Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:8]([CH2:11]O)[CH2:9]O)[CH:5]=C[CH:7]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[CH:21]([N:28]1[CH2:9][CH:8]([C:4](=[CH2:5])[C:3]([CH2:13][CH3:14])=[C:2]([Br:1])[CH3:7])[CH2:11]1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1c(Br)cccc1C(CO)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C(CC)=C(C)Br)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 24.5 %

Procedure:
A mixture of 2-(3-bromo-2-ethyl-phenyl)-propane-1,3-diol (D128) (8 g, 30.87 mmol) in 150 mL of CH3CN was added diphenylmethylamine (5.66 g, 30.87 mmol), trifluoromethanesulfonic anhydride, DIPEA at 0° C., and the reaction mixture was stirred for 12 hr at 70° C., then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to afford 1-benzhydryl-3-(3-bromo-2-ethyl-1-methylene-but-2-enyl)-azetidine (D129) (3 g,).
Reaction SMILES: C[C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CI.[C:16](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:2]=[C:10]([CH3:11])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: COc1c(C(=O)O)ccc(C)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 2-methoxy-4-methylbenzoic acid (1.5 g, 9.0 mmol, 1 eq) was dissolved in DMF, methyl iodide (0.86 ml, 13.5 mmol, 1.5 eq) was added to it followed by the addition of potassium carbonate (3.11 g, 22.5 mmol, 2.5 eq). The above mixture was stirred at room temperature for 12 h. Finally, the reaction mixture was passed through celite. The filtrate was evaporated and water was added and the product was extracted with ethyl acetate. The organic layer was washed with water and concentrated. Yield: 1.6 g (98%). 1H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 6.77 (s, 1H), 6.79 (d, 1H), 7.14 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14](OC)=[O:15])[C:8]=2[N:7]=[C:6]1[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].[CH3:31][Li].[CH2:33]1[CH2:37][O:36]CC1>CCOC(C)=O>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[CH2:6][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([CH2:31][CH:37]([OH:36])[CH3:33])=[O:15])[C:8]=2[N:7]=[C:4]1[C:3]1[C:2]([F:1])=[CH:29][CH:28]=[CH:27][C:26]=1[F:30]
Reactant: [Li]C
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Solvent: CCOC(C)=O
Product: CC(O)CC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To methyl 1-(2,6-difluorobenyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 102) (1.02 g, 2.46 mmol) suspended in THF (5 mL) was added 1.4 M methyl lithium (0.95 mL). After 0.5 h, the reaction was diluted with EtOAc and washed with NaHSO4 (10% soln) and NaCl(sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 1:1 ethylacetate/hexane and recrystallization from hexane, yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-benzimidazoyl-2-propanol (0.11 g, 0.27 mmol, 55% yield). M.p. 149-150° C. 1H-NMR (200 MHz, CD2Cl2): δ 7.55 (m, 1H, H4′), 7.48 (d, J=8.1 Hz, 1H, H5), 7.25 (m, 2H, H6,4″), 7.16 (dd, J=1.1, 7.6 Hz, 1H, H7), 7.10 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.82 (s, 1H, OH), 5.37 (s, 2H, CH2PhF2), 1.67 (s, 6H, CH3). Anal. (C23H18F4N2O) C,H,N.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[CH3:20])=[O:8])[CH3:4].Br[CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24].O>O1CCCC1>[CH3:26][O:25][C:23]([CH:22]([N:9]([C:7](=[O:8])[CH2:6][O:5][CH2:3][CH3:4])[C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[CH3:20])[CH3:27])=[O:24]
Reactant: CCOCC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCC(=O)N(c1c(C)ccc([N+](=O)[O-])c1C)C(C)C(=O)OC
Temperature: 55 °C

