Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[H-].[Na+].C([Li])CCC.[CH3:20][C:21]([CH3:23])=[O:22]>O1CCCC1.CCCCCC.O>[OH:22][C:21]([CH3:23])([CH3:20])[CH2:11][C:10](=[O:12])[CH:4]([C:2]([CH3:3])=[CH2:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(C(C)=O)=C(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=C(C)C(C(=O)CC(C)(C)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.00 g of ethyl 2-(1-methyl-ethylidene)-3-oxo-butanoate [described in Helv. Chim. Act., Vol. 54 (1971), p. 1797] were added dropwise at room temperature to a suspension of 860 mg of sodium hydride as a 50% mineral oil suspension in 50 ml of tetrahydrofuran and the mixture was refluxed for one hour and then cooled to room temperature. 13 ml of a solution of 1.6 M of butyllithium in hexane were added to the mixture at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The mixture was cooled to -10° C. and 1.60 ml of acetone were added thereto. The mixture was poured into water and the mixture was extracted with ether. The ether phase was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate and evaporated to about 100 ml to obtain a solution of ethyl 5-hydroxy-5-methyl-2-(1-methyl-ethenyl)-3-oxo-hexanoate and its isomer, ethyl 5-hydroxy-5-methyl-2-(1-methyl-ethenyl)-3-oxo-hexanoate.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:20])[CH3:19])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(F)ccc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(F)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-2-(methyloxy)aniline (Heterocycles 1992, 34, 2301-2311) (5.6 g, 40 mmol) and triethylamine (6.9 ml, 50 mmol) in dichloromethane (200 ml) at 0° C. was treated with acetyl chloride (2.85 ml, 40 mmol). After stirring at room temperature for 1 hour the solution was washed with 2N hydrochloric acid. The organic phase was separated, washed with water and brine then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:5 to 1:2 ethyl acetate in dichloromethane) to afford the title compound. MS (ES+) m/e 184 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]#[N:21])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[CH:33][NH:34]3)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[CH:3]=[C:4]([C:20]#[N:21])[C:5]4[CH:6]=[N:7][N:8]([S:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:9]=4[CH:10]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: N#Cc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Yield: 16.6 %

Procedure:
To a solution of 6-bromo-1-(phenylsulfonyl)-1H-indazole-4-carbonitrile (5 g, 13.80 mmol) in 1,4-dioxane (50 ml) and water (20 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (4.03 g, 16.57 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (1.010 g, 1.380 mmol) and potassium phosphate tribasic (8.79 g, 41.4 mmol). The mixture was heated at 60° C. for 1 h, cooled and evaporated in vacuo. The residue was partitioned between water (50 ml) and dichloromethane (100 ml). The suspended solid was collected and the organics were separated by hydrophobic frit and concentrated to approx 50 ml. The precipitated solid was collected as a beige solid (1.93 g) and the filtrate purified by silica (300 g) cartridge using a gradient of ethyl acetate and cyclohexane, to give the title compound as a pale yellow solid (0.91 g). The solid collected during partitioning was purified by pre-absorbing onto florisil and purification by silica (100 g) cartridge on Flashmaster 11 using a gradient of dichloromethane and ethyl acetate to give a further quantity of the title compound as a pale yellow solid (0.45 g).
Reaction SMILES: [Br:1][CH2:2][C@H:3]1[CH2:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[O:4]1.[Br:13]Br>C(O)(=O)C.CO>[Br:13][C:11]1[C:5]2[O:4][C@@H:3]([CH2:2][Br:1])[CH2:7][C:6]=2[CH:8]=[C:9]([F:12])[CH:10]=1
Reactant: BrBr
Reactant: Fc1ccc2c(c1)C[C@H](CBr)O2
Solvent: CC(=O)O
Solvent: CO
Product: Fc1cc(Br)c2c(c1)C[C@H](CBr)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-2-bromomethyl-5-fluoro-2,3-dihydro-benzofuran (3.20 g, 14 mmol) in acetic acid was added bromine (2.2 ml, 42 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The solvent was removed in vacuo and the residue dissolved in dichloromethane and washed with saturated aqueous sodium sulfite. The solvent was removed in vacuo and purification by flash column chromatography (silica, ethyl acetate:hexanes 1:19) afforded 3.16 g (74%) of as a light yellow oil. HRMS EI m/e 307.8846 (M)+, Calc'd. 307.8848. [α]D25=+24.8 (c 1% in methanol).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH2:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:35])[CH2:32][CH2:33][NH:34][C:10]([C:9]1[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)=[N:16][C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:11])[CH3:29]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(C#N)cc1
Yield: 77.1 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-Cyano phenoxy)-nicotinic acid 0.5 g (1.42 mmol) and 3-amino-propionic acid ethyl ester (0.166 g, 1.42 mmol) were used to afford 0.5 g of the required product. Percentage purity (LCMS): 30.7%, (M+1)=456.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Oc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 5 (100 mg, 0.24 mmol) was reacted with ethanesulfonyl chloride (31.0 mg, 0.24 mmol) for 18 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (20 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.98 (s, 1H) 8.89 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 7.76 (d, J=8.82 Hz, 1H) 7.45-7.50 (m, 1H) 7.36-7.42 (m, 2H) 7.25 (d, 2H) 7.17 (d, 2H) 6.33 (d, J=6.99 Hz, 1H) 3.47 (q, J=7.35 Hz, 2H) 2.75 (s, 3H) 2.40 (s, 3H) 1.34 (t, J=7.35 Hz, 3H); MS (DCI NH3+) m/z 466 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:23])[CH2:21][CH3:22])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)[CH3:2].C(OO)(=[O:26])C>>[O:26]1[C:20]([CH3:23])([CH2:21][CH3:22])[CH:19]1[CH2:18][CH2:17][C:3]([CH2:1][CH3:2])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)OO
Reactant: CCC(C)=CCCC(=CCOc1ccc2c(c1)OCCC2)CC
Product: CCC(=CCOc1ccc2c(c1)OCCC2)CCC1OC1(C)CC

