Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]([C:7]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3][CH2:2]1.[OH-].[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]Cl)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[OH:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]1[CH2:5][CH2:4][N:3]([CH2:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:2][CH2:1]1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: COc1ccc(CCCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 4 g of α,α-diphenyl-4-piperidinomethanol, 0.94 g of powdered potassium hydroxide and 200 mg of KI are dispersed in 50 ml of toluene in a 250 ml round-bottomed flask. Addition of 2.3 ml of 4-methoxyphenylethyl chloride is followed by heating under reflux for 3 days.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:17]3[CH:16]=[C:15]([C:18]([O:20]C)=[O:19])[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[C:17]3[CH:16]=[C:15]([C:18]([OH:20])=[O:19])[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2CCCc1ccccc1
Yield: 57.1 %

Procedure:
The title compound was synthesized from methyl 4-(3-phenylpropyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (210 mg, 0.74 mmol) and lithium hydroxide monohydrate (124 mg, 2.96 mmol) according to General Procedure 7. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-(3-phenylpropyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (36) as a light brown solid (113.8 mg, 57%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.42-1.59 (m, 2H), 1.64-1.84 (m, 2H), 1.90-2.01 (m, 1H), 2.52-2.75 (m, 5H), 2.88-2.97 (m, 1H), 6.61 (s, 1H), 7.10-7.20 (m, 3H), 7.21-7.28 (m, 2H); LCMS-MS (ESI+) 270.1 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CCC(OS(C)(=O)=O)CC2)cc1
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 4-(4-hydroxypiperidin-1-yl)benzoate (8.0 g, 32.1 mmol) in CH2Cl2 (200 mL) was added Et3N (23 mL, 165 mmol) under nitrogen, followed by MsCl (5.6 g, 48.9 mmol). The mixture was stirred for 5 minutes, washed with water (300 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford ethyl 4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate as a tan solid (10.5 g, 100%).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:13]2[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:34]=1)[CH:8]=C>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:41]1([CH2:40][O:39][C:35]2[CH:34]=[C:33]([C:13]3[C:12]4[C:16](=[CH:8][CH:7]=[C:10]([CH2:18][CH:17]=[O:2])[CH:11]=4)[N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[C:14]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:38]=[CH:37][CH:36]=2)[CH2:43][CH2:42]1
Reactant: C=CCc1ccc2c(c1)c(-c1cccc(OCC3CC3)c1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2cccc(OCC3CC3)c2)c2cc(CC=O)ccc2n1Cc1cccc(OC)c1
Reaction time: 18 h
Yield: 47.3 %

Procedure:
Sodium periodate (430 mg, 2.0 mmol) and osmium tetroxide (2.5 wt % solution in tert-butanol, 0.50 mL, 0.05 mmol) were added to a stirred solution of ethyl 5-allyl-3-[3-(cyclopropylmethoxy)phenyl]-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 132, 385 mg, 0.777 mmol) in tetrahydrofuran (10 mL) and water (1 mL). The reaction was stirred for 18 h and then diluted with water (100 mL). The product was extracted with ethyl acetate (3×50 mL) and then the combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 15% ethyl acetate/hexane gave 183 mg (47%) of product containing impurities. The material was used in the next reaction without further purification. Mass spectroscopy gave MH+=498.1 (exact mass calc'd for C31H31NO5=497.22).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>C(#N)C>[CH2:24]([O:12][C:10]1[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(O)c(C(=O)OC)cc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (10 ml) was treated with allyl bromide (0.35 ml, 4.0 mmol) and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The organic material was extracted with dichloromethane (2×20 ml), the combined organic extracts were evaporated in vacuo and the residue subjected to column chromatography on silica. Elution with 2-10% ethyl acetate in petroleum ether afforded methyl 4-allyloxy-2-hydroxy-5-isopropylbenzoate (330 mg, 60%) as a colourless solid. 1H NMR (DMSO-d6) 10.68 (1H, s), 7.55 (1H, s), 6.54 (1H, s), 6.06 (1H, m), 5.42 (1H, dm), 5.29 (1H, dm), 4.65 (2H, m), 3.88 (3H, s), 3.16 (1H, m), 1.16 (6H, d).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:25]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])=[CH:6][CH:5]=1
Reactant: ClCCN1CCCC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cn[nH]c2)c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cnn(CCN3CCCC3)c2)c2ccc(Br)cc21
Reaction time: 0.33 h

