Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1.[Cu][C:33]#[N:34].C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[C:13]([N:11]1[CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:33]#[N:34])[N:9]=[CH:10]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#C[Cu]
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C

Procedure:
To a solution of 4-(2-bromo-phenyl)-1-trityl-1H-imidazole (73.0 g, 163.3 mmol) in dimethylformamide (500 ml) was added copper (I) cyanide (17.5 g, 195.9 mmol). The reaction was heated to ˜80° C. under nitrogen for 14 h. After cooling to about 50° C., the reaction was diluted with toluene (ca. 300 ml) and slowly poured onto ammonium hydroxide (3N, 1.5 L) while stirring vigorously. The mixture was stirred for 40 min and then filtered in vacuo over a bed of celite (slow filtration, required ˜2 h). The phases were separated and the organic layer was washed with brine (75 ml×3) and dried (sodium sulfate). Concentration of the solvent afforded a light brown solid. The crude product contains ˜10–15% of trityl alcohol (by HPLC) and was used without further purification in the subsequent step.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[O:29][C:28]4=[O:38])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)(=O)C>[OH:8][CH2:9][CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:31][C@H:30]([CH2:32][N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[O:29][C:28]4=[O:38])=[CH:25][CH:26]=3)=[CH:19][CH:20]=2)[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3)cc2)=NO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NOC(CO)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
(5R)-3-{4′-[5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazol-3-yl]-1,1′-biphenyl-4-yl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.24 g, 0.45 mmol) was dissolved in THF (5 ml) at 25° C. Tetrabutylammoniumfluoride.3H2O (0.138 g, 0.495 mmol) was added as a solid and the reaction was stirred at 25° C. for 1.5 hours. The mixture was then diluted with ethyl acetate (50 ml) and poured into water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate (3×50 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent, giving 0.05 g desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][Br:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])C.O[Li].O.O.Cl>C1COCC1.CO>[Br:20][CH2:19][CH2:18][CH2:17][O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)oc2cccc(OCCCBr)c12
Temperature: 0 °C
Reaction time: 7 h
Yield: 112.9 %

Procedure:
4-(3-Bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (27.3 g), the compound in Example 5-a, was dissolved in THF (546 ml) and cooled at 0° C. To the solution were added LiOH.H2O (6.72 g), water (410 ml) and MeOH (135 ml). The mixture was stirred at room temperature for seven hours. To the reaction mixture was added 1N-HCl (133 ml). After evaporating the organic solvent, the mixture was mixed with ethyl acetate (1,400 ml). The organic layer was dried over anhydrous sodium sulfate and evaporated to give colorless needles. The colorless needles were washed with ethyl acetate-hexane (2:8) to obtain pure 4-(3-bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid (28.3 g). FAB-MS: m/z 312 (M+); 1H-NMR (CDCl3): δ 2.43 (2H, quintet, J=6.5 Hz), 2.78 (3H, s), 3.66 (2H, t, J=6.5 Hz), 4.25 (2H, t, J=6.5 Hz), 6.67 (1H, d, J=8 Hz), 7.17 (1H, d, J=8 Hz), 7.38 (1H, t, J=8 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:14][C:13]4[C:15](=O)[CH2:16][CH2:17][CH2:18][C:12]=4[C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:28].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:14][C:13]4[CH:15]([NH2:28])[CH2:16][CH2:17][CH2:18][C:12]=4[C:11]=3[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2c1sc1ccc(-c3ccccc3)cc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCc2c1sc1ccc(-c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 20 h
Yield: 22.9 %

Procedure:
To a solution of 8-phenyl-2,3-dihydrodibenzo[b,d]thiophen-4(1H)-one (0.28 g, 1.0 mmol, 1 eq), ammonium acetate (0.77 g, 10 eq) in MeOH (20 mL) was added NaBH3CN (160 mg, 2.5 eq) in one portion. The reaction mixture was heated to 50° C. and stirred for 20 h, After that the solvent was removed, diluted with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the title compound (64 mg, 23%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8]Cl)[N:7]=1.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:12]([CH3:11])[O:13][CH3:14])[N:7]=1
Reactant: CNOC
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)Cc1csc(N)n1
Temperature: 60 °C