Procedure:
Following the procedure of Example 17, 7-(3-ethyl-7-methyl-2,6-nonadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-ethyl-7 -methyl-2-nonenyloxy)-chromane, nD20 = 1.5292.
Reaction SMILES: O[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:33][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Yield: 81.6 %

Procedure:
To a mixture of ethyl (4-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.68 g) and toluene (50 mL) was added thionyl chloride (0.23 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (0.58 g, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH2:21]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:18](=[O:20])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCCN(C(=O)OCc2ccccc2)CC1
Yield: 97.7 %

Procedure:
15.29 g of N-tert-butoxycarbonyltyrosine and 12.73 g of N-benzyloxycarbonylhomopiperazine were dissolved in 280 ml of tetrahydrofuran, to the solution were added 8.09 g of 1-hydroxybenzotriazole hydrate and 11.77 g of DCC at a room temperature with stirring, and the reaction mixture was stirred for 16 hours. The reaction mixture was evaporated to remove the solvent under a reduced pressure, to the residue was added benzene, and insoluble matter was filtered by suction and washed with benzene. The benzene layers were combined and evaporated off under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:1), to obtain 26.42 g of the title compound in colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)[S:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Yield: 72.1 %

Procedure:
To a solution of 6-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (120 mg, 0.325 mmol) in CCl4 (3.5 ml) is added NBS (64 mg, 1.1 eq.). The mixture is heated to reflux for 15 minutes before AIBN (5 mg, 0.1 eq.) is added. The reaction is refluxed overnight, filtered through celite and washed with CCl4. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=9/95). 6-Bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl) benzothiazole (105 mg, 72%) is isolated.
Reaction SMILES: C[SiH](C)C1C=CC=CC=1[SiH](C)C.[CH3:13][N:14]([CH3:25])[C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:25]
Reactant: CN(C)C(=O)CCc1ccccc1
Agent: C[SiH](C)c1ccccc1[SiH](C)C
Solvent: Cc1ccccc1
Product: CN(C)CCCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 20-mL eggplant flask equipped with a three-way cock and a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with argon atmosphere. Into the flask, iron complex A (1.0 mg, 0.002 mmol) was admitted as catalyst and dissolved in toluene (0.5 mL). To the solution, 1,2-bis(dimethylsilyl)benzene (475 μL) was added through a syringe, and N,N-dimethyl-3-phenylpropanamide (177 mg, 1.0 mmol) was added. The solution was stirred at 100° C. for 30 minutes. Toluene was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (10/1) as developing solvent, obtaining N,N-dimethyl-3-phenylpropylamine (159 mg, 0.83 mmol, 83%). The results are shown as Entry 4 in Table 5. The resulting amine was identified for geometry by 1H and 13C-NMR spectroscopy and IR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)(Cl)=O.CN.[CH2:21]([N:23](CC)CC)C>CO.O.CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:23][CH3:21])=[O:14])[CH:6]=[CH:5]2
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: CN
Solvent: CO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
4 Liters of ethyl acetate and 25 mL of DMF were added to 500 g (1.99 mol) of 6-bromo-2-naphthoic acid. 188 mL (2.61 mol, 1.3 eq) of thionyl chloride was added dropwise at 30° C. or lower. The mixture was stirred at 65° C. for 30 minutes. After cooled to 25° C., a mixture of 408 mL (3.93 mol, 2 eq) of a 40% solution of methylamine in methanol and 558 mL (4.01 mol, 2 eq) of triethylamine was added dropwise at 25° C. or lower. The mixture was stirred at 25° C. for 3 hours. 2.5 Liters of water was added dropwise at 25° C. or lower. Crystals were filtered, and washed successively with 1.25 liters of a mixed solution of methanol/water=1/4. Vacuum drying (50° C.) to a constant weight afforded 422 g of 6-bromo-N-methyl-2-naphthamide (yield 80%).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[N:38][CH:39]=2)=[CH:18][CH:17]=1>CO>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][C:25]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[N:38][CH:39]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.63 mL, 1.9 mmol) was added to a THF (4 mL) and MeOH (2 mL) solution of ethyl 3-(5-(2-(((2′,4′-dichloro-[1,1-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (388 mg, 0.6 mmol) and the homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31]>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[CH:38][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:34][CH:35]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1