Procedure:
Sodium hydride (17.46 mg, 0.437 mmol) was added in a single portion to a solution of 6-bromo-3-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (101 mg, 0.257 mmol) (prepared by substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Example 1C) in DMF (10 ml) at room temperature under argon. The resulting bubbling solution was stirred for 20 minutes, then treated with 1-(2-chloroethyl)pyrrolidine (51.5 mg, 0.385 mmol) which was dissolved in 0.5 ml DMF and added dropwise via pipette. The resulting mixture was stirred at 70° C. for 3 hours, allowed to cool, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried with MgSO4, and filtered. The filtrate was concentrated and the residue was purified via silica gel chromatography eluting with 3 to 5% CH2Cl2/CH3OH to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C.O1CCCC1>[NH2:16][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: N#Cc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) suspension of crude 4′-fluoro-3′-nitrobiphenyl-2-carbonitrile (10.7 g, 44 mmol) in ethanol (80 ml) and tetrahydrofuran (80 ml) was treated with tin(II) chloride dihydrate (29.8 g, 132 mmol) and this mixture was stirred at ambient temperature for 12 h. The solvent was removed in vacuo and the residue treated with ice-cold 2N sodium hydroxide (400 ml). The resulting slurry was stirred at ambient temperature for 60 min then extracted with dichloromethane (2×400 ml). The organics were combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (5-40%) gave 3′-amino-4′-fluorobiphenyl-2-carbonitrile as a cream-coloured solid (4.3 g, 46% over 2 steps): δH (400 MHz, CDCl3) 3.85 (2H, br), 6.84 (1H, ddd, J 8, 4 and 2), 6.95 (1H, dd, J 8 and 2), 7.07 (1H, dd, J 11 and 8), 7.40-7.46 (2H, m), 7.57-7.62 (1H, m), 7.72-7.74 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:14](=O)([O:17]C)[O:15][CH3:16].[H-].[Na+]>>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][CH2:7][CH2:8][CH:9]([C:14]([O:15][CH3:16])=[O:17])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1CCCOc2ccc(Br)cc21
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCOc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
To a solution of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one from step H2 (5.41 g, 22.4 mmol) in dimethyl carbonate (28.3 ml, 337 mmol) was slowly added a sodium hydride dispersion in mineral oil (2.69 g, 112 mmol). The mixture was stirred at rt for 15 min, then at 80° C. for 2 h. The mixture was then cooled to rt and stirred for 16 h. The mixture was concentrated in vacuo and diethyl ether (150 mL) of was added. The organic layer was washed with of 1 N HCl (100 mL) followed by water, and dried over sodium sulfate. The solvent was removed in vacuo. The crude product was purified by silica-gel column chromatography (10-40% EtOAc/hexanes, linear gradient) to afford methyl 7-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]oxepine-4-carboxylate (3.32 g, 11.1 mmol, 50% yield) as a white solid. LCMS (M+H)+=300.95. 1H NMR (500 MHz, chloroform-d) δ 7.91 (d, J=2.4 Hz, 1H), 7.61-7.48 (m, 1H), 7.03-6.89 (m, 1H), 4.49 (ddd, J=12.4, 6.7, 3.9 Hz, 1H), 4.15-4.03 (m, 2H), 3.77 (s, 3H), 2.68-2.47 (m, 2H).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20](Br)=[C:19]([F:24])[C:18]=3[F:25])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([B-](F)(F)F)[CH2:28][CH2:27]1.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.CC([O-])=O.CC([O-])=O.[Pd+2].[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.C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH:26]4[CH2:28][CH2:27]4)=[C:19]([F:24])[C:18]=3[F:25])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)C1CC1
Reactant: CC(C)(C)Nc1ncccc1-c1nnnn1-c1ccc(Br)c(F)c1F
Agent: [Pd+2]
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)Nc1ncccc1-c1nnnn1-c1ccc(C2CC2)c(F)c1F
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
N-tert-Butyl-3-(1-(4-bromo-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1080 150 mg, 0.366 mmol), potassium cyclopropyltrifluoroborate (70.5 mg, 0.476 mmol), tricyclohexylphosphine (10 mg, 0.0366 mmol) and K3PO4 (272 mg, 1.283 mmol) were taken into toluene (1.5 ml), and water (750 μL). The reaction was degassed with nitrogen for 1 hour and Pd(OAc)2 (4.1 mg, 0.0183 mmol) was added. The reaction mixture was heated at 180° C. for 10 minutes under microwave irradiation. The reaction was found to be incomplete by HPLC analysis so tetrakis-(triphenylphosphine) palladium (0) (42 mg, 0.0366 mmol) was added to the mixture and microwave irradiation was continued for 10 minutes at 180° C. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the volatiles removed under reduced pressure to afford a crude brown oil, which was purified by column chromatography (SiO2), eluting with 0-20% EtOAc/hexanes, to afford 120 mg of N-tert-butyl-3-(1-(4-cyclopropyl-2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine (Compound 1084) as a colorless oil; ESMS (M+1)=371.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([CH:15]([OH:31])[CH:16]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=[O:31])[CH:16]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCC(=O)NC(c1cccc(C)c1)C(O)c1ccc2c(c1)n(C)c(=O)n2C1CCCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCC(=O)NC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCCC1)c1cccc(C)c1

