Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CC(c1ccc(Br)cc1)c1ccccc1F)c1ccc(=O)[nH]c1
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2F)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-(3-(4-bromophenyl)-3-(2-fluorophenyl)propanoyl)-pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=414.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrC1CC1.O>CS(C)=O>[CH:5]1([S:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:1]1
Reactant: CC(C)(C)[O-]
Reactant: Sc1ccccc1
Agent: BrC1CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(SC2CC2)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of potassium tert-butoxide (52.4 g, 467 mmol) in DMSO (200 mL) was added thiophenol (42.9 g, 389 mmol) at 0° C. and stirred for 30 minutes at 20-25° C., followed by addition of bromocyclopropane (37.3 mL, 467 mmol). The reaction mixture was heated to 60° C. and continued to stir for 24 hours at the same temperature (with cold water circulation in the condenser). Reaction monitoring was done by TLC showed completion of reaction. The reaction mixture was then cooled to 20-25° C., added water (800 mL) then extracted with diethyl ether (3×400 mL). Diethyl ether layer was washed with water (500 mL) then with brine (150 mL) and dried over anhydrous sodium sulfate (75 g). Sodium sulfate was filtered and wash with diethyl ether (50 mL), solvent was removed under reduced pressure using rotavapour (bath temperature 30-35° C.) to get the required oily product which was dried under vacuum for 30 minutes. The crude material was used for the next step with out any purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:17])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1cc(O)cc(C)c1CN1CCCCC1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a stirred solution 3-methoxy-5-methyl-4-piperidin-1-ylmethylphenol (563 mg, 2.4 mmol) and pyridine (0.77 mL, 10.0 mmol) in DCM (20 mL) at 0° C. was added trifluoromethanesulfonyl chloride (0.81 mL, 4.8 mmol). After the addition was complete the reaction was allowed to warm to ambient temperature. The mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (698 mg, 58%). 1H NMR (CDCl3, 300 MHz): 6.82 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.28 (s, 2H), 3.96 (s, 3H), 3.67-3.35 (m, 1H), 2.99-2.66 (m, 1H), 2.47 (s, 3H), 2.21-1.75 (m, 4H), 1.73-1.35 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(N2CCc3[nH]c4ccc(Cl)cc4c3C2)cc1
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(c2ccc(F)cc2)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]1([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]1)[C:12](=[O:29])[N:13]2[CH2:18][C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:22]=[CH:21][N:20]=1)C1C=CC=CC=1>C(O)(=O)C.[OH-].[OH-].[Pd+2].CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]1([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]1)[C:12](=[O:29])[N:13]2[CH2:18][C:19]1[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C1N(Cc2ncccc2C(F)(F)F)c2cccc(NCc3ccccc3)c2C12COc1cc3c(cc12)OCCO3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2Cc1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A mixture of 4′-(benzylamino)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.251 g, 0.45 mmol) and palladium hydroxide on carbon (0.251 g, 20 dry wt %, contains −50% water, 0.18 mmol), methanol (20 mL), glacial acetic acid (1 drop, catalytic amount) was placed under an atmosphere of hydrogen (1 atm) and stirred at ambient temperature for 16 h. Further, palladium hydroxide on carbon (0.100 g, 20 dry wt %, contains −50% water, 0.072 mmol) and acetic acid (1 drop, catalytic amount) were added, the reaction mixture was again placed under an atmosphere of hydrogen (1 atm) and allowed to react at ambient temperature for 72 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate (50 mL). The filtrate was washed with water (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 25% gradient of ethyl acetate in dichloromethane, to yield 4′-amino-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.070 g, 33%) as a colorless solid: mp 243-245° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=4.6 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.7 Hz, J=5.0 Hz, 1H), 6.91 (dd, J=8.0 Hz, J=8.0 Hz, 1H), 6.54 (d, J=12.1 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.08 (d, J=7.6 Hz, 1H), 5.14 (ABq, 2H), 4.71 (ABq, 2H), 4.52 (s, 2H), 4.17 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.0, 154.9, 152.6, 152.4, 144.7, 142.9, 142.8, 138.8, 134.2, 134.1, 129.4, 122.0, 118.6, 114.5, 112.8, 111.3, 99.0, 77.2, 64.5, 63.9, 57.2, 42.4; MS (ES+) m/z 469.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCc1ccccc1
Temperature: 110 °C
Yield: 94.1 %

