Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH:14]1[CH2:41][CH2:40][C:17]2[N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=[N:20][C:16]=2[CH2:15]1.C1C2C(=CC=CC=2)C=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1.C(O)(=O)C>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH:14]1[CH2:41][CH2:40][C:17]2[NH:18][CH:19]=[N:20][C:16]=2[CH2:15]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c2CCC(COCc2ccc4ccccc4c2)C3)cc1
Agent: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c2CC(COCc2ccc4ccccc4c2)CC3)cc1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2cc(COCC3CCc4[nH]cnc4C3)ccc2c1
Temperature: 70 °C

Procedure:
A solution of a mixture of 5-(((2-naphthyl)methoxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-(((2-naphthyl)methoxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (590 mg, 1.1 mmol) in a mixture of glacial acetic acid (5 ml) and water (0.6 ml) was heated to 70° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica, using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 300 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.C=O.[C:33]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20][CH2:21][N:22]([CH3:33])[CH2:23][CH2:24]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)cc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCN(C)CC3)cc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-3-Methyl-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole (32 mg, 0.08 mmol) and formaldehyde (37 wt. % solution in water, 120 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (24 mg, 0.38 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated and the compound purified by flash chromatography on silica gel (1% ammonia/8% methanol/methylene chloride) to afford 20 mg (61%). 1H-NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.30-7.40 (m, 5H), 7.21-7.44 (m, 1H), 4.40 (q, J=6.7 Hz, 1H), 3.39 (q, J=9.2 Hz, 1H), 3.33 (d, J=9.2 Hz, 1H), 2.59 (s, 3H), 2.54 (m, 2H), 2.19-2.26 (m, 4H), 2.03-2.07 (m, 2H), 1.46 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.7, 139.0, 128.7, 127.3, 127.2, 126.7, 124.9 (q, J=272 Hz), 122.9, 122.6 (q, J=32.6 Hz), 119.7, 117.4, 78.4, 52.0, 51.9, 46.6, 40.7, 32.6, 22.0, 11.9. Mass spec.: 418.19 (MH)+. Mass spec.: 432.09 (MH)+.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CC=3)=NOC=2C)=NC=1.[NH2:49][CH:50]([CH2:53][OH:54])[CH2:51][OH:52]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:49][CH:50]([CH2:53][OH:54])[CH2:51][OH:52])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: NC(CO)CO
Agent: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: O=C(NC(CO)CO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 38 %

Procedure:
As described for example 220, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, using 2-amino-1,3-propandiol instead of 3-amino-1-propanol, to the title compound (90 mg, 38%) which was obtained as a white solid. MS: m/e=402.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:20][CH2:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[H][H].ClCl.C(OC(C)C)(C)C>C(O)(C)C>[OH2:19].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:20][CH2:21][CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Agent: CN1CCCC1CCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: ClCl
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: Cl
Product: O
Temperature: 25 °C

Procedure:
A solution of crude 2-(4-chlorophenyl)-N-[2-(1-methyl-2-pyrrolidinyl) ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide (3.96 g, 0.0100 mole) in hot isopropyl alcohol was acidified with hydrogen chlorine in isopropyl alcohol. Isopropyl ether was added to the cloud point. Upon cooling to room temperature, a solid precipitated. The solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum to give 4.2 g (86%) of title compound, mp 171°-175° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:27]([CH3:29])[CH3:28]>CN(C)C=O>[F:19][C:2]([F:1])([F:18])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][CH:12]=2)[N:7]([CH:27]([CH3:29])[CH3:28])[CH:6]=1)=[O:4]
Reactant: CC(C)I
Reactant: O=C(c1c[nH]c2cc(C(F)(F)F)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-trifluoromethyl-1H-indol-3-yl)-ethanone (1.0 g, 3.56 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was treated with potassium carbonate (1.22 g, 8.89 mmol). The resulting mixture was stirred at 25° C. for 10 min. At this time, the reaction was treated with 2-iodopropane (0.53 mL, 5.34 mmol). The reaction was heated at 65° C. for 4 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (75 mL) and ethyl acetate (75 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (1×25 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2,2,2-trifluoro-1-(1-isopropyl-6-trifluoromethyl-1H-indol-3-yl)-ethanone (850 mg, 74%) as a pale orange solid: mp 92-93° C.; EI-HRMS m/e calcd for C14H11F6NO (M+) 323.0745, found 323.0739.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2>>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:32])=[CH:26]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Product: Cl
Yield: 98.3 %

