s, 1H), 8.58 (s, 1H), 8.25 (s, 1H), 7.52-7.38 (m, 4H), 7.23 (brs, 2H), 5.49-5.45 (m, 2H), 4.87 (brs, 2H), 3.56 (brs, 4H), 3.24 (brs, 2H), 2.87 (s, 3H). LC-MS: [M+H]+ 435.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][OH:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12].[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29]Br)=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][O:15][CH2:14][CH:13]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([Cl:3])[CH:5]=2)[C:16]([F:17])([F:18])[F:19])=[CH:23][CH:22]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1Cl
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(F)cc3)c2)C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, 60 mg of sodium hydride (60% oil dispersion) was added to 10 ml of dry THF. A solution of 0.41 g of 2-(3-chloro-4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.43 g of 3-(4-fluorophenoxy)benzyl bromide in 10 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (40:1) mixture] to obtain 255 mg of the desired compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([OH:19])[C:13]3[N:14]([N:16]=[CH:17][CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:20][C:18]1[CH:17]=[N:16][N:14]2[CH:15]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=3)[CH:11]=[C:12]([OH:19])[C:13]=12
Reactant: CC(C)(C)n1cc(-c2cc(O)c3ccnn3c2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)n1cc(-c2cc(O)c3c(Br)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (138 mg, 0.538 mmol) in acetonitrile (6 mL) was added N-bromosuccinimide (105 mg, 0.590 mmol). The solution was stirred at room temperature for 1 h. The reaction was diluted with dichloromethane, washed with water and 2N NaOH. The combined aqueous layers were neutralized and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 3-bromo-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol.
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][P:22](=[O:25])([O-:24])[O-:23].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[C:16]([NH:19][CH2:20][CH2:21][P:22]([OH:25])([OH:24])=[O:23])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1nc(Br)n2Cc1ccccc1
Reactant: NCCP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncnc2c1nc(NCCP(=O)(O)O)n2Cc1ccccc1
Temperature: 110 °C

Procedure:
A mixture of N9-benzyl-8-bromoadenine (1 mmol), aminoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at 110° C. under nitrogen. After 24 h the cooled reaction mixture was purified through preparative HPLC to give N9-benzyl-8-(2-phosphonoethylamino)adenine (3.1). Exact mass calculated for C14H17N6O3P+H+: 349.1178. Found: 349.1180.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:8]=[C:9](O)[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4]>C(#N)C>[Br:1][C:9]1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Reactant: BrBr
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1

Procedure:
After bromine addition, the ice bath was removed. 124 g of 3,5-di-tertbutylphenol (601 mmol) and 140 mL acetonitrile were added in one portion. The orange/white suspension converted into an orange solution upon heating. The mechanical stirrer was replaced by an egg-shape stir bar. The solution was stirred at gentle reflux temperature for three hours.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=1.[C:44](O)(=[S:46])[CH3:45]>O1CCCC1>[C:44]([O:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([Br:34])=[CH:36][CH:37]=1)(=[S:46])[CH3:45]
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(O)=S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=S)OCCc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
5 mmol (1 ml) of DIAD are added to a solution, cooled to 0° C., of 5 mmol (1.32 g) of triphenylphosphine in 16 ml of tetrahydrofuran. After stirring the mixture cold for 15 minutes, there is added dropwise thereto a mixture of 2.5 mmol (0.5 g) of 2-(4-bromophenyl)-1-ethanol and 5 mmol (0.83 ml) of thioacetic acid diluted with 5 ml of tetrahydrofuran. The mixture is stirred cold for a further 10 minutes and then the temperature is brought to ambient temperature for 18 hours. The solvents are evaporated off. The residue is taken up in diisopropyl ether and the precipitate formed is filtered off. The filtrate is concentrated and then purified by chromatography on silica gel. using petroleum ether as eluant, to yield the expected product.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[CH2:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:5])=[CH:22][C:10]=2[CH:11]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: Br[Mg]c1ccccc1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccccc3)ccc2o1

Procedure:
The product from Example 71E and phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.15 (d, 3H), 1.45 (m, 1H), 1.80 (m, 2H), 2.00 (m, 1H), 2.30 (m, 1H), 2.50 (m, 2H), 3.30 (m, 4H), 6.63 (s, 1H), 7.55 (m, 314), 7.65 (m, 1H), 7.80 (m, 3H), 7.98 (d, 1H); MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: [C:1]([O:9]C(C)(C)C)(=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH:6]=[CH2:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCC/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCC=CC(=O)O
Reaction time: 12 h
Yield: 68 %