Procedure:
A mixture of 2-amino-4-chloromethyl-thiazole hydrochloride (27.8 g, 0.15 mol), N,O-dimethylhydroxylamine hydrochloride (87.8 g, 0.90 mol), and anhydrous THF (300 mL) was rapidly stirred and DIPEA (157 mL, 0.90 mol) was added. The resulting mixture was heated at 60° C. for 10-15 hours. The mixture was cooled in an ice/salt bath and the solid byproduct (DIPEA hydrochloride) was removed by filtration and washed with cold THF (300 mL). The combined filtrate was concentrated to afford the N-(2-amino-thiazol-4-ylmethyl)-O,N-dimethyl-hydroxylamine as a dark oil (31 g, >100% theory), which partially crystallized on standing. This product was used in the next step without further purification.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH2:18](I)[CH2:19][CH3:20]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11])[CH2:19][CH3:20]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2cscc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 11.8 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.8 g. of 50% sodium hydride in mineral oil in 175 ml. of dimethylformamide is stirred for 2 hours. A 12.6 g. portion of n-propyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is poured into ice water. After 3 hours the brown crystals are recovered by filtration, washed thoroughly with water, then ether and dried. This solid is heated to boiling in 75 ml. of methanol, filtered while hot and the filtrate is stored in a chill room. The crystals which form are recovered by filtration, washed with ether and dried giving the desired product, mp. 166°-167° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[NH2:14])[CH:5]=[CH:6][C:7]=1[F:8].C1CCN2C(=NCCC2)CC1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCCC1c1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3,4-difluoro-phenyl)-cyclopentylamine (1.40 g, 7.10 mmol) from preparation 15, methylene chloride (20.0 mL) and the solution cooled to 0° C. DBU (1.27 mL, 8.52 mmol) and isopropylsulfonyl chloride (0.96 mL, 8.52 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 910 mg (42%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(=O)C(CBr)=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)ON=C(CBr)C(=O)OCC
Yield: 83.7 %

Procedure:
Ethyl 3-bromo-2-(hydroxyimino)propanoate (4.0 g, 19 mmole) and methacryloyl chloride (2.18 g, 20.8 mmole) in methylene chloride (100 ml) were treated with dry pyridine (1.66 g, 21 mmole). After a workup as in Example 1, 4.42 g (84% yield) of ethyl 3-bromo-2-(methacryloyloximino)propanoate was obtained as an oil. NMR and IR spectra confirm the structure.
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[N:14]([CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)[OH:19])=[N+:15]=[N-:16].O>CN(C)C=O>[N:14]([CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=1)[O:19][Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])=[N+:15]=[N-:16]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.3 %

Procedure:
Imidazole (0.46 g) and triethylsilyl chloride (0.82 g) were added to a solution of N-[5-((R)-2-azido-1-hydroxyethyl)-2-benzyloxyphenyl]methanesulfonamide (1.64 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 12 hrs. Imidazole (0.15 g) and triethylsilyl chloride (0.21 g) were added to the reaction mixture. After being stirred for additional 3 hrs, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to afford the title compound (1.84 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.O>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (120 mg, 3.01 mmol) was added to a solution of 2,4-difluorothiophenol (0.4 g, 2.74 mmol) in THF (10 mL) at 0° C., under argon. The reaction was allowed to warm to RT and 2-(3-bromopropoxy)tetrahydro-2H-pyran (672 mg, 3.01 mmol) added. The reaction was stirred at RT for 4 hours then poured into iced water (50 mL) and extracted into ethyl acetate (50 mL). The organics were washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-10% ethyl acetate in isohexane, to give the desired compound as a colourless oil (610 mg). 1H NMR δ (CDCl3): 1.49-1.61 (m, 4H), 1.65-1.73 (m, 1H), 1.75-1.90 (m, 3H), 2.96 (t, 2H), 3.46-3.52 (m, 2H), 3.79-3.87 (m, 2H), 4.55-4.56 (m, 1H), 6.80-6.86 (m, 2H), 7.38-7.44 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12]([O:14]C(C)(C)C)=O)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH:20]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:21](C(O)=O)[CH:22]([CH3:24])[CH3:23].C(OC([C@@]1(NC([C@@H]2C[C@@H](OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)C[C@H]2C(=O)N[C@H](C(=O)N[C@@H](C2CCCCC2)C(=O)NC)C(C)(C)C)=O)C[C@H]1C=C)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12](=[O:14])[C@@H:21]([NH:20][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH:22]([CH3:24])[CH3:23])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCC1
Yield: 94.4 %