Procedure:
A mixture of 2-bromo-pyridine-3-ol (50.4 g, 0.29 mol), benzyl bromide (45.5 g, 0.28 mol) and potassium carbonate (52 g, 0.38 mol) in dry N,N-dimethylformamide (DMF; 300 mL) was heated at 110° C. for 30 minutes. The mixture was filtered through a pad of Celite®, the solvent was removed under reduced pressure and the black residue was taken up between ice cold 0.5 M aqueous NaOH and EtOAc. The organic phase was washed twice with brine, dried (MgSO4), and concentrated under reduced pressure to yield 69.6 g (93%) of the title compound as a brown oil. HRMS m/z calcd for C12H10BrNO (M)+ 263.9946. found 263.9939. *Previously described in J. Med. Chem. 1996, 39, 5267–5275.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH2:10])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:4]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:10][CH2:9][C:7]2[N:6]=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: COc1cc(CN)nc(-c2ccccn2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CNS(=O)(=O)c2ccc(F)cc2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
A mixture of C-(4-Methoxy-[2,2′]bipyridinyl-6-yl)-methylamine (62.0 mg, 0.29 mmol), triethylamine (55.1 μL, 0.43 mmol), 4-Fluoro-benzenesulfonyl chloride (72.0 mg, 0.371 mmol) and dichloromethane (3 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography on silica gel (0-100% Ethyl acetate in Hexane) to afford 4-Fluoro-N-(4-methoxy-[2,2′]bipyridinyl-6-ylmethyl)-benzenesulfonamide as a white solid (48.1 mg, 38%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:16])[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:5][CH:4]=1.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O>[C:13]([CH:12]([NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:16])=[CH:8][CH:7]=1)=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:15])[CH3:14]
Reactant: CCOC(=O)C(C)(C)OCCCCCCI
Reactant: CC(=O)CNC(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCCCCCCC(NC(=O)c1ccc(C)cc1)C(C)=O
Yield: 73 %

Procedure:
A suspension (70 ml) of 1.81 g of 60% sodium hydride in N,N-dimethylformamide was cooled to −18° C. with ice-sodium chloride bath, and 21 ml of a solution of 8.67 g of 1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was added slowly. After 1-hour-stirring, 21 ml of a solution of 14.10 g of ethyl 2-(6-iodohexyloxy)-2-methylpropionate in N,N-dimethylformamide was added dropwise slowly. The bath was removed and the mixture was stirred for additional 18 hours at room temperature. The reaction solution was, after addition of ice-cold water, extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 12.20 g of the objective compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:27]=[CH:26][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]([NH:28][OH:29])=[NH:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 57) (355 mg, 1 mmol) in EtOH (60 mL) was added at 23° C. over 6 h 50% aqueous hydroxylamine solution (3.48 mL, 60 mmol) in 6 portions. The mixture was cooled in the ice-bath, diluted with H2O (100 mL) and stirred for 1 h. The precipitate was collected by filtration, washed with water and Et2O, and triturated with ethyl acetate to give the title compound as light yellow solid (336 mg).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][CH2:14][NH:15][C:16](N1C=CN=C1)=[O:17])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][C:5]=12)([CH3:2])[CH3:3]
Reactant: CC(C)c1c(CCNC(=O)n2ccnc2)[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)c1c2n(c3ccccc13)C(=O)NCC2
Yield: 33.8 %

Procedure:
A mixture of N-[2-(3-isopropylindol-2-yl)ethyl]-1-imidazolecarboxamide (2.0 g), 1.8-diazabicyclo[5.4.0]-undec-7-ene (1 g) and toluene (100 ml) was reflux for 1 hour. After cooling, the mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 3,4-dihydro-5-isopropylpyrimido[1,6-a]indol-1(2H)-one (0.52 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][O:32][CH2:33][CH3:34]>>[CH3:31][O:32][CH2:33][CH2:34][O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1
Reactant: CCOC
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: COCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 7 mmol of 2-methoxyethane chloride are treated as described in Example 5.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To a 5° C. solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1995:3482) in 10 mL of tetrahydrofuran was added 0.059 g of maleic anhydride. The cold solution stirred for 15 minutes, and then the ice bath was removed. The reaction warmed to room temperature where it continued stirring for 15 hours. The suspension was heated under reflux for 30 minutes and then stirred at room temperature another 15 hours. Another 0.059 g of maleic anhydride and 20 mL of tetrahydrofuran were added, and the reaction was refluxed for an additional 2 hours. After another 15 hours at room temperature, the reaction was refluxed for 15 hours. The reaction was filtered, and the light tan solid was recrystallized first from dimethyl-formamide and then a second time from methanol to afford 0.036 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].CC[O-].[Na+].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=O)[CH3:15]>CCO>[O:8]=[C:7]1[NH:9][C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:23])=[N:1][C:2]2[CH:6]=[CH:5][S:4][C:3]1=2
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1sccc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccsc2c(=O)[nH]1
Yield: 73.7 %

