Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31]>C1(C)C=CC=CC=1.O>[C:1]([N:5]1[C:9](=[O:10])[N:8]([CH2:31][C:30]#[CH:29])[C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCBr
Reactant: CC(C)(C)n1[nH]c(C2=CCCC=C2)nc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCn1c(-c2ccccc2)nn(C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of crude 345 g (1.2 mol) of 1-t-butyl-4-H-3-phenyl-1,2,4-triazol-5-one and 3.5 L of ethyl acetate containing 0.03% water was stirred at room temperature and 190 g (1.67 mol) of solid potassium carbonate (K2CO3) was added. The mixture was heated at reflux for 0.5 h and 248 g (1.67 mol) of an 80% weight solution of propargyl bromide in toluene was added dropwise over 30 minutes. Refluxing was continued for an additional 3 h. The mixture was allowed to cool to room temperature, diluted with 2 L of water and stirred for 15 min. The organic layer was separated, washed with brine and dried over magnesium sulfate (MgSO4). Removal of the solvent left 300 g of an oil which was crystallized from 500 mL of ether and 1500 mL of hexanes to furnish 180 g of the desired compound, mp 82°-83° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[CH:10]=1.CC1(C)CC(C2C=CC=CN=2)C2C=C(C(O)=O)C=CC=2O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(OC1C=CC(C#N)=CC=1)C#C>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[CH3:21][C:11]([CH3:22])([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1)[C:10]#[C:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1C1=CC(C)(C)Oc2ccc(C#N)cc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C#CC(C)(C)Oc1ccc(C#N)cc1
Solvent: CCNCC
Product: COc1ccccc1C#CC(C)(C)Oc1ccc(C#N)cc1
Reaction time: 48 h

Procedure:
The 4-(2-methoxyphenyl)-2.2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 2.34 g of 2-iodoanisole were added at room temperature to a solution of 9 mg of palladium(II) chloride, 26 mg of o triphenylphosphine and 19 mg of copper(I) iodide in 25 ml of diethylamine. This mixture was treated with 1.85 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile and the resulting mixture was stirred for 48 hours. The mixture was evaporated and the residue was dissolved in a mixture of ethyl acetate and water. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 0.99 g of 4-[1,1-dimethyl-3-(2-methoxyphenyl)-2-propynyloxy]benzonitrile in the form of an oil. (B) 0.99 g of 4-[1,1-dimethyl-3-(2-methoxyphenyl)-2-propynyloxy]benzonitrile was dissolved in 10 ml of 1,2-dichlorobenzene and heated at reflux for 1.5 hours. After cooling the solution was evaporated and the residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. After recrystallization from petroleum ether (boiling point 60°-80° C.) there were obtained 480 mg of 4-(2-methoxyphenyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile of melting point 109°-111° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:21]1[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])=[O:7].[SH:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48]([OH:50])=[O:49].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N:15]1([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]3[CH:4]=[C:3]([CH:43]=[CH:42][CH:41]=3)[CH2:2][S:44][C:45]3[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=3)[C:48]([OH:50])=[O:49])=[O:7])=[C:10]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)[CH:38]=[CH:39][N:40]=3)[CH:11]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Reactant: O=C(O)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reaction time: 16 h
Yield: 37.9 %

Procedure:
A mixture of 250 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-isonicotinamide 8.1a, 70 mg of 3-mercaptobenzoic acid, 10 mL of acetone, and 171 mg of K2CO3 was stirred for 16 h and then filtered. The solvent was removed by evaporation. The residue was dissolved in dichloromethane and the resulting solution was washed with aqueous hydrochloric acid. The solution was dried, and the solvent was evaporated. The residue was purified by silica gel chromatography to give 113 mg of product. MS (ES, m/z) 725 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH2:39][CH2:40][O:41][CH3:42])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>Cl.O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH2:39][CH2:40][O:41][CH3:42])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COCCN(C(=O)c1ccc(Oc2ccc(F)cc2)nc1)c1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COCCN(C(=O)c1ccc(Oc2ccc(F)cc2)nc1)c1ccc(CN2CCN[C@@H](C)C2)cc1
Reaction time: 2 h
Yield: 107.2 %

Procedure:
1,1-Dimethylethyl (2S)-4-[(4-{({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)[2-(methyloxy)ethyl]amino}phenyl)methyl]-2-methyl-1-piperazine carboxylate (D119) (0.077 g, 0.13 mmol) was dissolved in 4M HCl in dioxane (5 mL). A few drops of water were added and the reaction was stirred for 2 h. The solvent was removed in vacuo and the resulting yellow oil was dissolved in MeOH and loaded onto an SCX cartridge which was eluted with DCM, MeOH and 2M NH3 in MeOH. The ammoniacal fractions were combined and concentrated to give the title compound as a yellow oil (0.0667 g). MS (ES): MH+ 479.4.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[C:10]=2[N+:12]([O-])=O)[CH:5]=[CH:4][CH2:3]1>CO.[Pd]>[NH2:12][C:10]1[C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:8][CH:7]=[C:6]2[C:11]=1[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5]2
Reactant: COC(=O)c1ccc2c(c1[N+](=O)[O-])N(C)CC=C2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1N)N(C)CCC2
Reaction time: 16 h

