Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([CH2:11][NH2:12])[OH:10])=[CH:4][C:3]=1[Cl:13].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([CH:9]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[OH:10])=[CH:6][C:7]=1[Cl:8]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: BrCCCCCCOCCCCCCc1cnccn1
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCCCCCc2cnccn2)cc1Cl
Yield: 56.3 %

Procedure:
A solution of 4-amino-α-(aminomethyl)-3,5-dichlorobenzenemethanol (1.2 g), DEA (0.72 ml) and [6-[(6-bromohexyl)oxy]hexyl]pyrazine (1.16 g) in DMF (10 ml) was heated at 100°-110° for 3 h. The resulting dark solution was evaporated in vacuo and the residue purified by FCC eluting with System B (96:2:2→93:5:2) to give the title compound as pale yellow crystals (0.92 g), m.p. 60°-63°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a stirred solution of 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 2, 300 mg, 1.2 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (284 mg, 1.4 mmol) in dichloromethane (10 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (670 mg, 3.5 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (368 mg, 2.4 mmol), and triethylamine (3 mL). After being stirred overnight, the reaction was quenched by the addition of saturated sodium bicarbonate aqueous solution (50 mL). The aqueous layer was extracted with dichloromethane (50 mL×2) and the combined organic layers were washed with brine (50 mL), dried (sodium sulfate), and evaporated. The remaining residue was purified by flush column chromatography on silica gel (50 g) eluting with hexane/ethyl acetate (3/1) to afford 407 mg (85%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.39 (1H, dd, J=8.3, 3.1 Hz), 8.28 (1H, br.s), 8.05 (1H, d, J=3.1 Hz), 8.01 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=8.1 Hz), 7.17–7.05 (4H, m), 4.76 (2H, d, J=5.9 Hz), 3.91 (3H, s); MS (ESI) m/z 399 (M+H)+, 397 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[CH3:25]>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:15]=[CH:14][C:13]=2[CH3:25])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1ccc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1F
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Temperature: 55 °C
Yield: 86 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)-2-methyl-benzamide (150 mg, 0.42 mmol, 1.0 eq) in THF (5 mL) was added dropwise a solution of BH3 (1 M in THF, 3 mL, 3 mmol, 7 eq). The reaction was heated at 55° C. under N2 for 2 h, and then quenched by the addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give compound the title compound as a solid (124 mg, 86%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[F:15][C:16]([F:29])([F:28])[C:17]1[NH:26][C:25](=O)[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]=1.C(OCC)C>C1(C)C=CC=CC=1.O>[Cl:3][C:25]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]=[C:17]([C:16]([F:29])([F:28])[F:15])[N:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)nc2c1CCCC2
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nc(Cl)c2c(n1)CCCC2
Temperature: 25 °C

Procedure:
To a mixture of 6.0 mL of phosphorus oxychloride and 1.0 mL of dimethylaniline in 20 mL of toluene was added 3.0 g of 5,6,7,8-tetrahydro-2-trifluoromethyl-4-quinazolone. The resulting mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was poured into a ice cold mixture of diethyl ether and water. The organic layer was recovered washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield the product as a brown solid (3.46 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[C-:37]#[N:38]>[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.CN(C)C=O>[F:36][C:2]([F:35])([F:1])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:37]#[N:38])[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4]
Reactant: [C-]#N
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(OS(=O)(=O)C(F)(F)F)cccc31)C2)C(F)(F)F
Agent: [Pd]
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
