Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([N:15]([CH2:20][CH:21]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:22][CH2:23][O:24]C2CCCCO2)[CH2:16][CH2:17][O:18][CH3:19])=[O:14])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]>C(OCC)C.CO>[CH:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([N:15]([CH2:20][CH:21]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:22][CH2:23][OH:24])[CH2:16][CH2:17][O:18][CH3:19])=[O:14])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: COCCN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COCCN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1

Procedure:
A saturated solution of hydrochloric acid in diethylether is added to a solution of 2.2 g of the product obtained in step 3 in 30 ml of methanol, until the obtention of a pH value of 1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:2]2[CH:7]=[C:6]([C:8]3[S:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(F)c2)s1
Solvent: O
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC3CC3)c2)s1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
In a closed vessel, 600 mg (1.98 mmol) of 2-fluoro-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine (described, for example, in J. Med. Chem, 2005, 48, 5966-5979) in 10 ml cyclopropylamine are heated with stirring at 150° C. After 16 h, the reaction mixture is stirred into 100 ml of water and extracted with ethyl acetate (3×50 ml). The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The residue is then purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 520 mg (77%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.96 (d, 1H), 7.52 (m, 2H), 7.17 (m, 2H), 6.65 (s, 1H), 6.49 (s 1H), 6.45 (d, 1H), 3.04 (q, 2H), 2.37 (m, 1H), 1.36 (t, 3H), 0.55 (m, 2H), 0.33 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br.O>C1(C)C=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:9]3[C:10](=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:8][C:6]2=[S:7])[CH2:3][CH2:2]1
Reactant: COc1ccc(N(CC2CC2)C(N)=S)cc1
Reactant: O=Cc1ccccc1
Agent: Br
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=S)N2CC1CC1
Yield: 71.8 %

Procedure:
To a suspension of 2.36 g (0.01 mole) of N-cyclopropylmethyl-N-(p-methoxyphenyl) thiourea in 30 ml of toluene were added 1.21 g (0.011 mole) of benzaldehyde and 0.84 g (0.005 mole) of 48% hydrobromic acid. The resulting mixture was heated under reflux for 6 hours using a water separator. After cooling, the reaction mixture was washed with dilute hydrochloric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from isopropyl alcohol to give 2.33 g (72%) of 1-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinethione, m.p. 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:16]1[S:15][C:14]2[CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][NH:10][C:11]=3[C:18]=2[CH:17]=1
Reactant: BrBr
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Solvent: CC(=O)O
Product: Brc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cn1
Temperature: 80 °C
Yield: 95 %

Procedure:
6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.16 g, 0.5 mmol) was added with a solution of bromine in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated at 80° C. for 12 hr. The solution was cooled to room temperature and poured into ice water. The resultant precipitate was filtered, washed with water to provide the corresponding 2-Bromo-6-(6-bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.18 g, 0.48 mmol) as yellow solid in 95% yield.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([Br:59])=[CH:55][N:54]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:59][C:56]1[CH:57]=[CH:58][C:53]([NH:52][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:23])([F:22])[F:24])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:54][CH:55]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc(Br)cn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 352.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 155A, 73 mg, 0.07 mmol) and triphenylphosphine (79 mg, 0.08 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34 mmol). The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. At this time, reaction mixture was treated with 2-amino-5-bromopyridine (52 mg, 0.30 mmol) and a few drops of pyridine. The resulting reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was then diluted with methylene chloride (50 mL). The organic phase was washed with water (1×35 mL) and a saturated aqueous sodium chloride solution (3×35 mL), dried over magnesium sulfate and sodium sulfate, treated with charcoal, filtered through a pad of celite, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 70/30 hexanes/ethyl acetate) afforded N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionamide (128.3 mg, quant) as a white solid: mp 81-85° C.; EI-HRMS m/e calcd for C21H22BrF3N2O3S (M+) 518.0486, found 518.0489.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1.[NH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:29][C@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1
Reactant: CS(=O)(=O)c1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 2-difluoromethyl-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (770 mg), tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (525 mg), potassium carbonate (390 mg), and N,N-dimethylacetamide (19 mL) was stirred in a microwave reactor at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (310 mg) as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.F[C:18](F)(F)C(O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12]([CH3:18])[N:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(OCc2cnccn2)c(Cl)c1
Solvent: CO
Product: Cc1cncc(COc2ccc(N)cc2Cl)n1