Procedure:
Compound 54 (93 mg, 0.343 mmol) was deprotected and coupled to Z-Val-OH (95 mg, 0.378 mmol) according to the method for the preparation of 39. Flash column chromatography (toluene/ethyl acetate 4:1) gave 55 (131 mg, 94%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:42])[CH2:23][N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])[C:30](Cl)=[N:29][C:28]=2[N:27]([CH3:41])[C:25]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:42])[CH2:23][N:24]1[C:33](=[O:34])[C:32]2[N:31]([CH2:35][CH:36]=[C:37]([CH3:38])[CH3:39])[C:30]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:29][C:28]=2[N:27]([CH3:41])[C:25]1=[O:26]
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.30 g of 3-tert.-butyloxycarbonylamino-piperidine are added to a mixture of 2.51 g of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 880 mg of sodium carbonate in 8 ml of dimethylsulphoxide. The reaction mixture is stirred for 18 hours at 60° C. For working up it is combined with water and the precipitate formed is suction filtered. The solid crude product is dissolved in ethyl acetate, the solution is dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18]2>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH:20]3[CH2:23][CH:17]2[CH2:22][CH2:21]3)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CC2CC1CN2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2CC3CCC2C3)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A stirred solution of 4-bromobenzyl bromide (66 mg, 0.26 mmol), triethylamine (0.22 mL, 1.56 mmol) and 2-azabicyclo[2.2.1]heptane (71 mg, 0.52 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was cooled to ambient temperature, the solid removed by filtration and the filtrate concentrated under reduced pressure to afford the title compound (70 mg, quantitiative yield) that was used in the next step without further purification. LCMS (Method B): RT=2.04 min, M+H+=266/268.
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1O>O1CCCC1>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:6][CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cccc1Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Methyl iodide (850 μl, 13.646 mmol) and potassium carbonate (943 mg, 6.824 mmol) were added to 2-chloro-6-fluorophenol (1.0 g, 6.824 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between diethyl ether (50 ml) and water (50 ml). The organic phase was extracted and further washed with water (2×20 ml) then dried over sodium sulphate and concentrated in vacuo to afford the title compound as a colourless liquid in 94% yield, 1.03 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(C(C)C)CC)(C)C.[CH3:41][S:42]([Cl:45])(=[O:44])=[O:43]>C(Cl)Cl>[ClH:16].[ClH:45].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[CH:3]=[CH:4][C:5]=2[NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)=[N:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(NCC2CCN(c3ccncc3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(NCC2CCN(c3ccncc3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Product: Cl
Reaction time: 0.25 h