Procedure:
rac-cis-1-Acetyl-2,3-bis-(4-chloro-phenyl)-6-(4-methanesulfonyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 4-(methylsulfonyl)phenylboronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 553.09; the expected mass is 552.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1.CN1CCOCC1.[CH3:33][N:34]([CH3:51])[C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.O>[CH3:51][N:34]([CH3:33])[C:35]1([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:12]2)=[O:43])[CH2:37][CH2:36]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 30 %

Procedure:
1-hydroxybenzotriazole (675 mg, 5.0 mmole), 3-piperidine-3-yl-1H-indole (500 mg, 2.5 mmole) and N-methylmorpholine (0.555 ml, 5.0 mmole) were added in succession under argon to a solution of (4-dimethylamino-4-phenylcyclohexylidene)-acetic acid (739 mg, 2.5 mmole) in dry dimethylformamide (10 ml). The solution was cooled in an ice bath and dicyclohexylcarbodiimide (1.03 g, 5.0 mmole) was added. The reaction mixture was stirred for 5 days at RT, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Further urea together with 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone thereupon precipitated out (1.5 g). The aqueous phase was diluted with water (300 ml), 5M sodium hydroxide (7 ml, 35 mmole) was added, and the whole was kept for 16 hours at 5° C. The crude product thereupon precipitated out as a colourless solid (464 mg). The crude product of 2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone was purified chromatographically on silica gel (60 g) with EE/methanol (4:1) and (2:1) and obtained in a yield of 30% (322 mg)—2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)-piperidine-1-yl]-ethanone was obtained as a diastereoisomer mixture. A separation was not possible.
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][CH2:22][C:23]#[C:24][CH3:25])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][CH2:22][C:23]#[C:24][CH3:25])#[N:14]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: CC#CCNC(=NCCS)NC#N
Product: CC#CCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(2-butyn-1-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C([CH2:17][S:18]([CH2:21][S:22]([CH2:25][C:26](O)=O)(=[O:24])=[O:23])(=[O:20])=[O:19])(O)=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5](/[CH:6]=[CH:17]/[S:18]([CH2:21][S:22](/[CH:25]=[CH:26]/[C:5]2[C:4]([O:12][CH3:13])=[CH:3][C:2]([OH:1])=[CH:9][C:8]=2[O:10][CH3:11])(=[O:23])=[O:24])(=[O:19])=[O:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1cc(O)cc(OC)c1C=O
Solvent: CC(=O)O
Product: COc1cc(O)cc(OC)c1/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c1c(OC)cc(O)cc1OC
Yield: 62 %

Procedure:
A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 148-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc(Cl)cc1Br
Yield: 89.7 %

Procedure:
A solution of 2-bromo-4-chlorophenol (3.00 g; 14.5 mmol) in DCM (20 ml) was treated with chloromethyl methyl ether (1.3 ml; 17 mmol) DIEA (3.3 ml; 19 mmol) for 18 hours. The solvents were evaporated, the residue was taken up in EtOAc, washed with sat. NH4Cl solution and brine, dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound as a colorless oil (3.27 g, 90%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][C:33]1=[O:38]>>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][NH:32][C:33](=[O:38])[CH2:34]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: O=C1CNCCN1
Product: O=C1CN(CCCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CCN1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 2-piperazinone according to conditions described in general procedure L. A white powder is produced (0.102 g, 60%). Mp: 90-92° C. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.24 (d, J=6.3 Hz, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.75 (s, 1H), 7.56 (m, 2H), 7.45 (s, 1H), 7.42 (d, J=8.1, Hz, 1H), 7.16 (d, J=9.6 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.93 (s, 1H), 4.22 (br s, 2H), 3.31 (m, 4H), 3.17 (br s, 2H), 2.98 (s, 2H), 2.61 (m, 4H), 2.06 (m, 2H), 1.60 (brs, 6H). MS: 505.2 (M+1).