Procedure:
To a solution of 3 g of 55% sodium hydride in 70 ml of anhydrous tetrahydrofuran saturated with nitrogen is added dropwise, at room temperature, with stirring and while simultaneously introducing nitrogen, a solution of 16 g N-ethoxyacetyl-2,6-dimethyl-3-nitroaniline in 30 ml of the same solvent. After the weakly exothermic reaction has subsided, the mixture is heated to 55° C. and 12.7 g of methyl 2-bromopropionate in 20 ml of tetrahydrofurane are added. During this addition the temperature rises to 60° C. The mixture is stirred for 12 hours at 55° C., then cooled to room temperature, poured into 100 ml of water and extracted with two 100 ml portions of ethyl acetate. The combined extracts are washed with water, dried over sodium sulfate, and excess solvent is removed in vacuo. The oily crude product is purified by column chromatography over silica gel, using a 1:1 mixture of chloroform/diethyl ether as eluant. Fractions 5 to 30 are combined and the eluant is removed in vacuo. Compound 31 is a viscous oil with a refractive index of nD24 =1.5325.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[CH:7][CH:8]=1)[OH:6].[OH-].[Na+].[CH2:12](Cl)Cl>C(OCC)(=O)C>[CH2:12]1[O:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[O:9]1
Reactant: ClCCl
Reactant: Cc1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Yield: 71.9 %

Procedure:
A mixture of 4-methylcatechol (26.0 g, 209.4 mmol) and NaOH (18.4 g, 461.0 mmol) in CH2Cl2 (40.0 mL) was heated to 100° C. under nitrogen for 2 hours. The solution was allowed to cool to ambient temperature and diluted with ethyl acetate (500 mL). The mixture was washed with NaHCO3 (200 mL) and H2O (2×200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude oil. Flash chromatography eluting with hexane (100%) gradient to ether/hexane (1:1) afforded the title intermediate as a colorless oil 20.5 g (71.9%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].OS(O)(=O)=O.N([O-])=O.[Na+].[Na+].[I-:25]>O>[I:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: [I-]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(I)c(C(F)(F)F)c1
Yield: 94.6 %

Procedure:
To a mixture of 3.1 g (15.0 mmol) of 2-amino-5-nitrobenzotrifluoride in 60 mL of 40% (v/v) H2SO4 stirred in an ice-bath was added dropwise a solution of 2.1 g (30.4 mmol) of NaNO2 in 10 mL of H2O. The resulting yellow solution was stirred in an ice-bath for 1 h and it was added dropwise into a well stirred solution of 10 g of NaI in 250 mL of H2O cooled in an ice bath. Gas releasing and precipitate was observed. The mixture was stirred overnight at 25° C., filtered and washed by water, and dried to leave pale yellow solid (4.5 g, 94%), mp 81°-82° C. 1H NMR (CDCl3), 8.047 (dd, 1), 8.272 (d, 1), 8.483 (d, 1).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]2[CH2:36][C@H:35]3[N:37]([CH3:38])[C@H:31]([CH2:32][CH2:33][CH2:34]3)[CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:41][CH3:42].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO.O>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[NH:6][C:5]3[C:11]2=[N:12][C:2]([NH:21][C:22]2[CH:40]=[CH:39][C:25]([C:26]([NH:28][CH:29]4[CH2:36][C@H:35]5[N:37]([CH3:38])[C@H:31]([CH2:32][CH2:33][CH2:34]5)[CH2:30]4)=[O:27])=[CH:24][C:23]=2[O:41][CH3:42])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)NC2C[C@H]3CCC[C@@H](C2)N3C)ccc1N
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2C[C@H]3CCC[C@@H](C2)N3C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2
Temperature: 160 °C
Yield: 54.3 %