Procedure:
To a solution of methyl 1-methyl-8-nitro-1,2-dihydroquinoline-7-carboxylate (1.25 g, 5.04 mmol) in degassed MeOH (25 mL) at rt was added Pd/C (125 mg). The mixture was stirred under 1 atm H2 for 16 h. The resulting mixture was filtered through celite and concentrated to afford methyl 8-amino-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate in pure form.
Reaction SMILES: [CH2:1]1[CH2:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2]1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[S:7][C:3]2[CH2:2][CH2:1][CH2:10][C:8](=[O:9])[C:4]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=C1CCCc2sccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCCc2sc([N+](=O)[O-])cc21
Temperature: -5 °C
Reaction time: 0.83 h
Yield: 75 %

Procedure:
was prepared using a literature procedure (Asprou et al., J. Heterocyclic Chem., 17:87-92 (1980) (“Asprou”), which is hereby incorporated by reference). To a 50 mL round bottom flask charged with a stir bar was added 4-keto-4,5,6,7-tetrahydrothianaphthene (0.61 g, 4 mmole) and concentrated sulfuric acid (6 mL). The solution was then cooled in an ice/salt bath to −5° C. and stirred while a solution of concentrated nitric acid (0.3 mL) in concentrated sulfuric acid (3 mL) was added dropwise over 30 minutes. Solution was stirred for another 50 minutes and allowed to gradually warm to 5° C. The reaction mixture was then poured onto crushed ice and the yellow precipitate filter and washed with several portions of ice-cold water to give product as a yellow solid (0.594 g, 75% yield). Spectral data were consistent with the literature values (Asprou, which is hereby incorporated by reference).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][NH2:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCc1nc(-c2ccccc2)cs1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCCc1nc(-c2ccccc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 70 %

Procedure:
This compound was synthesized from 3-(4-phenylthiazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (100 mg, yield 70%). 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 8.17-8.14 (m, 1H), 7.96-7.94 (m, 1H), 7.80-7.78 (m, 2H), 7.45-7.41 (m, 1H), 7.34-7.29 (m, 4H), 3.70-3.66 (q, J=6.3 Hz, 2H), 3.27-3.23 (t, J=6.7 Hz, 2H), 2.29-2.23 (m, 2H). MS (ESI) m/z: Calculated for C22H17F3N4O2S: 458.10. found: 459.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:23][CH:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[H-].[Na+].[CH3:41]I>C1COCC1>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:21][CH:22]([N:24]([CH3:41])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NC(=O)OC(C)(C)C)C2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(N(C)C(=O)OC(C)(C)C)C2)n1
Yield: 95 %

Procedure:
Reaction of tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinylcarbamate (Example 30) with NaH/MeI in THF as in previous examples gave tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl(methyl)-carbamate in 95% yield: mp (CH2Cl2/MeOH) 186-188° C.; 1H NMR (DMSO-d6) δ 8.00 (d, J=8.3 Hz, 1H), 7.75 (t, JHF=53.0 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.88 (br, 1H), 4.40-4.15 (m, 4H), 3.97 (s, 3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.89 (s, 3H), 1.41 (s, 9H); Anal. Calcd. for C25H32F2N8O4: C, 54.9; H, 5.9; N, 20.5. Found: C, 55.1; H, 5.9; N, 20.6%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH2:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH:18][C:19](=[O:21])[CH3:20]
Reactant: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cncc(C#Cc2ccc(F)c(NC(C)=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.3 %

