Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (4.00 g; 17.4 mmol) is dissolved in methylene chloride (125 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (6.36 g; 20.9 mmol), diisopropylethylamine (7.27 g; 55.8 mmol), and PyBOP (10.89 g; 20.9 mmol) are added sequentially. The mixture is stirred for 14 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([CH2:12][CH3:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:16])=O>C(O)=O>[CH2:12]([CH:10]([NH2:16])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: CCC(=O)CCCc1ccccc1
Reactant: NC=O
Solvent: O=CO
Product: CCC(N)CCCc1ccccc1

Procedure:
Ethyl magnesium bromide was reacted with 4-phenylbutylnitrile to provide ethyl 3-phenylpropyl ketone. The ketone was reacted with formamide and formic acid to afford 1-ethyl-4-phenylbutylamine. Methylation of the amine by reaction with formaldehyde and formic acid provided N,N-dimethyl-1-ethyl-4-phenylbutylamine. Quaternization of 6.2 g. of the dimethylamine according to the procedure of Example 62 afforded 6.56 g. of N,N,N-Trimethyl-1-ethyl-4-phenylbutylammonium bromide. M.P. 183°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:14][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C1(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1(C(=O)Cl)CC1

Procedure:
To solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (144 mg, 1 mmol) was added 2M oxalyl dichloride (1.0 mL, 2.0 mmol) in DCM followed by a few drops of DMF. The reaction mixture was stirred until gas evolution ceased (˜1 h). Excess oxalyl chloride and DCM were evaporated to afford methyl 1-(chlorocarbonyl)cyclopropanecarboxylate. To a solution of methyl 1-(chlorocarbonyl)cyclopropanecarboxylate in DCM (2 mL) was added 4,4-difluoropiperidine/HCl (173 mg) and DIPEA (0.384 mL) at 0° C., and then the reaction mixture was allowed to warm to rt. The reaction mixture was purified by silica gel FCC to yield Cap P-20. 1H NMR (500 MHz, CDCl3) δ ppm 3.77-3.82 (2H, m), 3.75 (3H, s), 3.64 (2H, t, J=5.42 Hz), 1.96-2.09 (4H, m), 1.51-1.57 (2H, m), 1.33-1.39 (2H, m). Hydrolysis of methyl 1-(4,4-difluoropiperidine-1-carbonyl)cyclopropanecarboxylate (by 2 mL of 1N NaOH, 1 mL of THF and 1 mL of MeOH) to afford Cap P-20 as a white solid (194 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.78-3.73 (4H, m), 1.97-2.10 (4H, m), 1.59-1.65 (2H, m), 1.42-1.48 (2H, m).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl.O.CC(C)=O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH2:16][C:17]1=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.4 %

Procedure:
1 g of 2-(N-methylamino)-phenol were dissolved in chloroform, followed by the addition of 10 ml of sat. NaHCO3 in water. To this suspension was added slowly under vigorous stirring a solution of 1 g of 2-chloroacetylchloride in acetone. The reaction mixture was stirred for 2 hours at room temperature. The layers were separated. The organic layer was washed with water and dried over Na2SO4. After evaporating the solvent, the red oil was taken up in 30 ml DMF and 1 g of K2CO3 were added and the slurry was heated at 70° C. for additional 2 hours. The cyclization was followed by TLC. 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 5× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1.45 g of pure 4-methyl-4H-benzo[1,4]oxazin-3-one.
Reaction SMILES: [NH2:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11]C1C=CC=C2C(NC(=O)C=12)=O>CO>[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[CH2:10][CH2:11][NH2:1]
Reactant: CN1CCNCC1CCc1cccc2c1C(=O)NC2=O
Reactant: NN
Solvent: CO
Product: CN1CCNCC1CCN