A solution of trifluoromethanesulfonic acid 9-[8-(2,2, 2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-ylidene]-9H-xanthen-4-yl ester in a deoxygenated solvent such as dimethyl formamide (0.5 to 2 M solution) may be treated with a catalytic amount of a palladium catalyst such as tetrakis(triphenylphosphine) palladium ( 0.01 to 0.1 equiv) and a cyanide source such as zinc cyanide (1.5 to 3 equiv). The mixture may be heated to 100° C. to 150° C. under an argon atmosphere for 1 to 5 hr. After cooling, the mixture may be partitioned between a saturated sodium bicarbonate solution and an organic solvent such as ethyl acetate. The organic phase may be separated, dried over an appropriate drying agent such as sodium sulfate, filtered, and evaporated. The residue may be purified over silica gel using a mixture of organic solvents or via reverse phase chromatography to yield Compound 2b.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]([Mg]Br)=[CH:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[N:7]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[C:27]([CH3:26])=[C:28]([CH3:29])[NH:14][C:9]=12)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ccncc1[N+](=O)[O-]
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)ccnc2c1C
Temperature: -20 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
(4-Fluorobenzyl)-(3-nitropyridin-4-yl)-carbamic acid tert-butyl ester (10.2 g) prepared in Step 2 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 110 ml, 130.5 mmol) was added at −78° C. to the solution, which was stirred for 5 hours at −20° C. 20 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, (v/v)) to give the titled compound as a pale yellow solid (3.8 g, 28.9%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[C:11](O)=[O:12]>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1
Reactant: COc1cc(Br)cc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
Lithium aluminium hydride (1M in THF, 22.07 ml) was added dropwise to a stirred solution of the product of step (ii) (5.1 g) in THF (50 ml) at 0° C. and stirred at RT overnight. The reaction was quenched in 2M HCl, extracted with ether, dried (MgSO4) and evaporated under reduced pressure to give an oil, which was purified by flash column chromatography (eluent 1:1 isohexane/diethylether) to give the subtitle compound (5.38 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:36][CH:35]([CH3:37])[CH2:34][N:12]([C:10]([C:2]1[N:3]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)=[O:11])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1
Reactant: BrCCc1ccccc1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (147 mg) was dissolved in dimethylformamide (12 ml), (2-bromoethyl)benzene (58 μl) and cesium carbonate (200 mg) were added and the mixture was stirred at 65° C. for 3 hr. (2-Bromoethyl)benzene (58 μl) was added, and the mixture was further stirred for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (164 mg). MS (ESI+, m/e) 618 (M+1)
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:19]([CH2:23]Cl)=[CH:20][CH:21]=[CH:22][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5].[C-:25]#[N:26].[Na+].O.[OH-].[NH4+]>CS(C)=O>[CH2:2]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:19]([CH2:23][C:25]#[N:26])=[CH:20][CH:21]=[CH:22][C:8]=2[N:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc2cccc(CCl)c2n1Cc1ccccc1Cl
Reactant: [C-]#N
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2cccc(CC#N)c2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A mixture of 2-n-butyl-7-chloromethyl-1-(2-chlorophenyl)methyl-1H-benzimidazole, hydrochloride (1 g, 2.6 mmol) in dimethylsulfoxide (10 mL) was treated with sodium cyanide (153 mg, 3.12 mmol). The solid slowly went into solution, and after stirring for 3 hours at 25° C., the reaction was poured into water, some ammonium hydroxide solution was added and the resulting white precipitate was isolated to give 0.77 g of crude product; mp 122°-124° C. Crystallization from methylene chloride/hexane provided 0.68 g (84% of 2-n-butyl-1-(2-chlorophenyl)methyl-7-cyanomethyl-1H-benzimidazole; mp 124°-125° C.