Procedure:
A solution of 5-amino-N-(5-chloropyridin-2-yl)-2-[1-(4-pyridinyl)piperidin-4-ylmethylamino]benzamide (90 mg, 0.21 mmol) and diisopropyl ethylamine (0.036 mL) in methylene chloride (2 mL) was treated with methanesulfonyl chloride (0.016 mL, 0.21 mmol). After 0.25 h, the mixture was concentrated and the residue partitioned between EtOAc and water. The aqueous layer was treated with 1 N NaOH and the resulting solid collected by filtration. The material was further purified by RPHPLC yielding the title compound as a hydrochloride salt.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:10]=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[C:14]([NH:15][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:13][C:12]([CH3:16])=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:10]=1
Reactant: CCCC(=O)Cl
Reactant: COc1cc(OC(F)(F)F)ccc1-c1nc(OC)c(N)cc1C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Butyryl chloride (0.174 ml, 1.675 mmol) is added to a solution of 2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine (0.5 g, 1.523 mmol) and diisopropylethylamine (0.32 ml, 1.83 mmol) in CH2Cl2 (10 ml) at room temperature. The mixture is stirred at room temperature for 30 minutes. EtOAc (50 ml) is added and the mixture is washed with 1 N NaOH and brine. After drying over Na2SO4, the solvent is removed under reduced pressure. The residue is purified by flash column chromatography (hexane/EtOAc=4:1) to give N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-butyramide. Rf (hexane/EtOAc=4:1)=0.46.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]([C:9]3[CH:10]=[N:11][C:12]([NH:15][CH2:16][CH2:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[N:13][CH:14]=3)=[N:8][C:4]=2[C:3]=1[CH3:28].CO.[CH3:31]C1C(C=O)=CN=C(NCCCC2CCN(C)CC2)N=1.FC1C(C)=C(N)C(N)=CC=1>C1(C)C=CC=CC=1.O=[Mn]=O>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[NH:6][C:7]([C:9]3[C:14]([CH3:31])=[N:13][C:12]([NH:15][CH2:16][CH2:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[N:11][CH:10]=3)=[N:8][C:4]=2[C:3]=1[CH3:28]
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Reactant: Cc1c(F)ccc2[nH]c(-c3cnc(NCCCC4CCN(C)CC4)nc3)nc12
Agent: O=[Mn]=O
Agent: Cc1c(F)ccc(N)c1N
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1-c1nc2c(C)c(F)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
[5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. To a mixture of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-methanol (0.14 g, 0.49 mmol) in toluene (3 mL) was added MnO2 (0.22 g, 2.48 mmol). After 30 min at 70° C., the mixture was filtered through diatomaceous earth. The filtrate was concentrated and immediately dissolved in DMF. A portion of this solution (corresponding to 0.05 g, 0.17 mmol of 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde) was then treated with 4-fluoro-3-methyl-benzene-1,2-diamine (1.1 equiv.) and Na2H2S2O5 (1.25 equiv.) at 90° C. for 12 h. The reaction mixture was purified by FCC to afford the title compound. MS: mass calcd. for C22H29FN6, 396.24; m/z found, 397.2 [M+H]+. 1H NMR (CD3OD): 8.62 (s, 1H), 7.55 (dd, J=8.0, 3.9 Hz, 1H), 7.17 (dd, J=10.3, 8.8 Hz, 1H), 3.60 (t, J=6.9 Hz, 2H), 3.10-2.99 (m, 2H), 2.71 (s, 3H), 2.66 (d, J=1.4 Hz, 3H), 2.44 (s, 3H), 2.26-2.17 (m, 2H), 1.98-1.88 (m, 2H), 1.87-1.77 (m, 2H), 1.55-1.36 (m, 5H).
Reaction SMILES: C1[CH2:5][O:4][CH2:3]C1.[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18].[H-].[Na+].COCCl>O>[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]([CH3:15])([CH3:17])[CH3:16])[C:8]=1[O:18][CH2:3][O:4][CH3:5]
Reactant: Cc1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1c(Br)cc(C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, a THF 50 ml solution of 2-bromo-4-methyl-6-tert-butylphenol(23.41 g, 100 mmol) was added dropwise at 0° C. with stirring to a 100 ml THF suspension of sodium hydride (60%, 5.20 g, 130 mmol). After 2 hours, a THF 20 ml solution of methoxymethyl chloride (95%, 12.71 g, 150 mmol) was added dropwise to the mixture obtained above, the resulting mixture was brought up to room temperature and stirred for 10 hours. The reaction liquid thus obtained was cooled to 0° C., 100 ml of water was added thereto, and the aqueous layer was extracted with toluene (extracted twice with 200 ml of toluene). The organic solution layers were combined, washed with 100 ml of saturated aqueous sodium chloride solution, then dried with anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel column chromatography to obtain a colorless oil. The 1H-NMR spectrum data of the oil are shown below. The NMR data were determined by using EX-270 (mfd. by JEOL).