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 2-(N-methylpiperazinyl)ethylphthalimide (218 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]1[C:26]([OH:27])=[C:25]([O:28][CH3:29])[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[CH3:32])=O.Cl(O)(=O)(=O)=O.[C:38](O)(=[O:40])[CH3:39]>CCOCC.[Pd]>[C:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:21]1[C:26]([OH:27])=[C:25]([O:28][CH3:29])[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[CH3:32])(=[O:40])[CH3:39]
Reactant: CC(=O)O
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCO)c(O)c1OC
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: COc1cc(C)c(CCCCCCCCCCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
To a solution of 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5-methylphenol (1.4 g) in acetic acid (30 ml) are added 5% palladium-on-carbon (50% hydrous) (0.5 g) and 70% perchloric acid (0.05 ml), and catalytic reduction is carried out at atmospheric temperature and pressure. After the absorption of hydrogen has subsided, the catalyst is filtered off and the filtrate is concentrated under reduced pressure, whereupon a colorless oil is obtained. This product is dissolved in ether and the ether layer is washed with 5% aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent is then distilled off and the resultant crude crystals are recrystallized from hexane. The above procedure yields 6-(18-acetoxyoctadecyl)-2,3-dimethoxy-5-methylphenol (1.4 g) as colorless needles, m.p. 53° C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][NH:8][C:7](=[O:12])[C:6]1=[O:13].C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.[CH2:33]([O+](CC)CC)[CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]=[C:7]([O:12][CH2:33][CH3:34])[C:6]1=[O:13]
Reactant: C[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NC[C@H](C)N(Cc2cccc(C(F)(F)F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
To an ice cooled solution of Intermediate 4 (1.0 g, 3.1 mmol) and sodium carbonate (6.6 g, 62 mmol) in DCM (45 mL) was added triethyloxonium tetrafluoroborate (1M in DCM, 15.6 mL, 15.6 mmol) dropwise. The ice bath was removed and the reaction was stirred at rt for 1.5 h. Water was added and the mixture was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a yellow oil (1.1 g, 99%), which was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.C[O:31][B:32](OC)[O:33]C.[Cl-].[NH4+].OS([O-])(=O)=O.[K+].OS(O)(=O)=O>O1CCCC1.CCCCC.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:15]=2)[CH:10]=[C:9]1[B:32]([OH:33])[OH:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 78 °C
Reaction time: 0.53 h
Yield: 56 %

Procedure:
To a solution of 1 g 1-(tert-butoxycarbonyl)-6-(tert-butyldimethylsiloxy)indole in 15 mL anhydrous tetrahydrofuran at −78° C. under nitrogen is added tert-butyllithium (2.30 mL of a 1.5 M solution in pentane) over 3 min, and the reaction is stirred at ˜78° C. After 32 min, 0.66 mL trimethylborate are added in one portion, and the reaction is stirred at 0° C. After 2 h, 9 mL saturated aqueous ammonium chloride are added, the mixture diluted with 25 mL ether, and stirred at ambient temperature. The reaction is acidified with 4 mL of a solution made from 10% aqueous KHSO4 (60 mL) and concentrated H2SO4 (2 mL). After stirring for 15 min, the layers are separated and the organics are washed with water (15 mL) and brine (15 mL) successively, dried (Na2SO4), and the solvent is removed under reduced pressure to yield a partially solidified material. The material is washed with hot hexanes (5 mL) and filtered. The collected solid is washed with hexanes (2×5 mL) to give 635 mg (56%) of 1-(tert-butoxycarbonyl)-6-(tert-butyldimethylsiloxy)indole-2-boronic acid as a white powder.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH2:10][C:11]2[NH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:14]([CH3:16])[N:15]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:27](OC)(=[O:30])[C:28]#[CH:29]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:29]=[CH:28][C:27](=[O:30])[N:15]3[C:14]([CH3:16])=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:12][C:11]=23)=[O:23])=[CH:7][CH:8]=1
Reactant: Cc1nc(CC(=O)c2ccc(F)cc2)[nH]c1-c1ccccc1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1c(-c2ccccc2)[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n12

Procedure:
The compound is prepared as described in example 25 with 300 mg (0.91 mmol) of 1-(4-fluorophenyl)-2-(4-methyl-5-phenyl-1H-imidazol-2-yl)ethanone hydrochloride (example LI), 90 mg (1.80 mmol) of sodium methylate and 76 mg (0.91 mmol) methyl propiolate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 120 °C
Yield: 59.6 %

Procedure:
A mixture of 8-bromo-1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (66 mg, 0.14 mmol), 3-tributylstannanyl-pyridine (0.069 mL, 0.22 mmol) and PdCl2(PPh3)2 (20 mg, 0.029 mmol) in 4 mL of DMF was heated at 120° C. for 2.5 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH) to give 38 mg of the title compound. MS: (+) m/z 456.41 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]([NH2:11])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5].C1(=O)[N:18]([CH2:19][CH2:20][C:21](Cl)=[O:22])C(=O)C2=CC=CC=C12>>[I:1][C:2]1[C:10]([NH:11][C:21](=[O:22])[CH2:20][CH2:19][NH2:18])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Product: NCCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I

Procedure:
The same procedure is used as for Compond I, using 2,4,6-triiodo-3-amino-benzoic acid as iodo starting material and β-phthalimidopropionic acid chloride.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 96 %

Procedure:
Using general procedure A, 4-trifluoromethoxy-phenylamine (354 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-trifluoromethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (692 mg, 96%) as a white crystalline solid.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[CH2:25][CH:24]([CH2:26][C:27](O)=[O:28])[CH2:23][C:22](=[O:30])[NH:21]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27](=[O:28])[CH2:26][CH:24]2[CH2:23][C:22](=[O:30])[NH:21][C:20](=[O:19])[CH2:25]2)[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)CC1CC(=O)NC(=O)C1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (500 mg), (2,6-dioxopiperidin-4-yl)acetic acid (311 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg), 1-hydroxy-1H-benzotriazole monohydrate (322 mg), triethylamine (0.627 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give the title compound (47 mg, 13%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:37][C:38]1[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:41]2[CH:51]=[CH:52][CH:53]=[CH:54][C:40]=2[N:39]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:37][C:38]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[C:41]3[CH:51]=[CH:52][CH:53]=[CH:54][C:40]=3[N:39]=2)[C:18]2([CH3:28])[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(CN(Cc2nc3ccccc3n2COCC[Si](C)(C)C)C2(C)CCCc3cccnc32)cc1)Cc1ccccn1
Yield: 47.2 %

