Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]([O:45][CH3:46])=[O:44])=[O:36])[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][O:27]C2CCCCO2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]([O:45][CH3:46])=[O:44])=[O:36])[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][OH:27])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cccc(OCCOC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cccc(OCCO)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a mixture of methyl (1R,2S)-2-[(N5-[(benzyloxy)carbonyl]-N2-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]benzoyl}-L-ornithyl)amino]cyclopentanecarboxylate (0.64 g), methanol (10 ml), and methylene chloride (6.0 ml) was added p-toluenesulfonic acid monohydrate (0.22 g) under ice-cooling, followed by stirring at room temperature over one night. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[3-(2-hydroxyethoxy)benzoyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.O.[N:25]([O-])=[O:26].[Na+]>CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:3]=1[N:25]=[O:26]
Reactant: O=N[O-]
Reactant: Nc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(OCCOc2ccccn2)nc(N2CCOCC2)c1N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
6-Amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (1.90 g, 6.00 mmol, 1.0 equiv.) was dissolved in 8 mL HOAc, and 8 mL H2O was added. The solution was cooled to 0° C., and NaNO2 (0.414 g, 6.00 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 0° C. for 1 hour. Water (20 mL) was added to dilute the slurry, and the solid was collected by filtration, washed with water, EtOAc (2 mL), then dried to yield 6-amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlino-5-nitroso-pyrimidine (1.47 g, 4.25 mmol, 85% yield) as blue solid. The nitroso compound (1.385 g, 4.00 mmol, 1.0 equiv.) was treated with 5 mL water and enough 2 N HCl so that a clear dark blue solution was formed. Na2S2O4 (2.79 g, 16.00 mmol, 4.0 equiv.) was added in three portions, and the solution was stirred at room temperature for 1 hour. The resulting clear yellow solution was carefully neutralized with cold 2 M NaOH solution, and subjected to EtOAc extraction. 5,6-Diamino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (0.80 g, 2.41 mmol, 60%) was obtained as light yellow solid after usual workup.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH2:19][O:20]CC=C)[O:8][C@@H:7]([O:24][CH2:25][C@H:26]([CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:6]1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)C=C.II.O>O1CCCC1.C(Cl)(Cl)Cl.[Ir]>[CH2:59]([O:58][C@@H:6]1[C@@H:5]([OH:4])[C@@H:10]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:9]([CH2:19][OH:20])[O:8][C@H:7]1[O:24][CH2:25][C@H:26]([CH2:42][O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: C=CCOC[C@H]1O[C@@H](OC[C@H](COCCCCCCCCCCCCCC)OCCCCCCCCCCCCCC)[C@H](OCc2ccccc2)[C@@H](OCC=C)[C@H]1OCc1ccccc1
Agent: [Ir]
Agent: II
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Yield: 87.4 %

Procedure:
Iridium complex (1,5-cyclooctadiene bis(methyldiphenylphosphine)iridium hexafluorophosphate, 112 mg, 0.096 mmol) was suspended in tetrahydrofuran (5 mL), and activated by stirring under H2 flow. To this solution, Compound 5 (864 mg, 0.95 mmol) dissolved in tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 2 hours under argon gas flow. Then, iodine (484 mg), water (24.7 mL) and tetrahydrofuran (15 mL) were added thereto, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was diluted with chloroform, and washed successively with saturated sodium thiosulfate solution, saturated aqueous sodium hydrogencarbonate, and saturated brine. The chloroform layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:EtOAc=5:2) to obtain Compound 6 (686.6 mg, 87.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[H-].[Na+].CCOCC>CN(C=O)C>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])=[C:7]2[CH3:12])=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(-c2c(C)[nH]c3ccc(OC)cc23)c1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. mixture of the indole from Step 3 (285 mg, 0.96 mmol) and 4-bromobenzyl bromide (310 mg, 1.05 mmol) in DMF (5 mL) was added NaH (44 mg, 1.1 mmol). The mixture was warmed up to r.t. and stirred for 1.5 h after which time it was poured on a mixture of ice water and Et2O. The organic layer was washed with brine, dried with MgSO4 and the solvent removed to yield a residue which was used as such in the next step.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:51])([F:50])[C:14]1[CH:15]=[C:16]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:17][N:18]1[C:22]([N:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)=[C:21]([C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[C:32]([CH3:42])=[N:31][N:30]=2)[N:20]=[N:19]1>C1COCC1>[F:51][C:13]([F:50])([F:12])[C:14]1[CH:15]=[C:16]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[CH2:17][N:18]1[C:22]([N:23]2[CH2:28][CH2:27][S:26](=[O:9])[CH2:25][CH2:24]2)=[C:21]([C:29]2[N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:41])[C:32]([CH3:42])=[N:31][N:30]=2)[N:20]=[N:19]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2N2CCSCC2)n1Cc1ccccc1Cl
Solvent: C1CCOC1
Product: Cc1nnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2N2CCS(=O)CC2)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add m-chloro-perbenzoic acid (29 mg, 0.13 mmol) to a solution of 4-{3-(3,5-bis-trifluoromethyl-benzyl)-5-[4-(2-chloro-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-3H-[1,2,3]triazol-4-yl}-thiomorpholine (69 mg, 0.11 mmol) in THF (1 mL) at −78° C. After 30 minutes, quench with 1N Na2S2O3 at −78° C., warm to RT. Dilute with 20% i-PrOH/CHCl3, wash with 1N HCl, saturated NaHCO3 solution, and brine. Dry the combined organic layers over MgSO4 and concentrate. Purify the residue by flash chromatography on silica gel eluting with 0-4% MeOH/CHCl3 to afford the title compound: MS(IS) 618 (M+1). TLC: Rf=0.18 (5% MeOH/CHCl3).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10]([CH:17]([Cl:22])[C:18]([F:21])([F:20])[F:19])([C:13]([F:16])([F:15])[F:14])[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.[H][H].[Pd]>[NH2:1][C:4]1[C:12]2[O:11][C:10]([CH:17]([Cl:22])[C:18]([F:21])([F:19])[F:20])([C:13]([F:14])([F:15])[F:16])[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2