Procedure:
Compound 31A was prepared by a route analogous to that used for the preparation of Compound 16A. Analytical HPLC retention time=1.593 min. (Chromolith Speed ROD column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% trifluoroacetic acid, 4 mL/min, monitoring at 254 nm) and a LC/MS M++1=250+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[Li]C(C)(C)C.CCCCC.C(Br)C[Br:29]>C1COCC1>[Br:29][CH2:16][Si:13]([CH3:15])([CH3:14])[C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: BrCCBr
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CBr
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 17.9 %

Procedure:
To a solution of the compound of example 45 (1.28 g, 5 mmol) in THF (30 mL) at -78° C. was added a 1.7M solution of t-BuLi in pentane (6.5 mL, 11 mmol, 2.2 eq) such that the temperature was less than -70° C. The reaction was stirred at -78° C. for 1.5 h and ethylene dibromide (0.52 mL, 6.0 mmol, 1.2 eq) was added. The reaction was stirred for 15 min at -78° C. and worked up in the usual manner. The crude product was purified by RC and recrystallized from aq methanol to afford the title compound as white needles (0.30 g, 18%). m.p. 98°-99° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(N)=[O:23].O>O1CCOCC1>[OH:23][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: NC=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CO)c1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 55 %

Procedure:
A solution of 19 in dioxane was added to formamide-water (10:1) and the mixture was stirred at 110° C. for 6.5 hrs., then was worked up as for 12 above. Purification by column chromatography gave 20 (55%) whose structure was established by spectral data. Calcd for C17H15NO3 : 281.1052 Found: 281.1052 (HREIMS).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=O)=[C:4]([F:12])[CH:3]=1.[NH:13]([C:15](=[S:17])[NH2:16])[NH2:14].O=P(Cl)(Cl)Cl>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]2[S:17][C:15]([NH2:16])=[N:13][N:14]=2)=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2c(F)cc(Br)cc2F)s1
Temperature: 78 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A stirred mixture of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol) and hydrazinecarbothioamide (2.88 g, 31.6 mmol) was cooled under nitrogen in an ice bath. POCl3 (5.9 mL, 63.3 mmol) was added drop-wise and the reaction was stirred at ice bath temperature for 15 minutes then heated at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath then quenched by addition of ice water (150 mL). The resulting solid was sonicated for 30 minutes to give a free stirring suspension which was left to slurry at room temperature for 72 hours. The solid was collected by vacuum filtration, rinsed with water, and re-suspended in saturated NaHCO3(aq) (150 mL). This suspension was stirred at room temperature for 18 hours then the solid was collected by vacuum filtration, rinsed with water, and dried in a vacuum oven for 24 hours to give the title compound (5.174 g, 84% yield) which was used in the next step without further purification. LC-MS: Rt 0.99 min; MS m/z 294.2 [M+2]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (d, J=8.08 Hz, 2H), 7.57 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.ClC1C=C(C([NH:21][C@H:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C@H:23]2[O:33][CH2:34][CH2:35][CH3:36])=O)NC=1C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:21][C@@H:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][C@@H:23]1[O:33][CH2:34][CH2:35][CH3:36])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)c1cc(Cl)c(C)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO2006087543, 1.77 g, 9.13 mmol) and ethyl (3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73, 2.1 g, 9.13 mmol) in dichloromethane (150 mL) was added N-Hydroxybenzotriazole (1.67 g, 10.95 mmol) and N-methylmorpholine (2.76 g, 27.39 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.023 g, 16.43 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (30 mL) and the layers were separated. The organic layer was washed with sodium bicarbonate (40 mL), water (60 mL) and finally with brine successively, and dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate 3.3 g (89.1%) as solid.
Reaction SMILES: [NH3:1].[O:2]=[C:3]1[CH2:7][C@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[C@@H:11]([CH2:16][CH3:17])[C:12](OC)=[O:13]>O>[O:2]=[C:3]1[CH2:7][C@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]1[C@@H:11]([CH2:16][CH3:17])[C:12]([NH2:1])=[O:13]
Reactant: N
Reactant: CCC[C@H]1CC(=O)N([C@@H](CC)C(=O)OC)C1
Solvent: O
Product: CCC[C@H]1CC(=O)N([C@@H](CC)C(N)=O)C1
Reaction time: 6 h