Procedure:
Reaction of N-tert-Butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (120 mg, 0.26 mmol), 2-chloromethyl-1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole (234 mg, 0.79 mmol) and diisopropylethylamine (229 uL, 1.31 mmol) in DMF (2.6 mL) for 18 h at 90° C. followed by purification of the crude material by radial chromatography (2 mm plate, 20:2:1 CHCl3-MeOH—NH4OH) afforded 90 mg (48%) of N-tert-butoxycarbonyl-N-(2-pyridinylmethyl)-N′-(1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-ylmethyl)-N′-(8-methyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Li+].[Cl-].[I:11]I>C1COCC1>[Cl:1][C:2]1[C:7]([I:11])=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: II
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ncnc(Cl)c1I
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
4,6-Dichloropyrimidine 6 (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. I2 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:4) furnished compound 8a (227 mg, 83%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dichloro-5-nitropyrimidine (0.53 g, 2.75 mmol) in THF (3 mL) was added a solution of (2-aminophenyl)(phenyl)methanone (0.30 g, 1.55 mmol) and N,N-diisopropylethylamine (0.5 mL, 3.0 mmol) in THF (2.0 mL). The reaction was stirred for 2.0 hours. The reaction was then poured onto ice and allowed to warm to room temperature then was filtered, washing the solid with water. The isolated solid was dried under vacuum to give {2-[(2-chloro-5-nitropyrimidin-4-yl)amino]phenyl}(phenyl)methanone (496 mg, 90%) as a yellow solid. 1H NMR (DMSO-d6/D2O): δ 9.06 (s, 1H), 7.96 (d, 1H), 7.76-7.44 (m, 8 H). MS m/z 354 (M+1).
Reaction SMILES: CC1(C)[O:6][C@@H:5]2[C@@H:7]([CH2:23][N:24]([CH:50]([CH3:52])[CH3:51])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[N:33](COCC[Si](C)(C)C)[C:32]4[CH:42]=[C:43]([C:46]([F:49])([F:48])[F:47])[CH:44]=[CH:45][C:31]=4[N:30]=3)[CH2:8][C@@H:9]([N:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH:20]5[CH2:22][CH2:21]5)[C:13]=4[CH:12]=[CH:11]3)[C@@H:4]2[O:3]1.[ClH:54]>CO>[ClH:54].[ClH:54].[ClH:54].[CH:20]1([NH:19][C:18]2[C:13]3[CH:12]=[CH:11][N:10]([C@@H:9]4[CH2:8][C@H:7]([CH2:23][N:24]([CH:50]([CH3:51])[CH3:52])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]5[NH:33][C:32]6[CH:42]=[C:43]([C:46]([F:49])([F:48])[F:47])[CH:44]=[CH:45][C:31]=6[N:30]=5)[C@@H:5]([OH:6])[C@H:4]4[OH:3])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21][CH2:22]1
Reactant: CC(C)N(CCCCc1nc2ccc(C(F)(F)F)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CC(C)N(CCCCc1nc2ccc(C(F)(F)F)cc2[nH]1)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-{[propan-2-yl({4-[6-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl})amino]methyl}-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (199 mg) was dissolved in methanol (2 ml), and conc. HCl solution (2 ml) was slowly added. The reaction was heated to 40° C. and stirred at this temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between sat. NaHCO3(aq) (10 ml) and EtOAc (10 ml). A small amount of MeOH (−1 ml) was added to aid dissolution, and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 ml), the combined organics were then dried (Na2SO4) and concentrated. The crude material was purified by preparative TLC, eluting twice with 7.5% 2M NH3 in MeOH in DCM to afford 48.2 mg (29.6%) of the free base of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][C:17]3([CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl>[N:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][C:17]3([CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CC1)CCN(c1ccncc1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCC3(CCCNCC3)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.0 ml) was added to a solution of tert-butyl 3-(pyridin-4-yl)-3,9-diazaspiro[5.6]dodecane-9-carboxylate (250 mg, 0.724 mmol) in methylene chloride (3 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to give the desired product which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1ccc(NC(=S)Nc2ncccc2OCc2c(F)cccc2Cl)cc1
Reactant: N
Product: N=C(Nc1ccc(F)cc1)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of yellow men:uric oxide (0.65g, 0.003 mol), N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-4-fluorophenylthiourea (1 .0g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirred for 3 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.38 g, (40%), m.p. 152°-154 ° C.