Procedure:
N-[2-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-hydroxy-1-m-tolyl-ethyl]-3-methoxy-propionamide (433 mg, 0.96 mmol) was dissolved in methylene chloride (9.6 mL) and N-methylmorpholine N-oxide (168.7 mg, 1.44 mmol) was added. After stirring for ten minutes, TPAP (20.2 mg, 0.06 mmol) was added. The reaction was stirred for 1 hour, after which time LCMS and TLC (ethyl acetate) indicated complete reaction. The reaction mixture was poured into saturated aqueous sodium bicarbonate and additional methylene chloride was added. The organic phase was separated and washed with brine, followed by aqueous copper sulfate. The organic phase was then filtered through a plug of silica gel, eluting with ethyl acetate. Concentration of the filtrate afforded 294 mg of a white X solid that was used without further purification.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:11][CH2:12]2)[CH:2]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Product: Cc1cccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)c1

Procedure:
Example 9 was prepared according to Example 2 except that in Step A 1-(m-tolyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 135°-136° C.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42]Br)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][N:29]1[CH2:28][CH2:27][CH:26]([C:24](=[O:25])[NH:23][C:10]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)[CH2:31][CH2:30]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: N#Cc1ccc(Oc2cc(NC(=O)C3CCNCC3)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: CC(C)(C)OC(=O)NCCN1CCC(C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.8 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine (0.8 g, 1.82 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.49 g, 2.19 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 1.42 (4H, m), 2.31 (3H, m), 1.8 (2H, t), 2.81 (2H, m), 3.15 (1H, m), 3.7 (1H, m), 6.76 (1H, s), 7.26 (6H, m), 7.86 (4H, d).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:12][C:13]([F:21])([C:17]([F:20])([F:19])[F:18])[CH:14](O)[CH3:15].C(Cl)CCl.CCCCCC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([O:3][CH:14]([C:13]([F:21])([F:12])[C:17]([F:20])([F:19])[F:18])[CH3:15])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(O)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(OC(=O)c1ccc(C=O)cc1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h
Yield: 67 %