Procedure:
10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 127; 62 mg, 0.21 mmol) and 4-amino-3-methoxy-N-[(1S,5R)-9-methyl-9-azabicyclo[3.3.1]non-7-yl]benzamide (Intermediate 161; 63 mg, 0.21 mmol) were taken up in 4-methyl-2-pentanol (2 mL) and p-toluenesulphonic acid monohydrate (81 mg, 0.42 mmol) added. The reaction mixture was heated at 160° C. by microwave irradiation for 60 minutes. The cooled reaction mixture was treated with a mixture of methanol & water (5:2 v/v, 7 mL). The resultant solution was loaded onto an SCX-3 cartridge (5 g) pre-wet with methanol. The cartridge was washed through with Methanol (˜40 mL). Products were then eluted with 2M ammonia in methanol (˜30 mL). The ammoniacal solution was evaporated and the resultant material was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (64 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.S(=O)(=O)(O)[OH:17].[OH-:21].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:17])=[O:21])=[C:4]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: N#Cc1ccc(Cl)cc1NC1CCCC1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1NC1CCCC1

Procedure:
4-Chloro-2-(cyclopentylamino)benzonitrile and concentrated sulfuric acid were added to water, followed by stirring while heating under reflux. The reaction liquid was neutralized by adding sodium hydroxide to the reaction liquid, and the organic layer was extracted with chloroform to obtain 4-chloro-2-(cyclopentylamino)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Cl[CH:12]([O:14]C)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[CH:4][C:3]=1[CH3:10])[CH:12]=[O:14]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(O)cc(C)c1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(O)c(C=O)c(C)c1Cl
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-3,5-dimethylphenol (16 g, 0.1 mole) in dichloromethane (100 ml) was stirred and cooled to 2° C. in an ice bath. Titanium tetrachloride (35 g, 0.18 mole) was added dropwise over a period of 10 minutes and dichloromethylmethyl ether (11.5 g, 0.1 mole) was added slowly to the dark red solution, the temperature being kept below 10° C. throughout. After the solution had been stirred at 5° C. for 30 minutes the temperature was allowed to rise and to remian at 20° C. for 30 minutes. Finally the solution was warmed at 35° C. for 15 minutes and then poured into ice water (200 ml). The mixture was shaken vigorously until almost colourless and then the dichloromethane layer was separated and the aqueous phase was extracted with more dichloromethane (2×50 ml). The combined organic layers were washed with water thoroughly (4×200 ml) and then dried over anhydrous magnesium sulphate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure using a rotary evaporator. The product, 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde was isolated as a white solid (13 g, 70%), mp 89°-90° C. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.40 (3H, s); 2.64 (3H, s); 6.71 (1H, s); 10.23 (1H, s); 11.91 (1H, s).
Reaction SMILES: C([Mg][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)CC.[Br-].CO[SiH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH2:33]1[CH2:37]OC[CH2:34]1>>[CH2:34]([CH:5]1[CH2:6][CH2:7][CH:8]([Si@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:9][CH2:10]1)[CH2:33][CH3:37]
Reactant: CCC[Mg]C1CCCCC1
Reactant: C1CCOC1
Reactant: CO[SiH]1CCC(c2ccc(-c3ccc(F)cc3)cc2)CC1
Agent: [Br-]
Product: CCCC1CCC([Si@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)cc3)CC2)CC1

