Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>C(O)(C)(C)C>[C:20]([O:19][C:17]([NH:16][CH2:15][C@H:10]([N:9]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:11]([O:13][CH3:14])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: BrCCCCCBr
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
14.4 ml (104 mmol) of triethylamine are added to a solution of 8.0 g (31 mmol) of commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride in 160 ml of tert-butanol, and then the reaction medium is stirred for 30 min at 40° C., and filtered in order to remove the triethylammonium salts. 6 ml (44 mmol) of 1,5-dibromopentane are added to the filtrate thus obtained, and the reaction medium is heated at 80° C. for 3 days. After the insoluble material has been filtered off, the filtrate is concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 5.3 g (59%) of methyl(S)-3-tert-butoxycarbonylamino-2-piperidin-1-ylpropanoate are obtained in the form of a colorless oil.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[C:37](O)([C:39](F)(F)F)=O.CC(O)=O.C(O[C:51]1(O[Si](C)(C)C)[CH2:53][CH2:52]1)C.[BH3-]C#N.[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O.[OH-].[Na+]>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[S:27][C:21]3[C:20](=[O:35])[N:19]([C:16]4[CH:15]=[N:14][C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([N:7]([CH:51]6[CH2:53][CH2:52]6)[CH:6]6[CH2:39][CH2:37]6)[CH2:9]5)=[CH:18][CH:17]=4)[CH2:24][CH2:23][C:22]=3[CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3CCc4cc(-c5ccc(Cl)cc5)sc4C3=O)cn2)C1
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1c2sc(-c3ccc(Cl)cc3)cc2CCN1c1ccc(N2CC[C@@H](N(C3CC3)C3CC3)C2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Dissolve ((R)-1-{5-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno [2,3-c]pyridin-6-yl]-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.393 g, 0.750 mmol) in CHCl3 (5 mL) and treat with TFA (2 mL). Stir the mixture at RT for 30 min. Remove the excess reagent in vacuo. Dissolve the crude material in CH3OH (10 mL) and treat with HOAc (90.22 mL, 3.93 mmol), and (1-ethoxy-cyclopropoxy)trimethylsilane (0.47 mL, 2.36 mmol). Stir the mixture at RT for 10 min. Add NaBH3CN (90.36 g, 5.69 mmol) and reflux the reaction overnight. Dilute the mixture with EtOAc (50 mL) and 2.0 M NaOH (920 mL) and then stir at RT for 5 min. Filter and wash the mixture with EtOAc (30 mL). Separate the organic layer and dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 5% CH3OH (2M NH3)/CHCl3 to give 0.35 g (93%) of 2-(4-chloro-phenyl)-6-[6-((R)-3-dicyclopropylamino-pyrrolidin-1-yl)-pyridin-3-yl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:23][CH2:22][N:21]([C@@:24]4([CH3:36])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:13]=2)=[CH:4][N:3]=1.[ClH:37].O1CCOCC1>CO.C1(C)C=CC=CC=1>[ClH:37].[CH3:20][C@H:15]1[CH2:16][O:17][CH2:18][CH2:19][N:14]1[C:12]1[N:13]=[C:8]([C:5]2[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=2)[C:9]2[CH2:23][CH2:22][N:21]([C@@:24]3([CH3:36])[CH2:28][CH2:27][NH:26][CH2:25]3)[C:10]=2[N:11]=1
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCNC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a flask containing tert-butyl(3S)-3-{4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-methylpyrrolidine-1-carboxylate (3290 mg, 6.625 mmol) in 31 mL MeOH was added 4 N HCl in dioxane (33 mL, 132 mmol) dropwise at 0° C. and the mixture was stirred at room temperature for 2 h. The mixture was diluted with toluene and concentrated. Additional toluene was added and the solution was concentrated to give the title compound (3.73 g, >99%) as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (br s, 2 H), 8.69 (s, 2 H), 7.33-7.11 (m, 2H), 4.63-4.52 (m, 1 H), 4.20 (d, J=11.5 Hz, 1 H), 4.03-3.89 (m, 2 H), 3.83-3.18 (m, 10 H), 3.14-3.03 (m, 2 H), 2.71-2.55 (m, 1 H), 2.20-2.04 (m, 1 H), 1.48 (s, 3 H), 1.28 (d, J=6.7 Hz, 3 H). m/z (APCI+) for C20H28N8O 397.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[C:32]([F:31])=[CH:38][C:37]([F:39])=[CH:36][C:35]=3[F:40])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3c(F)cc(F)cc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 11.2 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.100 g, 0.268 mmol), thionyl chloride (3.0 mL), 2,4,6-trifluoroaniline (0.059 g, 0.403 mmol), THF (10.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.52 (s, 6H), 2.24 (s, 3H), 3.10 (s, 2H), 7.24-7.32 (m, 4H), 7.41 (d, J=7.2 Hz, 1H), 7.45 (s, 1H), 9.12 (s, 1H), 10.91 (s, 1H); MS [M+H]+: 501.37.