Procedure:
A mixture of 4-carboxybenzaldehyde (21.9 g, 145.9 mmol), 3,3,4,4,4-pentafluoro-2-butanol (24.1 g, 146.9 mmol), EDC (33.5 g, 174.8 mmol) and DMAP (18.1 g, 148.1 mmol) was dissolved in DMF (60 ml) at rt. It was stirred for 36 h at rt. Hexane was added, it was washed with 1 N HCl, sat NaHCO3 and brine. The aqueous layers were extracted three times with hexane. It was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography (ethyl acetate:hexane 1:10) to yield the desired aldehyde as a yellow oil (67%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1.O>CO>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)c([N+](=O)[O-])cn1
Yield: 55.1 %

Procedure:
Sodium methoxide (26.1 g) was added to a solution of 2-chloro-4-methyl-5-nitropyridine (19.0 g) in methanol (100 ml) and the resulting mixture was refluxed for 12 hours. Upon cooling, the mixture was poured over water (1 L), and the product was extracted with ethyl acetate and washed with water. The organic phase was dried (anhydrous magnesium sulfate) and concentrated, and the residue dissolved in hot ether and filtered. Crystallization from ether provided 10.2 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([N:87]3[CH2:91][CH2:90][CH2:89][CH2:88]3)[N:82]=[C:81]([S:92][CH2:93][C:94]3[N:95]=[C:96]([C:99]4[CH:104]=[CH:103][C:102]([Cl:105])=[CH:101][CH:100]=4)[S:97][CH:98]=3)[C:80]=2[C:106]#[N:107])=[CH:75][CH:74]=1)=[O:68])[CH3:66]>CN(C=O)C.O.C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([N:87]3[CH2:88][CH2:89][CH2:90][CH2:91]3)[N:82]=[C:81]([S:92][CH2:93][C:94]3[N:95]=[C:96]([C:99]4[CH:100]=[CH:101][C:102]([Cl:105])=[CH:103][CH:104]=4)[S:97][CH:98]=3)[C:80]=2[C:106]#[N:107])=[CH:75][CH:74]=1)=[O:68])[CH3:66])=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
166 mg (0.478 mmol) of N2,N6-bis(tert-butoxycarbonyl)-L-lysine were initially charged in 6.4 ml of DMF. 88 mg (0.652 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 100 mg (0.522 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.379 ml (2.173 mmol) of N,N-diisopropylethylamine were added, 330 mg (0.435 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate (Example 40) were then added and the mixture was stirred at RT overnight. Water/acetonitrile was added to the reaction solution in such an amount that a clear solution was formed. This was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 216 mg (44% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCN(CC)C(=O)c1ccccc1Br
Product: CCN(CC)C(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N,N-diethylbenzamide. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59-8.54 (m, 1H), 8.11 (d, J=1.5, 1H), 8.00-7.90 (m, 1H), 7.50-7.36 (m, 5H), 7.36-7.29 (m, 1H), 4.69 (s, 2H), 3.87-3.69 (m, 1H), 3.17-2.92 (m, 2H), 2.85-2.66 (m, 1H), 0.99 (t, J=7.1, 3H), 0.81 (t, J=7.1, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:39][CH2:40][O:41][C:42](=[O:44])[CH3:43])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (64.5 mg, 0.131 mmol) in N,N-dimethylformamide (2.5 ml) was added sodium hydride (6 mg, 0.158 mmol), 60% dispersion in mineral oil, then acetic acid 2-bromo-ethyl ester (17 μl, 0.158 mmol). The reaction stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched the following day with water and diluted with ethyl acetate. The organic layer was washed twice with water, then brine. After the organic layer was dried over magnesium sulfate the solvent was distilled off under reduced pressure to give the title compound, 132 mg (100%).