Procedure:
Dissolve 2-fluoro-5-(5-methoxypyridin-3-ylethynyl)-phenylamine, (prepared as described in EXAMPLE 111), (200 mg, 0.83 mmol) in pyridine (3 mL) and add acetic anhydride (84 mg, 0.83 mmol). Stir under nitrogen at room temperature for 48 h and concentrate. Purify by silica gel chromatography, eluting with 100% ethyl acetate to give the title compound as a light yellow solid (180 mg, 76%).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][OH:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[C:9]2[NH:10][CH:11]([CH2:14][O:15][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc2c1NC(CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2COc3cccc([N+](=O)[O-])c3N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
(5-Nitro-3,4-dihydro-2H-benzo[1,4]oxazin-3-yl)-methanol (6.5 g, 31.0 mmole) was dissolved in methylene chloride (200 mL), N, N-diisopropylethylamine (10.8 mL, 62 mmole) and 4-DMAP (1.18 g) were added, followed by p-toluenesulfonyl chloride (12.85 g, 67.4 mmole) and the mixture stirred at room temperature under nitrogen overnight. The mixture was diluted with methylene chloride (100 mL), washed with HCl (1N, 200 mL), saturated sodium bicarbonate (200 mL), saturated sodium chloride (200 mL) and dried (Na2SO4). Filtration, evaporation in vacuum and column chromatography on silica gel with 1:1 hexane/methylene chloride as eluent gave 10.5 g (93%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 8.20 (d, 1H); 7.70 (d, 1H); 7.65 (dd, 1H); 7.40 (d, 2H); 7.05 (dd, 1H); 6.55 (dd, 1H); 4.10 (m, 5H); 2.40 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:13]([O:15]C(Cl)Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:13]=[O:15])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (1.5 g, 10 mmol) in anhydrous dichloromethane was treated with titanium tetrachloride (1.86 mL, 17 mmol) followed by ∀,∀-dichloromethyl ether (0.9 mL, 20 mmol). The reaction was allowed to warm to ambient temperature over 1 h, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography using 2-2.5% ethyl acetate in hexane as the eluent to afford the title compound (1.37 g, 77%). 1H NMR (300 MHz, CDCl3): δ 11.02 (s, 1H), 9.81 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (dd, J=8.2, 1.7 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C)C=O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][CH2:3][CH2:2][C:1]([NH2:5])=[O:4]
Reactant: NCc1ccccn1
Reactant: C=CC(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CCNCc1ccccn1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
Acrylamide (3.29 g; 46.24 mmol) and triethylamine (0.468 g; 4.624 mmol; 6.62 μl)) are added dropwise in succession at ambient temperature, with stirring and under an argon atmosphere, to a solution of 2-(aminomethyl)-pyridine (5 g; 46.24 mmol; 4.77 ml) in 19 ml of dimethylformamide. The reaction mixture is then heated to 40° C. and stirred at that temperature for 72 hours. At the end of the reaction, the reaction mixture is concentrated and the residue is purified by chromatography on silica gel (eluant: CH2Cl2/EtOH/NH4OH 80/20/2) to yield the title product in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH:14]([C:22]([OH:24])=O)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[C:27]1([CH2:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.Cl.CNC(NC)CCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:22]([N:44]2[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][CH2:38][CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:46][CH2:45]2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: c1ccc2c(CCCCN3CCNCC3)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(C(C(=O)O)c2ccc(F)cc2)CC1
Agent: CCN=C=NCCC(NC)NC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
0.49 g of 1-t-Butoxycarbonyl-4-[carboxy-(4-fluorophenyl)methyl]-3,6-dihydro-2H-pyridine obtained in Example 11(2) was dissolved in 5 ml of dimethylformamide, and 0.55 g of 1-(4-naphthalen-1-yl-butyl)piperazine dihydrochloride, 0.34 g of 1-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.34 g of 1-hydroxybenzotriazole monohydrate and 0.5 ml of triethylamine were added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 0.53 g of 1-t-butoxycarbonyl-4-{1-(4-fluorophenyl)-2-[4-(4-naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-3,6-dihydro-2H-pyridine as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>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.O.O1CCOCC1>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 16.3 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (100 mg, 0.28 mmol), and dioxane water (3:1, 2 mL) were dissolved together. 4-fluorophenyl boronic acid (59 mg, 0.42 mmol), potassium carbonate (116 mg, 0.84 mmol) were added and a stream of Ar was passed through the solution for 5 min and then Pd(PPh3)4 was added (32 mg, 0.028 mmol). Argon was passed through the solution for 5 min and then the mixture was heated on the microwave at 150° C. for 20 min. The reaction mixture was concentrated and purified by HPLC to afforded 17 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1O)C(=O)OC(C)(C)C
Reactant: Fc1ccc(CCc2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
10 g (21.81 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(5-fluoro-2-hydroxyphenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 106A), 5.98 g (23.99 mmol) of 1-(chloromethyl)-4-[2-(4-fluorophenyl)ethyl]benzene and 4.52 g (32.71 mmol) of potassium carbonate in 240 ml of acetonitrile were heated to 110° C. and stirred at this temperature overnight. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). This gave 14.11 g (21.03 mmol, 96% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:30][CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: NCc1cccs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCc3cccs3)(CC1)CC2
Yield: 75.4 %

Procedure:
In a similar manner to Example 92, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-thienylmethylamine (38.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-thienylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (48.8 mg).