Reaction SMILES: [NH2:1][C:2]([CH2:4][CH2:5][C:6]([O-:8])=O)=[O:3].[NH2:9][OH:10]>O1CCOCC1>[OH:10][NH:9][C:6](=[O:8])[CH2:5][CH2:4][C:2]([NH2:1])=[O:3]
Reactant: NC(=O)CCC(=O)[O-]
Reactant: NO
Solvent: C1COCCO1
Product: NC(=O)CCC(=O)NO

Procedure:
3-Aminocarbonylpropionate 3 (0.1 mmol) was treated with dioxane (1 mL) and hydroxylamine (50% in water, 2 mL) for 1 to 3 days, and then can be purified by preparative reverse-phase (C18) HPLC to afford the desired N-hydroxy-3-aminocarbonylpropionamide.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12]O)[CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12][Cl:3])[CH:11]=1
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mL (2.20 mmol) of thionyl chloride was added at −10° C. to a solution of 0.60 g (2.00 mmol) of [5-bromo-2-(2-pyrrolidin-1-ylethoxy)phenyl]methanol and 0.42 mL (3.00 mmol) of triethylamine in 30 mL of THF and the mixture was stirred for 16 hours at RT. Ice and dilute aqueous sodium bicarbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic phases were washed with water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.39 g (62% of theoretical); C13H17BrClNO (M=318.637); calc.: molpeak (M+H)+: 318/320/322 (BrCl); found: molpeak (M+H)+: 318/320/322 (BrCl); HPLC-MS: 5.84 minutes (method A).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])=[CH:22][CH:21]=1)=[C:14]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH:13]=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CCO>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([C:14]2[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][S:31][CH2:32][CH2:33][CH2:34][C:35]([F:40])([F:41])[C:36]([F:39])([F:38])[F:37])=[CH:22][CH:21]=3)=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17]3)=[CH:47][CH:46]=1
Reactant: COc1ccc(-c2ccc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
Add dry Pd/C (0.110 g, 0.104 mmol) to 6-benzyloxy-2-(4-methoxy-phenyl)-1-{4-[4-(4,4,5,5,5-pentafluoro-pentylsulfanyl)-butoxy]phenoxy}-naphtalene (0.590 g, 0.847 mmol). Add EtOH (25 mL), followed by ammonium formate (0.382 g, 6.058 mmol). Heat to reflux and stirred for 1.5 hours. Cool to room temperature and add additional Pd/C (0.610 g, 0.547 mmol), and ammonium formate (0.385 g, 6.105 mmol). Heat to reflux and stirred for 3 hours. Add celite (10 g) and filter washing with CH2Cl2 and CH3OH. Concentrate the solution in vacuo. Dissolve the resulting residue in CH2Cl2 (20 mL) and wash the solution with H2O (2×15 mL). Separate the layers and dry the organic (Na2SO4), filter and concentrate in vacuo. Purify by radial chromatography (eluting with 30% EtOAc in hexanes) to afford 0.318 g (62%) of the desired 6-(4-methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentylsulfanyl)-butoxy]-phenoxy}-naphthalen-2-ol as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.83 (t, J=9.3 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.47 (m, 3H), 7.16 (d, J=2.4 Hz, 1H), 7.0 (m, 1H), 6.83 (dd, J=2.0, 6.8 Hz, 2H), 6.58 (m, 4H), 3.81 (t, J=5.9 Hz, 2H), 3.76 (s, 3H), 2.65-2.75 (m, 2H), 2.54 (m, 2H), 2.06-2.29 (m, 3H), 1.68-1.93 (m, 5H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Yield: 88 %

Procedure:
(R)-[3-[1-((2R)-2-Hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 18a (0.12 g, 0.19 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-((2R)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 18 (0.12 g, yield 88%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:11][C@H:12]([CH2:16][N:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]2=[O:27])[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:54]([N:57]([CH:71]([CH3:73])[CH3:72])[P:58](N(C(C)C)C(C)C)[O:59][CH2:60][CH2:61][C:62]#[N:63])([CH3:56])[CH3:55]>ClCCl>[CH:71]([N:57]([CH:54]([CH3:56])[CH3:55])[P:58]([O:59][CH2:60][CH2:61][C:62]#[N:63])[O:15][C@H:13]([CH3:14])[C@@H:12]([CH2:16][N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]1=[O:27])[CH2:11][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:73])[CH3:72]