Procedure:
A mixture of 3-aminothiophene-2-carboxamide (1.23 g, 8.65 mmol) and EtOH (25 mL) was treated with NaOEt (1.2 g, 17.3 mmol) and diethyloxalate (2.3 mL, 17.3 mmol), refluxed for 18 h, cooled, concentrated in vacuo, treated with water, acidified with HOAc and filtered to give the title compound (1.43 g, 74%) as a cream solid: IR νmax Nujol)/cm−1 3180, 3119, 3078, 3006, 2955, 2924, 2854, 1737, 1667, 1651, 1300 and 1176; NMR δH (400 MHz, DMSO) 1.37 (3H, t, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 7.58 (1H, d, J 5.0 Hz), 8.30 (1H, d, J 5.1 Hz), and 12.92 (1H, s).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([O:30]C)=[O:29])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=[O:29])[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccs3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylate (435 mg, 0.94 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 360 mg (86%) of the acid. HR-MS: m/z Calculated for C21H21NO6S2 448.0883; Found 448.0882.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:9]=1
Reactant: O=C1CCCN1
Reactant: N#Cc1ccc(F)cc1Br
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1N1CCCC1=O
Temperature: 105 °C
Yield: 86.9 %

Procedure:
A 48 mL pressure vessel containing 2-bromo-4-fluorobenzonitrile (1.00 g, 5.00 mmol), 2-pyrrolidinone (0.46 mL, 6.00 mmol), Cs2CO3 (2.28 g, 7.0 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xantphos) (0.231 g, 0.40 mmol) in dioxane (6 mL) was degassed with argon for 15 min. Pd2 dba3 was introduced and the reaction mixture heated at 105° C. for 48 h. The mixture was cooled, diluted with ethyl acetate or dioxane, and then filtered through Celite. The resulting mixture was concentrated in vacuo and subjected to column chromatography on silica gel with hexanes:ethyl acetate (3:7) gradient as the eluent to afford the title compound as a white solid (0.887 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=5.8, 8.6 Hz), 7.22 (1H, dd, J=2.5, 9.6 Hz), 7.07 (1H, ddd, J=2.5, 7.6, 8.6 Hz), 3.96 (2H, t, J=7.0 Hz), 2.62 (2H, t, J=8.1 Hz), 2.30-2.22 (2H, m); LCMS (+ESI, M+H+) m/z 205.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19]([OH:21])=O.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][C:49]([CH2:53][N:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][C:49]([CH2:53][N:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:19](=[O:21])[CH2:18][C@@H:3]1[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]1[S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CN[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N(C)[C@@H]2CCCc3cc(CN4CCCCC4)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 10 ml of dry DCM, 0.5 mmol of (R)-2-(3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid and 0.5 mmol of PyClU were combined. Next, 0.6 mmol of (R)—N-methyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (prepared in Example 11) and 1.5 mmol of DIEA were added and the mix was stirred at room temperature under nitrogen for 1 h. The reaction was then quenched with 20 ml of saturated sodium bicarbonate, then extracted with EtOAc (2×30 ml), washed with brine (1×20 ml), dried with sodium sulfate, and concentrated. Purification by chomatography over silica gel using 0 to 15% MeOH (2M ammonia) in ethyl acetate gave the title compound. MS 551 (ESI, pos. ion). Similarly, N-methyl-2-((R)-3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydropyrazin-2-yl)-N—((R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide, N-methyl-2-((R)-3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)-N—((R)-7-(piperidin-1-ylmethyl)choman-4-yl)acetamide, N-methyl-2-((R)-3-oxo-1-(phenylsulfonyl)-1,2,3,4-tetrahydropyrazin-2-yl)-N—((R)-7-(piperidin-1-ylmethyl)choman-4-yl)acetamide, N—((R)-7-((tert-butylamino)methyl)choman-4-yl)-N-methyl-2-((R)-3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetamide, and N—((R)-6-((tert-butylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-N-methyl-2-((R)-3-oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetamide were prepared.
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].[CH3:21]I.[H-].[Na+]>CN(C=O)C.O>[CH3:21][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4]
Reactant: CI
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1OC(c1ccccc1)C(C#N)OC
Yield: 68.9 %

Procedure:
2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile dissolved in 25 ml of anhydrous DMF and 7.1 g of methyl iodide were stirred at 0° C. Addition was made, in portions, of 2.18 g of 55% NaH. After the addition, the whole was stirred at 0°-5° C. for 1 and a half hours. Under an atmosphere of nitrogen the whole was then decomposed cautiously with water, diluted with plentiful water, extracted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, in this way obtaining 1.95 g of 2-methoxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as an oil. Yield=69%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])=[CH:4][N:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=1)=[O:9]
Reactant: Cc1ccc(C(=O)c2sc(N)nc2-c2ccco2)cn1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
Compound 312 (200 mg, 0.701 mmol) was dissolved in DMF (3.5 mL), and isonicotinic acid (259 mg, 2.10 mmol), EDC hydrochloride (403 mg, 2.10 mmol) and 1-hydroxybenzotriazole monohydrate (322 mg, 2.10 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 313 (170 mg, 62%).