Procedure:
Using an analogous procedure to that described for the synthesis of the starting material in Example 201, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.6 mmol), (prepared as described for the starting material in Example 1), was reacted with 5-amino-2-methylindole (1.07 g, 7.3 mmol) to give 7-benzyloxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline hydrochloride (2.9 g, quanti.).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH2:32])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].O>CN(C)C(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:32][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:20]=[CH:21][C:22]=1[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: COc1cc(N)ccc1S(=O)(=O)c1ccccc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.80 g, 11.4 mmol) in N,N-dimethylacetamide (40 mL) was added thionyl chloride (1.36 g, 11.4 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 3-Methoxy-4-(phenylsulfonyl)benzeneamine (2.00 g, 7.6 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution filtered through a pad of Celite. The Celite was washed with methylene chloride (200 mL), the organic extract dried (MgSO4), and the solvent removed in vacuo to yield a brown oil which was purified by flash column chromatography (10% v/v ethyl acetate/methylene chloride). The resulting white solid (2.52 g, 82%) melted at 202°-204° C. 1 H-NMR (250 MHz, d6-DMSO): 1.56 (s, 3H, CH3) 3.87 (s, 3H, OCH3) 7.70-7.54 (m, 6H, aromatic+OH) 7.85-7.88 (m, 2H, aromatic) 7.93 (d, 1H, J=8.7 Hz, aromatic) 10.32 (s, 1H, NH). MS (CI, CH4): 404 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:16]1.C(OO)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCCC.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:16])[CH:5]=[N:4][C:3]=1[O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Clc1cccnc1OC1CCOCC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCCC
Product: Oc1cnc(OC2CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
3-Chloro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (Preparation 25, 1.40 g, 6.55 mmol) and bis(pinacolato)diboron (6.65 g, 13.11 mmol) were dissolved in heptane (30 mL) and degassed five times with nitrogen. Di-tert-butyldipyridyl (0.017 mg, 0.066 mmol) was added, followed by (1,5-cyclooctadiene)(methoxy)lridium(I) dimer (0.022 mg, 0.033 mmol). The mixture was again degassed five times with nitrogen and stirred at room temperature for 18 hours. The reaction was quenched by slow addition of methanol (50 mL) and concentrated in vacuo to afford a red/orange oil, which was purified by silica gel chromatography eluting with 66% EtOAc in heptane to afford an impure product. The obtained crude product was dissolved in and a 1:1 mixture of acetic acid:water (30 mL) was added and cooled to 5° C. (ice bath). Peracetic acid was slowly added over 2 minutes. The reaction was stirred at 5° C. for 30 minutes, then a 1 M aqueous solution of sodium thiosulfate was added. The reaction was allowed to slowly warm to room temperature over 30 minutes, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil, which was purified by silica gel chromatography eluting with EtOAc to afford an off-white solid. The solid was triturated in heptane to afford the title compound as a white solid (0.483 g, 43%):
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C.ClCCl>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCOCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-aminoethoxy)ethanol (30.3 g, 288 mmol) in a minimal amount of dichloromethane was added dropwise to a stirred mixture of 4-chloro-3-nitroquinoline (50.0 g, 240 mmol), potassium carbonate (33.1 g, 240 mmol), and triethylamine (36.4 g mL, 360 mmol) in DMF (200 mL) at 0° C. A yellow precipitate formed and more dichloromethane (several mL) was added. The mixture was allowed to warm to room temperature and stir overnight. A yellow solid was isolated by filtration, washed with water and dichloromethane, and dried. The filtrate was washed twice with brine, dried over magnesium sulfate, and filtered. Additional orange solid was isolated from the filtrate after concentration under reduced pressure. The solids were dried in a vacuum oven to afford 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethanol.
Reaction SMILES: S1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CN[C@@H:20](C([O-])=O)[CH2:21]C([O-])=O>>[CH:5]1[CH:4]=[CH:3][C:2]([C:6]2([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:20][CH:21]=1
Reactant: c1csc(C2(N3CCCCC3)CCCCC2)c1
Reactant: CN[C@H](CC(=O)[O-])C(=O)[O-]
Product: c1ccc(C2(N3CCCCC3)CCCCC2)cc1

Procedure:
N[1-(2-thienyl)cyclohexyl]piperidine (TCP); N-methyl-D-aspartate (NMDA); D(-)2-amino-5-phosphovaleric acid (AP-5); (+) 5 methyl-10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (dibenzocycloalkenimine) (MK-801).
Reaction SMILES: [C:1]([N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][O:9][C:8]1=[O:18])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[CH2:19]([N:26]([CH2:30][Si](C)(C)C)[CH2:27]OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:19]([N:26]1[CH2:30][C@@H:3]([CH2:4][CH3:5])[C@H:2]([C:1]([N:7]2[C@@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:10][O:9][C:8]2=[O:18])=[O:6])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The compound from step 7b (490 mg, 2 mmol) was dissolved in methylene chloride (9 mL), and the solution was cooled to 0° C. and flushed with N2. N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (498 mg, 2.1 mmol) was added, the mixture was stirred for 20 minutes and trifluoroacetic acid (1M, 0.2 mL, 0.20 mmol) was added dropwise over 20 minutes with stirring at 0° C. The mixture was stirred at 0° C. for 1 hour and at room temperature for 24 hours, then diluted with 50 mL of methylene chloride, washed with 10% aqueous K2CO3 and dried over Na2SO4. The solvent was removed and the residue was dried under vacuum (767 mg). The isomers were separated by medium pressure liquid chromatography on silica gel, eluting with 0.5% methanol/methylene chloride. The major isomer (3R,4R) (290 mg) was taken to the next step. MS m/z 379 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1cccc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cccc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
207 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 86 mg of 2-aminopyrazine, 79 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 111 mg of sodium t-butoxide and 43 mg of tris(dibenzylideneacetone) (chloroform)dipalladium were added in turn to 4 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 202 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 128 mg of the objective compound as pale orange powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.Cl.[C:30]1([C:36]2([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:28][C:23]1[CH:22]=[C:21]([C:8]2([CH2:7][CH2:6][N:39]3[CH2:38][CH2:37][C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:42]([NH2:44])=[O:43])[CH2:41][CH2:40]3)[CH2:12][CH2:11][N:10]([C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:9]2)[CH:26]=[CH:25][C:24]=1[Cl:27]
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)c2ccccc2)C1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1