Procedure:
A 12 ml THF solution of 2.0M n-propylcyclohexyl magnesium bromide (24 mmol) was dripped into a mixed solution of 3.00 g (10.0 mmol) of 4-(4-methoxy-4-silacyclohexyl)-4'-fluorobiphenyl and 30 ml of THF. The silacyclohexane rings of the product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 2.57 g (yield 65%) of the target product, i.e. trans, trans isomers.
Reaction SMILES: C(N(CC)CC)C.[Cl:8]CCl.[S:11]1[CH:15]=[CH:14][C:13]2[C:16]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[CH:17][CH:18]=[CH:19][C:12]1=2.[C:36](Cl)(=[O:38])[CH3:37]>O>[ClH:8].[S:11]1[CH:15]=[CH:14][C:13]2[C:16]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][CH:30]4[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: CC(=O)Cl
Reactant: ClCCl
Reactant: c1cc(N2CCN(CCCOC3CCNCC3)CC2)c2ccsc2c1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(OCCCN2CCN(c3cccc4sccc34)CC2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Triethylamine (0.28 ml, 2.0 mmol) was added to a dichloromethane solution (15 ml) of 1-benzo[b]thiophen-4-yl-4-[3-(piperidin-4-yloxy)-propyl]-piperazine (0.45 g, 1.25 mmol) and the mixture was cooled in an ice bath. To this, acetyl chloride (0.1 ml, 1.4 mmol) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure. To the residue, 0.5 N hydrochloride-methanol solution (3 ml) was added. The crystal produced was obtained by filtration and dried to obtain 1-benzo[b]thiophen-4-yl-4-[3-(1-acetylpiperidin-4-yloxy)propyl]piperazine hydrochloride as white powder (0.36 g, 66% yield).
Reaction SMILES: CNC.[Br:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[C:9]=1[CH3:10].BrC1[C:23](Br)=[C:22](C)[N:21]([CH:26](C)[C:27](O)=O)N=1>>[Br:4][C:5]1[C:6]([CH3:17])=[N:7][N:8]([CH:11]([CH2:15][CH3:16])[C:12]([N:21]([CH2:26][CH3:27])[CH2:22][CH3:23])=[O:14])[C:9]=1[CH3:10]
Reactant: Cc1c(Br)c(Br)nn1C(C)C(=O)O
Reactant: CCC(C(=O)O)n1nc(C)c(Br)c1C
Agent: CNC
Product: CCC(C(=O)N(CC)CC)n1nc(C)c(Br)c1C

Procedure:
Following the procedure of Example 1, Part C, but substituting diethylamine for dimethylamine and further substituting the 4-bromo-α-ethyl-3,5-dimethylpyrazole-1-acetic acid prepared in Example 60, Part B, above, for the 3,4-dibromo-α,5-dimethylpyrazole-1-acetic acid, there was prepared the corresponding 4-bromo-N,Nα-triethyl-3,5-dimethylpyrazole-1-acetamide having a melting point at 42° to 44° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][C:19]([N:6]1[CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:20]
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1Cc2ccccc2Cc2ccccc21
Temperature: 95 °C