Procedure:
To a solution of oxalyl chloride (3.36 mL, 39.2 mmol) in CH2Cl2 (100 mL) at −78° C. was added DMSO (5.56 mL, 78.3 mmol). After stirring for 5 min, 4-penten-1-ol (2.00 mL, 19.6 mmol) was added, and after another 15 min Et3N (13.6 mL, 97.9 mmol) was added. The reaction mixture was warmed to rt and then treated with 0.1M HCl. The organic layer was separated, washed with saturated aqueous NaCl solution, dried (MgSO4), and treated with Ph3PCHCO2t-Bu (7.38 g, 19.6 mmol) at rt. The reaction mixture was stirred for 5 h and then treated with saturated aqueous NH4Cl solution and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was filtered through a silica plug (CH2Cl2/pentane 1:1) to give t-butyl (E)-2,6-heptadienoate. To a solution of this ester in CH2Cl2 (40 mL) was added TFA (5 mL) at rt. After stirring for 12 h, the reaction mixture was concentrated under reduced pressure. Purification of the crude product by FC (hexane/EtOAc 15:1→5:1) afforded 2,6-heptadienoic acid 6 (1.67 g, 68%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.12-7.05 (m, 1H), 5.88-5.76 (m, 2H), 5.08-5.02 (m, 2H), 2.37-2.32 (m, 2H), 2.26-2.21 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH2:27]1[O:42][C:41]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:30][C:29]=2[O:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:27]1[O:42][C:41]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([C:19]6[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=6)[CH:14]=5)=[CH:5][CH:4]=4)[CH2:35][CH2:34]3)=[CH:30][C:29]=2[O:28]1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCN(Cc5ccc6c(c5)OCO6)CC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
In DMF (3ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200mg), and to the solution were added 1-(3,4-methylenedioxybenzyl)-piperazine (158mg) and potassium carbonate (382mg). The mixture was stirred at room temperature for 16 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[1-(3,4-methylenedioxybenzyl)-4-piperazinylmethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 57) (266mg) as colorless crystals.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.CCOC(C)=O.[ClH:45].CCOC(C)=O>CCOCC>[ClH:45].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1cccc2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1)c1cccc2ccccc12

Procedure:
Prepared according to the method described in Example 1(b) above from crude (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(1-naphthyl)ethyl]ornithine amide (7.5 g; from step (a) above), EtOAc (150 mL) and HCl/EtOAc (75 mL), 6 hours reaction time. The resulting heterogeneous solution was diluted with Et2O and the solids collected and dried to afford the sub-title compound as a white solid (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH:29]OS([O-])=O.[K+]>>[Cl:1][C:2]1[C:3]([S:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:29])=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Sc3ccc(Cl)cc3)cc2OC1C(F)(F)F
Agent: [K+]
Product: O=C(O)C1=Cc2cc(Cl)c(S(=O)c3ccc(Cl)cc3)cc2OC1C(F)(F)F

Procedure:
Following a procedure similar to that described in Example 128, ethyl 6-chloro-7-[(4-chlorophenyl)thio]-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 192) was treated with OXONE® yielding the products labeled Example 193 and Example 194: mp 213.8–217.4° C. 1H NMR (acetone-d6/300 MHz) 7.91 (s, 1H), 7.83 (d, 2H, J=8.7 Hz), 7.62 (m, 4H), 5.98 (q, 1H, J=6.8 Hz). 19F NMR (acetone-d6/282 MHz) −79.3 (d, J=7.2 Hz). ESLRMS m/z 435 (M−H). ESHRMS m/z 434.9470 (M−H, Calc'd 434.9472). Anal. Calc'd for C17H9Cl2F3O4S: C, 46.70; H, 2.07; Cl, 16.22; S, 7.33. Found: C, 46.80; H, 2.28; Cl, 16.75; S, 7.39.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:14][N:13]([CH2:15][C:16]([OH:18])=O)[C:12](=[O:19])[CH:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:10]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:9]1=2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH:63]1[CH2:68][CH2:67][CH:66]([CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])[CH2:65][CH2:64]1>CN(C)C=O>[CH2:73]([O:72][C:70](=[O:71])[CH2:69][CH:66]1[CH2:67][CH2:68][N:63]([C:16](=[O:18])[CH2:15][N:13]2[CH2:14][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C:9]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:10]=3[CH:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12]2=[O:19])[CH2:64][CH2:65]1)[CH3:74]
Reactant: CC(C)CC1C(=O)N(CC(=O)O)CC(c2ccccc2Br)c2cc(Cl)ccc21
Reactant: CCOC(=O)CC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1CCN(C(=O)CN2CC(c3ccccc3Br)c3cc(Cl)ccc3C(CC(C)C)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg of the compound from Example 6 (0.32 mol) are dissolved in 2 ml of dimethylformamide, and 147 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.39 mol) and 67 μl of diisopropylethylamine (50 mg, 0.39 mol) are added. After stirring at room temperature for 30 min, 80 mg of ethyl 4-piperidylacetate hydrochloride (0.39 mol) and a further 135 μl of diisopropylethylamine (100 mg, 0.77 mol) are added. The reaction mixture is stirred at room temperature overnight and then purified directly by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 130 mg (65% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][CH2:21][CH2:22][N:23]([CH3:33])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:10](=[N:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
t-Butyl 3-[4-(4-bromophenyl)-2-(phenylimino)thiazol-3(2H)-yl]propylcarbamate (250 mg) was dissolved in N,N-dimethylformamide (2 ml), and thereto was added sodium hydride (26 mg, 60% dispersion in oil) under nitrogen atmosphere in an ice bath, and the mixture was stirred for 15 minutes. To the reaction mixture was added methyl iodide (41 μl), and the mixture was warmed to room temperature, and stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (10:1)] to give the title compound (249 mg) as colorless oil.