Procedure:
2-[1-Benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]ethyl methanesulfonate (191 mg, 0.43 mmol) was treated with the 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (144 mg, 0.599 mmol) and NaHCO3 (90 mg, 1.07 mmol, 2.5 eq.) in THF/H20 (5 mL/1 mL) at reflux for 21 hours. The solution was concentrated in vacuo and the aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with 6% methanol in dichloromethane to give 146 mg (44%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C@@H:7]([NH2:13])[C@@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([NH:13][C@@H:7]([C@@H:8]([OH:12])[CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:14])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](O)[C@H](N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.3 %

Procedure:
A solution of (2S,3S)-2-amino-3-hydroxy-4-methyl-pentanoic acid tert-butyl ester (297 mg, 1.37 mmol) and triethylamine (139 mg, 1.37 mmol) in anhydrous methylene chloride (2 ml) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added N-(benzyloxycarbonyloxy)-succinimide (343 mg, 1.37 mmol). The resulting mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was partitioned between ether and water. The organic layer was washed with cold 1N hydrochloric acid and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo, to provide tert-butyl (2S,3S)-2-{[(benzyloxy)carbonyl]-amino}-3-hydroxy-4-methylpentanoate (445 mg, 96%) as a yellow oil.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([N:29]2[CH2:35][CH:34]3[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:28])[C:13]1=[O:38])=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C.C(OCC)(=O)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH2:19][CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:15]=2[N:14]([CH2:26][C:27]([N:29]2[CH2:35][CH:34]3[CH2:33][CH2:32][CH:31]([CH2:37][CH2:36]3)[CH2:30]2)=[O:28])[C:13]1=[O:38]
Reactant: CCC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c(C)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (1.23 g), 10% palladium on carbon (50% wet, 250 mg) and ammonium formate (600 mg) in ethanol (15 ml) was stirred at room temperature for 1 hour. The catalyst was filtered off and the filtrate was evaporated in vacuo to afford a residue, which was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine successively. After drying over sodium sulfate, the solvent was evaporated in vacuo to afford a residue, which was triturated in diisopropyl ether and collected by filtration to give (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-5-ethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one (792 mg, 87.0% yield) as a crystalline powder.
Reaction SMILES: [I:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH2:7]1[CH2:11][O:10][CH2:9]C1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].IC1COC1>CN(C=O)C.CCOC(C)=O.O>[I:1][C:2]1[CH:6]=[CH:5][N:4]([CH:7]2[CH2:9][O:10][CH2:11]2)[N:3]=1
Reactant: C1CCOC1
Reactant: Ic1cc[nH]n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: IC1COC1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccn(C2COC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-iodo-1H-pyrazole (503 mg, 2.6 mmol) was added as a solution in DMF (1 mL) to a 1.0 M THF solution of NaHMDS (2.9 mL, 2.9 mmol) that had been pre-cooled in an ice water bath. Additional portions of DMF (2×1 mL) were used to ensure complete transfer. 3-iodooxetane (0.41 mL, 4.7 mmol) was added in one portion and the reaction mixture was allowed to warm to r.t. After 1 h, the reaction mixture was heated to 45° C. and allowed to stir for an additional 75 h. The mixture was cooled and diluted with EtOAc, and water. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with water and were dried over Na2SO4, filtered and concentrated to afford a crude residue that was purified by silica gel chromatography (0-30% EtOAc in hexanes) to provide 3-iodo-1-(oxetan-3-yl)-1H-pyrazole 7.53 (414 mg). Regiochemistry was confirmed as drawn via NOE studies. LCMS-ESI+ (m/z): [M+H]+ calcd for C6H8IN2O: 251.0; found: 251.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[S:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41]1([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[S:36][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2cccs2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4cccs4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-(thiophen-2-yl)-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.