Procedure:
In a 100 ml round bottom flask equipped with magnetically stirring, thermometer, reflux condenser and addition funnel, 6,11-dihydro-5H-dibenz[b,e]azepine (1.0 g, 5,1 mmol, prepared in a similar way as described in Coll. Czech. Chem. Commun., 23, 1958, 1330) was dissolved in dry toluene (25 ml). 3-Chloropropionyl chloride (0.78 g, 6,1 mmol) was added slowly. When addition was complete, the reaction mixture was heated at 95° C. for 30 minutes and then allowed to cool to room temperature. With stirring, 0.2N sodium hydroxide (2.5 ml) was added. More toluene (50 ml) was added and the phases were separated. The organic phase was washed with 0.2N sodium hydroxide (10 ml) until pH>10, and then with water (3×10 ml) and brine (10 ml). After drying (MgSO4), the solvent was evaporated in vacuo affording 3-chloro-1-(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)-1 -propanone as an oil which was obtained in quantitative yield and used for further reactions without purification.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]([C:10]1[C:11]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:14][CH:15]=1)=[O:9].Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH2:37]([NH:36][C:11]1[C:10]([C:8]([NH2:7])=[O:9])=[CH:15][N:14]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:12]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(NCc4ccccc4)n3)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cnc(Nc2ccc(N3CCNCC3)cc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A 10 ml 1,4-dioxane solution of 738 mg of tert-butyl 4-(4-{[5-(aminocarbonyl)-4- (benzylamino)pyrimidin-2-yl]amino }phenyl)piperazin- 1 -carboxylate was mixed with 2.77 ml of 4 M hydrogen chloride/1,4-dioxane solution and 3 ml of water, followed by stirring at 90° C. for 2 hours. The reaction mixture was cooled down to room temperature, diluted with water, mixed with saturated sodium bicarbonate aqueous solution and then extracted with an ethyl acetate-THF mixed solution. After washing of the organic layer with saturated brine and subsequent evaporation of the solvent, the resulting solid was recrystallized (THF-ethanol) to obtain 413 mg of 4-benzylamino-2- {[4-(piperazin- 1 -yl)phenyl]amino}pyrimidine-5- carboxamide as ivory-colored crystals.
Reaction SMILES: C(N)[CH2:2][C:3]1[CH:8]=CC=CC=1.C([N:12](CC)CC)C.Cl.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:23]=[C:22]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]3[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=3)[CH:37]=2)[N:21]=1>C1COCC1>[CH:3]1([NH:12][S:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:38]3[CH:37]=[C:36]([C:22]4[N:21]=[C:20]([C:19]([F:53])([F:52])[F:18])[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[N:23]=4)[CH:41]=[CH:40][N:39]=3)[CH:43]=2)(=[O:50])=[O:49])[CH2:2][CH2:8]1
Reactant: NCCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(NC1CC1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of phenethylamine (0.165 g, 3.0 mmol), triethylamine (0.28 ml, 2.0 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.56 g, 0.96 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.49 g, 96%). MS (ISP) 564.7 [(M+H)+]; mp 195.5° C.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C@@H:10]1[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[N:13]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:12](=[O:29])[N:11]1[CH3:30].[ClH:31].O.N([O-])=O.[Na+].[S:37](=[O:39])=[O:38]>O.C(O)(=O)C.[Cu]Cl>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([C@@H:10]2[C:15]([C:16]#[N:17])=[C:14]([CH3:18])[N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:12](=[O:29])[N:11]2[CH3:30])=[C:2]([S:37]([Cl:31])(=[O:39])=[O:38])[CH:7]=1)#[N:9]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2N)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=S=O
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Under argon, (4R)-4-(2-amino-4-cyanophenyl)-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (2.1 g, 5.1 mmol) was initially charged in a 2:1:1 mixture of acetic acid/conc. hydrochloric acid/water (50 ml in total) at −10° C. A solution of sodium nitrite (371 mg, 5.38 mmol) in water (2 ml) was slowly added dropwise, and the mixture was stirred at −10° C. to −5° C. for 40 min. This solution was then added to 45 ml of a suspension, pre-cooled to −10° C. and saturated with sulfur dioxide, of copper(I) chloride (101.4 mg, 1.0 mmol) in glacial acetic acid (44 ml). The mixture was stirred at 0° C. for about 30 min and then at +15° C. for 1 h (reaction monitored by HPLC and LC-MS). The reaction mixture was then once more cooled to 0° C. and then pipetted into about 300 ml of ice-cold water. The precipitate was filtered off and taken up in ethyl acetate (150 ml). The solution was washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained as a solid (2.13 g, 77% of theory, 92% pure) which was used without further purification for subsequent reactions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([N:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[CH3:16])=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: C[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H]1CCCN1C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(3S)-Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (purchased from Astatech, Inc, 0.5 g, 2.3 mmol) was dissolved in DCM (20 mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of (S)-2-methyl-pyrrolidine (purchased from Advanced Asymmetric, Inc., 235 mg, 2.76 mmol, 1.2 equiv.) in 1 mL of DCM, followed by N-methylmorpholine (700 mg, 6.9 mmol, 3 equiv.) and 1-hydroxylbenzotriazole (HOBT) (404 mg, 3 mmol, 1.3 equiv.) sequentially, and finally EDC.HCl (576 mg, 3 mmol, 1.3 equiv.). The resultant clear light brown solution was stirred at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS detected the product peak at a retention time of 3.238 min with MS 227 (M-t-Bu). The reaction was quenched with aqueous saturated sodium bicarbonate solution (10 mL) and 10 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (15 mL×2). The combined DCM extracts were washed successively with sodium bicarbonate (10 mL) and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuum to obtain the title compound, 0.65 g (100% yield), as a thick oil.