Procedure:
Ammonia gas was condensed in 2 ml water at 0–5° C. and the temperature of the system was maintained at 0–5° C. 0.68 g of methyl (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanoate obtained such as described above was then added dropwise, maintaining the reaction mixture at 0–5° C. The system was then stirred for 6 hrs, with TLC indicating completion of reaction. After standing overnight at ambient temperature the reaction mixture was concentrated at 40° C. under vacuum and further dried by azyeotropic distillation with toluene to give 150 mg of crude (2S)-2-[2-oxo-(4S)-4-propyl-1-pyrrolidinyl]butanamide.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](C(N)CCBr)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([O:20][C:18](=[O:19])[NH:10][CH2:9][CH2:8][CH2:7][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Reactant: c1ccc(C2(c3ccco3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCN1CCC(c2ccccc2)(c2ccco2)CC1
Yield: 32 %

Procedure:
A solution of 4-phenyl-4-furan-2-yl-piperidine and 3-Boc-aminopropylbromide (0.30 g, 1.3 mmol) with 0.5 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.21 g (0.54 mmol, 32% for two steps) of 3-(4-phenyl-4-(furan-2-yl)piperidin-1-yl)propylcarbamic acid tert-butyl ester as a colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.13 g, 0.45 mmol, 84%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1COCC1.C(O)C>[CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCN
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: NCCCCCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of benzaldehyde (1.0 ml, 10.0 mmol) in THF (50 ml) was added with heating at reflux to a solution of 1,6-diaminohexane (5.81 g, 50.0 mmol) and p-toluene sulfonic acid (9.5 1 g, 50.0 mmol) in ethanol (50 ml) and then it was heated to reflux for 3 h under a nitrogen atmosphere. After cooling to room temperature, sodium borohydride (1.13 g, 30.0 mmol) was added to the solution and it was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue dissolved in chloroform. The chloroform phase was washed with water, and dried over magnesium sulphate, the solvent was removed under reduced pressure. The residue was washed with water (25 ml), and it dissolved in chloroform and washed again with water (2×50 ml). Then dried over magnesium sulphate, and the solvent removed under reduced pressure to yield a yellow oil (1.61 g, 78%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCO
Product: O=C(NCCCCO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl trifluoroacetate (3.3 mL; 28 mmol) was added dropwise to cooled (0° C.) 4-amino-1-butanol (2.0 g; 22.4 mmol). The mixture was stirred for 2 h at 0° C. and evaporated. The clear liquid was dried on the high vacuum. The product was obtained in a yield of 4.1 g (99%). 1H-NMR (500 MHz, CDCl3): δ=1.61-1.67 ppm (m, 2H), 1.68-1.74 ppm (m, 2H), 2.31 (bs, 1H), 3.38 ppm (dt, 2H), 3.72 ppm (t, 2H), 7.40 ppm (bs, 1H); 13C-NMR (500 MHz, CDCl3): δ=26.02, 29.70, 40.01, 62.48, 116.20 ppm (q, J=1144.0 Hz), 157.66 ppm (q, J=146.5 Hz). HRMS [+Scan]; calculated m/z for C6H11NO2F3 186.0747; observed mass: 186.0741.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:19][CH2:18]1)([CH2:13][CH2:14][CH:15]=[CH2:16])[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[CH3:33][C:34]1([CH3:41])[C:38]([CH3:40])([CH3:39])[O:37][BH:36][O:35]1.O>ClCCl.[Ir+].