Reactant: COc1ccc(C(OC[C@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.9 %

Procedure:
To a stirred solution of 47 (0.98 g, 1.75 mmol) in 30 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.3 g) followed by 0.8 g (2.66 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 20 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was p twice by re-dissolving in small (˜10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing precipitate as an oil and decanting the liquid. Drying in vacuo afforded 1.1 g (83%) of 48 as an amorphous white solid. 31P NMR (DMSO-d6): δ 145.84, 144.94.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:67]1[CH:68]=[CH:69][C:70]([N+:78]([O-:80])=[O:79])=[C:71]([CH:77]=1)[CH2:72][NH:73][C:74](=[O:76])[CH3:75]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:74]([NH:73][CH2:72][C:71]1[CH:77]=[C:67]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[CH:68]=[CH:69][C:70]=1[N+:78]([O-:80])=[O:79])(=[O:76])[CH3:75]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)NCc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)NCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To an oven-dried flask, 1-boc-piperazine (3.19 g, 17.1 mmol), Cs2CO3 (5.82 g, 17.86 mmol), Pd2(dba)3 (1.44 g, 1.57 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.89 g, 1.43 mmol), toluene (8 mL) and compound 14 (3.89 g, 14.26 mmol) were added. While stirring the reaction mixture at room temperature, the air in the flask was removed and replaced by N2. This process was repeated three times. The reaction temperature was brought to 110° C. and stirred for 8 h. Ethyl acetate (40 mL) was added to the mixture at room temperature, washed with H2O (15 mL), brine (10 mL), dried over Na2SO4 and evaporated. The brown oily material was chromatographed on a silica column, eluting with hexanes:ethyl acetate (3:7) and then changing to (1:1) to obtain the title compound 15 as light yellow solid (3.88 g, 72%). IR (KBr) νmax. cm−1: 3441 (NH), 3060 (Ar—H), 2963 (Alph-H), 1696 (C═O), 1607, 1577 (C═C), 1484, 1421 (NO2), 1243 (C—N), 1168 (C—O). 1H NMR (500 MHz, CDCl3) δ=1.49 (s, 9H, (C(CH3)3), 2.17 (s, 3H, CH3), 3.42 (br. s, 4H, 2CH2), 3.61 (br. s, 4H, 2CH2), 5.54 (s, 2H, CH2), 6.76 (dd, 1H, J=2.3, 9.3 Hz, H-6), 6.88 (br. s, 1H, H-2), 8.17 (d, 1H, J=9.4 Hz, H-5). 13C NMR (125.7 MHz, CDCl3) δ=20.93 (CH3), 28.39 (C(CH3)3), 46.82 (CH2), 50.02 (CH2), 66.12 (CH2), 80.42 (C(CH3)3), 112.30 (aromatic-C), 112.48 (aromatic-C), 128.17 (aromatic-C), 135.60 (aromatic-C), 137.03 (aromatic-C), 153.02 (aromatic-C), 154.56 (CO), 170.29 (CO). Calculated (%) for C18H26N4O5 (378.19); C, 57.13; H, 6.93; N, 14.81. found (%); C, 57.07; H, 6.99; N, 14.71.
Reaction SMILES: Cl[Si](Cl)(Cl)Cl.[N-:6]=[N+:7]=[N-:8].[Na+].[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[CH2:33][CH3:34])[CH:26]=1)[C:19]([CH3:37])([CH3:36])[CH2:18]2)=[O:14])[CH3:11]>C(#N)C>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[C:32]([CH2:33][CH3:34])=[N:8][N:7]=[N:6]3)[CH:26]=1)[C:19]([CH3:37])([CH3:36])[CH2:18]2)=[O:14])[CH3:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)CC)c1)N2
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3CC)c1)N2
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a stirred solution of tetrachlorosilane (5.3 mL, 46.3 mmol), sodium azide (5.6 g, 87 mmol) in dry acetonitrile (20 mL) was added 3,3-dimethyl-2-(3-propionylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.2 g, 5.8 mmol) at room temperature. Then the mixture solution was stirred at room temperature for over night. LC/MS showed that reaction finished completely. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) afforded 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 66%) as a white solid: LC/MS m/e calcd for C23H27N5O2 (M+H)+: 406.50, observed: 406.2.