Procedure:
84 g of 4-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 7 were dissolved in 500 ml of tetrahydrofuran and hydrogenated with 15-20 bar of hydrogen for 5 hours at room temperature on 5 g of palladium-on-charcoal (5%). The mixture was then filtered and the filtrate was concentrated and distilled under vacuum. The yield was 31 g (40% of theory) and the boiling point was 70° C. at 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 19F NMR: -68.6 and -81.5 ppm. 1H NMR: 4.69 ppm.
Reaction SMILES: [ClH:1].Cl.C(OC1C=CC([CH:12]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=CC=1OC(F)(F)F)C.[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38](C(C2(O)CCCCC2)CN2CCN(C(OC(C)(C)C)=O)CC2)=[CH:37][C:36]=1[O:63][C:64]([F:67])([F:66])[F:65])[CH3:33]>>[ClH:1].[ClH:1].[CH2:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:13]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH2:12][C:20]2([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:37][C:36]=1[O:63][C:64]([F:65])([F:66])[F:67])[CH3:33]
Reactant: CCOc1ccc(C(CN2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Reactant: CCOc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1OC(F)(F)F
Agent: Cl
Product: CCOc1ccc(C(CC2(O)CCCCC2)N2CCNCC2)cc1OC(F)(F)F

Procedure:
In an analogous manner to Example 135, step 4 1-{1-[4-ethoxy-3-(trifluoromethoxy)phenyl]-2-piperazin-1-ylethyl}cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-[4-(ethoxy)-3-(trifluoromethoxy)phenyl]-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. MS (ES) m/z 417.1; HRMS: calcd for C21H31F3N2O3+H+, 417.23595; found (ESI, [M+H]+), 417.2354
Reaction SMILES: [Cl:1][C:2]1[N:19]=[C:5]2[C:6]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>ClCCCl>[Cl:1][C:2]1[N:19]=[C:5]2[C:6]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1C#Cc1cccn2nc(Cl)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccccc1C#Cc1cccn2nc(Cl)nc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
189 b) To a cooled solution of 2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenylamine (840.0 mg, 3.126 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) in 1,2-dichloroethane (10 mL) in a ice/water bath at 5° C. was added dropwise methanesulfonyl chloride (0.64 mL, 8.2 mmol). The mixture was stirred 1 hour at 5° C. then at room temperature overnight. 0.1N hydrochloric acid (50 mL) was added to reaction mixture, stirred for 20 minutes then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, filtered and evaporated to a tan solid (1.34 g). To a suspension of the tan solid (1.34 g) from in tetrahydrofuran (10 mL) was added 1.0 M of tetra-n-butylammonium fluoride in tetrahydrofuran (12.50 mL, 12.50 mmol). The mixture was stirred at room temperature for 18 hours. The volatiles were evaporated to yield a viscous oil. Hydrochloric acid (2N, 30 mL) was added to viscous oil and stirred then was extracted with ethyl acetate (3×50 mL). The combined organic layer were dried over magnesium sulfate, filtered and evaporated. The residue was purified via chromatography (silica gel column 40 g 20%→100% ethyl acetate:hexane). N-[2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenyl]-methanesulfonamide was isolated as a tan solid (0.90 g, 83%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 7.93 (br s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.1 Hz, 1H), 3.17 (s, 3H). MS=347, 349 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 69 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (360 mg, 1.15 mmol) was reacted with tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (480 mg, 1.73 mmol) to afford the desired product (440 mg, 69%) as an orange solid: ESI MS m/z 554 [C27H32BrN5O3+H]+.
Reaction SMILES: C(C1C=C2C(=CC=1)N(C)C=C2C1CCC(=O)CC1)#N.O1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[N:32]([CH2:41][CH2:42][CH3:43])[CH:31]=3)[CH2:26][CH2:25]2)[O:23]CC1>>[C:39]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:41][CH2:42][CH3:43])[CH:31]=[C:30]2[CH:27]1[CH2:28][CH2:29][C:24](=[O:23])[CH2:25][CH2:26]1)#[N:40]
Reactant: CCCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Agent: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Product: CCCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Yield: 72.6 %