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]([CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[O:24][C:25]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:21][CH2:22]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:36]1[O:37][C:38]([CH3:40])([CH3:39])[C:34]([CH3:41])([CH3:33])[O:35]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)hex-5-enamide (240 mg, 0.52 mmol) in dichloromethane (4 mL), was treated with chloro-1,5-cyclooctadiene iridium(I) dimer (10.4 mg, 3 mol %) and 1,2-bis(diphenylphosphino) ethane (12.2 mg, 6 mol %). The solution was stirred at room temperature for 30 minutes and then 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.152 mL, 1.04 mmol) was added dropwise, and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification of the crude product by flash column chromatography (silica gel, 30-100% ethyl acetate in heptane) gave 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide as a colorless oil (212 mg, 69%). 1H NMR (CDCl3, 300 MHz) δ 7.24 (d, J=2 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.12 (dd, J1=8.5 Hz, J2=2 Hz, 1H), 6.97 (s, NH, 1H), 5.48 (s, NH, 1H), 4.32 (m, 2H), 3.02 (m, 2H), 2.84 (m, 1H), 2.47 (tt, J1=12.5 Hz, J2=3 Hz, 1H), 2.01 (s, 3H), 1.86 (m, 2H), 1.30-1.55 (m, 6H), 1.34 (s, 9H), 1.24 (s, 12H), 1.02-1.22 (m, 1H), 0.75 (t, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH:18][CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20](O)=[O:21])=[O:17])=[CH:10]2>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:20]([CH:19]([NH:18][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:6])=[CH:15][CH:14]=2)=[O:17])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:2]
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCNCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)C(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Diethylamine (1.2 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.6 mmol) were coupled according to procedure A (0-25° C. for 5 days) substituting the following workup: the crude product was suspended in 1:1 chloroform/dichloromethane, sonicated, filtered to remove solids, concentrated, and the residue purified by column chromatography on silica gel eluted with 10, 20 and 30% ethyl acetate in hexanes: Yield 14 mg, 6%; HPLC (60/40) 8.88 minutes (98%); PBMS 398/400 (MH+, 100%);
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:14](=[O:24])[NH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Cl.[CH3:26][N:27]1[CH2:33][C:32]2[CH:34]=[C:35](/[CH:38]=[CH:39]/[C:40](O)=O)C=N[C:31]=2[NH:30][C:29](=O)[CH2:28]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[N:30]([CH3:31])[CH2:29][C:28]2[N:27]([CH3:26])[C:33]3[C:39]([CH:40]=2)=[CH:38][CH:35]=[CH:34][CH:32]=3)=[CH:5][C:4]=1[C:14]([NH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:24]
Reactant: Nc1ncc(C=CC(=O)O)cc1C(=O)NCCN1CCOCC1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc(N)c(C(=O)NCCN2CCOCC2)c1
Yield: 23 %

Procedure:
According to the procedure of Example 1, except substituting 3-[6-amino-5-(2-morpholin-4-yl-ethylcarbamoyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (170 mg, 23%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.87-10.61 (m, 1H), 9.69-9.66 (m, 1H), 9.40-9.28 (m, 1H), 8.70-8.31 (m, 3H), 7.95-7.39 (m, 4H), 7.15-6.97 (m, 2H), 6.40-6.08 (m, 1H), 5.27-4.85 (m, 2H), 3.94-3.55 (m, 12H), 3.20-2.96 (m, 6H); MS (ESI) m/e 477 (M+H)+.