Reaction SMILES: [N:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:15])[C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:15])[C:10]2[S:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1
Reactant: O=NN1CCN(C(=O)c2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: NN1CCN(C(=O)c2cccs2)CC1
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a solution of 1-nitroso-4-(2-thenoyl)piperazine (1.78 g) in a mixture of acetic acid (8 ml) and water (8 ml) was added Zn powder (1.55 g) in several portions at 6°-15° C. The suspension was stirred for 1.5 hours below 10° C. To the mixture was added acetic acid (4 ml) and Zn powder (780 mg) at 8°-12° C. The mixture was stirred for 2 hours at ambient temperature. To the suspension was added 17% aqueous sodium hydroxide solution (70 ml). The insoluble materials were filtered off. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by 5% methanol in dichloromethane) to yield 1-amino-4-(2-thenoyl)piperazine (1.17 g) as a pale yellow syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: C1CNCCN1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCNCC3)nncc2c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 64.2 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.146 g, 0.6 mmol), piperazine (0.1 g, 1.2 mmol) and potassium carbonate (0.08 g, 0.6 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=293, 295). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give (0.113 g) 6-bromo-1-(piperazin-1-yl)phthalazine as a yellow solid. Found MS (ES+): 293, 295(M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]([CH3:33])=[C:21]([CH3:32])[C:22]3[O:26][C:25]([CH3:28])([CH3:27])[CH:24](O)[C:23]=3[C:30]=2[CH3:31])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:34]>C(OCC)(=O)C>[ClH:34].[ClH:34].[CH2:6]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]([CH3:33])=[C:21]([CH3:32])[C:22]3[O:26][C:25]([CH3:27])([CH3:28])[CH:24]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:23]=3[C:30]=2[CH3:31])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(Cc3ccccc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Yield: 93 %

Procedure:
Using pyrrolidine and 5-(4-benzyl piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 42, the free base was obtained in the same manner as in Example 57. The free base was treated with a 4 N hydrochloric acid in ethyl acetate solution (10 ml) to obtain the title compound. Yield 93%. mp. 224–227° C. (decomposition) (ethyl acetate-ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:14]N1C(=O)CCC1=O.O.C(OCC)C>CC1CCCO1>[Br:14][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2c1OC(C)(C)C2
Solvent: O
Solvent: CCOCC
Solvent: CC1CCCO1
Product: COc1cc(Br)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
56 g 7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran are dissolved in 200 ml 2-methyltetrahydrofuran, 58 g N-bromosuccinimide are added portion wise, while keeping the temperature of the reaction mixture below 50° C., and the reaction is stirred for one hour at RT. Water and diethyl ether are added to the reaction mixture, the phases are separated, the organic phase is washed with 1 M aqueous sodium carbonate solution, dried over MgSO4, and the solvent is removed under reduced pressure. The resulting crude product is purified by distillation under vacuum yielding 5-bromo-7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][N:10]2[C@@H:4]([CH2:5][N:6]([C:16](=[O:38])[C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:37])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:18]=3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9]2)[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[ClH:61]>CS(C)=O>[ClH:61].[C:31]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([N:6]3[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH2:9][N:10]4[CH2:11][C:2](=[O:1])[CH2:3][C@@H:4]4[CH2:5]3)=[O:38])=[CH:18][CH:19]=2)=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Nc1ccc(C(=O)N2C[C@H]3C[C@@H](O)CN3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C[C@@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3CN2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a solution of (2R,11aR)-2-hydroxy-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.4 g) prepared in Example 45 and obtained in the form of free base in dimethyl sulfoxide (8 ml), there was added, at room temperature, 1.6 g of N,N′-dicyclohexyl carbodiimide and 0.135 g of trifluoroacetic acid. After stirring the reaction solution at room temperature for 15 hours, a 6N hydrochloric acid solution was added thereto and the reaction solution was stirred for additional 30 minutes. The precipitates separated out were filtered off and washed with water. The filtrate and the wash liquid were combined, the mixture was alkalified with a saturated aqueous solution of sodium carbonate and then extracted with ethyl acetate. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/acetone (4/1) to thus give 0.23 g of (11aR)-10-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-2-one in the form of amorphous powder. The resulting amorphous powder (0.23 g) was dissolved in ethyl acetate and 0.12 ml of a 4N hydrochloric acid-ethyl acetate solution was added to the resulting solution at room temperature. After stirring the mixture at room temperature for one hour, the resulting precipitates separated out were recovered by filtration, followed by washing them with ethyl acetate and then dried to thus give 0.15 g (yield 34.2%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.C(N(CC)CC)C.O1CCOCC1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[CH2:33]Br>C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([N:7]2[CH2:33][C:24]3[C:23](=[CH:28][CH:27]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:25]=3)[CH2:22]2)=[CH:5][CH:4]=[N:3]1
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1
Reactant: Cn1nccc1N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1nccc1N1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
1-Methyl-1H-pyrazol-5-amine (1.53 g) and triethylamine (4.60 mL) were added to a 1,4-dioxane (53 mL) solution of 1,2-bis(bromomethyl)-4-(trifluoromethyl)benzene (5.25 g) at a room temperature, and the obtained solution was then stirred at 100° C. for 1 hour. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water and a saturated saline. The resultant was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=2:1 to 40:60), so as to obtain the title compound (785 mg) in the form of a colorless solid.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl-].[Li+].[F:28][C:29]([F:39])([F:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=O>C(#N)C.C(OC)(C)(C)C>[CH2:12]([O:14][C:15](=[O:25])/[CH:16]=[CH:36]/[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([F:28])([F:38])[F:39])[CH3:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CCCCCCCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COC(C)(C)C
Product: CCOC(=O)/C=C/CCCCCCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (436 μL, 2.92 mmol) was added to a solution of (diethoxy-phosphoryl)-acetic acid ethyl ester (633 μL, 2.43 mmol) and lithium chloride (144 mg, 3.41 mmol) in acetonitrile (20.0 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. A solution of 8,8,8-trifluoro-octanal (2.43 mmol) in acetonitrile (4.3 mL) was added dropwise to the reaction solution at 0° C., and the mixture was stirred for 10 minutes. Thereafter, the reaction mixture was stirred at room temperature for one hour and diluted with methyl tert-butyl ether (200 mL). The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution (30 mL), H2O (30 mL) and saturated brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (E)-10,10,10-trifluoro-dec-2-enoic acid ethyl ester as a colorless oily substance (426.6 mg, 70%).
Reaction SMILES: NCC(N)C.[C:6]1([CH2:12][C@H:13]([NH2:16])[CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17]([NH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29](O)=O)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:12]([CH:13]1[CH2:14][NH:15][C:29]([C:28]2[CH:32]=[CH:33][N:34]=[C:26]([NH:25][C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:27]=2)=[N:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NC[C@@H](N)Cc1ccccc1
Agent: CC(N)CN
Product: O=C(Nc1cc(C2=NC(Cc3ccccc3)CN2)ccn1)c1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with (S)-3-phenylpropane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-benzyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 34% yield: MS (ES+) m/z 357.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15](C)[CH:14]=[CH:13][C:12]=2[N+:18]([O-])=O)=[O:10])=[N:6][CH:7]=1.[H][H]>CO.[Pt]>[NH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][N:6]=1)=[O:10].[Cl-:1]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Nc1ccccc1C(=O)Nc1ccccn1
Product: [Cl-]

Procedure:
To a solution of the compound of N-(5-chloro(2-pyridyl))(5-methyl-2-nitrophenyl)carboxamide (1.48 g, 5.1 mmol) in methanol (10 ml) was added 5% Pt/C (1.48 g, 0.19 mmol). The mixture was applied hydrogen balloon at r.t. for 2 hrs. After the filtration by Celite, the filtrate was concentrated to give (2-aminophenyl)-N-(2-pyridyl)carboxamide, C, chloride, N (1.36 g, 100%). MS found for C13H12ClN3O M+=262, (M+2)+=264. Step 3: To a solution of the compound of (2-aminophenyl)-N-(2-pyridyl)carboxamide, C, chloride, N (1.36 g, 5.2 mmol) in dichloromethane (10 ml) was added 3-cyanobenzoly chloride (860 mg, 5.2 mmol) and pyridine (1.26 ml, 15.6 mmol). The mixture was stirred at r.t. overnight. After the evaporation of the solvent, the crude residue was purified by silica gel column chromatography using solvent system 25% ethyl acetate in hexane as eluent to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}(4-cyanophenyl)carboxamide as a solid (830 mg, 41%). MS found for C21H15ClN4O2 M+=390, (M+2)+=392. Step 4: To a lotion of the compound of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}(4-cyanophenyl)carboxamide (830 mg, 2.1 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10 ml) was saturated with hydrogen chloride gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine (0.926 ml, 10.5 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for C24H22ClN5O2 M+=448, (M+2)+=450.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[C@@H:22]([C@H:23]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:20][C@H:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH3:10])[C:43]([C:42]2[CH:41]=[CH:40][C:39]([CH2:38][C@H:19]3[CH2:20][CH2:21][C@@H:22]([C@H:23]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]3[C:16]([O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:17])=[CH:47][CH:46]=2)=[O:44])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CNCc1cccc(Br)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cccc(Br)n1)C(=O)c1ccc(C[C@H]2CC[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.2 %

Procedure:
1-(6-Bromopyridin-2-yl)-N-methylmethanamine (115 mg, 0.571 mmol) was added to a stirred, room temperature mixture of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (300 mg, 0.571 mmol), HATU (260 mg, 0.685 mmol, 1.2 equivalents) and DIPEA (498 μL, 2.85 mmol, 5 equivalents) in DMF (2.8 mL). The reaction was stirred at room temperature for 12 hours, and then diluted with EtOAc and partitioned with water. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography using silica gel (0-50% hexanes/ethyl acetate). The product was collected and concentrated in vacuo to afford the title compound (110 mg, 27%). LC-MS=608.2 & 610.2 (M-Boc+H)+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[S:6]([N+:10]12[CH2:17][CH2:16][N:13]([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)([OH:9])(=[O:8])=[O:7].B(F)(F)[F:19].FF>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[F:1][B-:2]([F:5])([F:4])[F:3].[F:19][N+:13]12[CH2:14][CH2:15][N+:10]([S:6]([OH:9])(=[O:7])=[O:8])([CH2:11][CH2:12]1)[CH2:17][CH2:16]2
Reactant: FB(F)F
Reactant: O=S(=O)(O)[N+]12CCN(CC1)CC2
Agent: FF
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: O=S(=O)(O)[N+]12CC[N+](F)(CC1)CC2

Procedure:
A solution of 1-sulfo-4-aza-1-azoniabicyclo[2.2.2]octane tetrafluoroborate (28 g, 10 mmole) and boron trifluoride gas (6.7 g, 10 mmole) in acetonitrile (125 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 12 mmole). The reaction was evaporated, the remaining solid washed with DME and dried to afford 1-fluoro-4-sulfo-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Clc1ccn2ccnc2c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 25 °C
Yield: 361.2 %

Procedure:
Heat a mixture of 7-chloro-imidazo[1,2-a]pyridine (100 g, 152.5 mmol, 1 eq), 4-methylsulfonylphenyl boronic acid (157.3 g, 786.8 mmol, 1.2 eq), Pd(PPh3)4 (19 g, 16.3 mmol, 0.025 eq) and cesium carbonate (472.4 g, 1.44 mol, 2.2 eq) in a mixture of anhydrous DME (2000 mL) and EtOH (1000 mL) at 80° C. under N2 atmosphere for 24 hours. Cool the mixture to room temperature and filter through Celite® to remove Pd catalyst. Add water (5000 mL) and extract this solution with CH2Cl2 (3×2000 mL). Dry the organic phase over MgSO4 and evaporate. Add to the crude 2000 mL of CH2Cl2 and heat to reflux. Remove insoluble materials by filtration and evaporate the solvent to afford a yellow solid. Wash the solid with ethyl ether to give 150 g of the desired compound as a light yellow solid. (Yield: 85%). MS (ES), m/z 273 (M+1).