Procedure:
This compound was prepared in the manner described above for intermediate 6a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-n-propyl-indole (2.64 g, 8.2 mmol) to afford 1.67 g (73%) of the title compound as a white solid: mp 103-104° C.; MS EI m/e 280 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.O>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3[nH]cnc23)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,6-Dichloropurine [CAS No. 5451-40-1] (5.0 g) was dissolved in acetonitrile (70 mL), and then piperazine-1-carboxylic acid t-butyl ester (4.93 g) and triethylamine (4.1 mL) were added to this solution, and the reaction solution was stirred at room temperature for 22 hours. Water (200 mL) was added to the reaction solution, and this was stirred at room temperature for one hour, and then the white precipitate was collected by filtration. The white solid obtained was washed with water and hexane to give the title compound (8.5 g).
Reaction SMILES: [Br-:1].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][NH2:26].C(O)C>>[BrH:2].[Br-:1].[CH3:25][NH:26][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN
Agent: [Br-]
Solvent: CCO
Product: Br
Product: CNCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
(3-bromopropyl)(triphenyl)phosphonium bromide (5.7 g, 12 mmol) was treated with 33% methylamine in ethanol (40 mL, 400 mmol) in a sealed tube. The mixture was heated at 100° C. for 1.5 hours and cooled to room temperature. The volatiles were removed, and the resultant semi-solid was taken up in methanol (23 mL) and heated at 50° C., at which point all the solids dissolved. The temperature was lowered to 40° C., and methyl t-butyl ether (68 mL) was added drop wise, giving a slurry. The slurry was cooled to room temperature and filtered, washing the product cake with methyl t-butyl ether (20 mL) to afford the title compound (4.0 g) in a 66% yield as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:16]([CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:31])=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:28][N:27]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:26][CH2:25][N:24]1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:31])=[O:30])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1Cc1ccccc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)C(Cc2ccccc2)C1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 2-benzyl-1-(2-naphthylsulphonyl)piperazine to give 2-benzyl-1-(2-naphthylsulphonyl)4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 70% yield; m.p. 186-188° C.;
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][O:11][C:12](=[O:19])[C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:19])[C:13]([CH3:18])([CH3:17])[CH2:14]/[CH:15]=[N:8]/[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9]
Reactant: COC(=O)C(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: COC(=O)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 98.1 %

Procedure:
Step D In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.09 g, 8.32 mmol) was reacted with 2,2-dimethyl-4-oxo-butyric acid methyl ester (1.2 g, 8.32 mmol) in CH2Cl2 at room temperature for 18 h to give 4-[(E)-tert-butoxycarbonylmethylimino]-2,2-dimethyl-butyric acid methyl ester as a colorless oil (2.1 g, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[OH:7].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)[OH:7]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccco1)C1CCCN1
Yield: 7.2 %

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-furaldehyde (2.9 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (200 mL). The separated organic layer is washed with saturated aq. ammonium chloride (3×50 mL) followed by brine (50 mL), dried (MgSO4), and concentrated The crude product is purified by column chromatography (heptane/EtOAc, 8/1; 5/1) to afford 4.97 g of 2-furyl(N-Boc-pyrrolidin-2-yl)methanol as a mixture of diastereomers. The resulting 2-furyl(N-Boc-pyrrolidin-2-yl)methanol (4.43 g) is dissolved in dichloromethane (200 mL) and trifluoroacetic acid (30 mL) is added. The mixture is poured into a 1 M solution of sodium hydroxide. The organic layer is separated and washed with saturated aq. sodium bicarbonate (2×100 mL). The aqueous layers are extracted with dichloromethane (4×50 mL) and the combined organic layers are concentrated. The crude product is purified by column chromatography (CH2Cl2/methanol/NH4OH, 95/5/1; 90/10/1). The resulting oil is distilled in a Kugelrohr apparatus (0.175-200° C., 0.2 Torr) to afford 0.20 g of the title compound as a mixture of diastereomers. Physical characteristics. MS (ESI+) m/z 168 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>CN1CCCC1=O>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:21]1[CH:22]=[C:17]([Cl:16])[C:18]([N+:27]([O-:29])=[O:28])=[CH:19][C:20]=1[N+:24]([O-:26])=[O:25])[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 1.60 mmol) was added to a mixture of tert-butyl ethyl malonate (300 mg) in 1-methyl-2-pyrrolidinone (3 mL) and was followed by 1,5-dichloro-2,4-dinitrobenzene (0.45 g). The reaction mixture was stirred for 15 minutes and was then quenched by addition of a diluted aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/hexane, 5/95 to 15/85) to give 0.4 g of 2-(5-chloro-2,4-dinitro-phenyl)-malonic acid tert-butyl ester ethyl ester.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].B(Br)(Br)Br.C(OCC)(=O)C.O>ClCCl>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (26.2 g) in dichloromethane (100 mL) was added dropwise boron tribromide (1.0 M dichloromethane solution, 170 mL) at 0° C. After stirring for 18 hr, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (22.1 g, 87%) as a colorless solid.