Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18](OC)=[O:19])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].O>CO>[O:22]=[C:11]1[NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18](=[O:19])[N:10]1[CH2:9][C:8]1[CH:23]=[CH:24][C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)Nc2ccsc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cn2c(=O)[nH]c3ccsc3c2=O)cc1
Temperature: 60 °C
Yield: 95.1 %

Procedure:
To a suspension of 253 (422 mg, 1.21 mmol) in MeOH (15 ml) was added NaOH (145 mg, 3.63 mmol). The reaction mixture was heated at 60° C. during 16 h. Water (1 ml) was then added and the reaction mixture was stirred for 1 more hour. The solvent was evaporated and the residue was dissolved in water and acidified to pH 5 with HCl 1M. The precipitate was filtered to afford the desired compound 254 (348 mg, 95%) as a white solid. LRMS: 302.0 (Calc.); 303.0 (found).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=O)=[N:5]1)([CH3:3])[CH3:2].[N:33]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[C:22]([O:31][CH3:32])=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH2:16][CH2:15]2)[CH2:10][C:11]([NH:40][CH2:39][CH2:38][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: NCCN1CCCC1
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)NCCN2CCCC2)c2ccn(C(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
(±)-3-(1-Isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (220 mg, 0.50 mmol) and 2-(pyrrolidin-1-yl)ethanamine (114 mg, 1.0 mmol) were suspended in anhydrous DMF (6 mL) N,N-Diisopropylethylamine (0.2 mL, 1.2 mmol) was added and the mixture was stirred at ambient temperature for 5 min followed by addition of HATU (300 mg, 0.79 mmol). After 1 h at ambient temperature, LC-MS and TLC indicated completion of reaction (LC/MS [M+H]+ 534.6). Water (5 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (3×30 mL) and concentrated. The residue was purified by silica gel chromatography using 2 to 5% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH to afford the title compound (230 mg, 86%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.20 (br, 1H), 8.81 (d, 1H, J=2.8 Hz), 8.03 (d, 1H, J=8.4 Hz), 7.51 (d, 1H, J=8.4 Hz), 7.34 (d, 1H, J=2.8 Hz), 7.27 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.0 and 8.0 Hz), 6.16 (s, 1H), 4.52 (septet, 1H, J=6.8 Hz), 4.34 (br, 1H), 3.90 (s, 3H), 3.58 (m, 2H), 3.52-3.40 (m, 4H), 3.20-2.80 (m, 4H), 2.63 (t, 2H, J=6.8 Hz), 2.54 (br s, 4H), 2.20 (br s, 2H), 2.02 (m, 2H), 1.78 (br s, 4H), 1.47 (d, 6H, J=6.8 Hz). MS (ES) m/z 534.6 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1.O.O.Cl[Sn]Cl.Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>CCO>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:13]([NH2:15])=[N:14][C:6]=2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(-c2ccco2)c2ncn(Cc3cccc([N+](=O)[O-])c3)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(Cn2cnc3c(-c4ccco4)nc(N)nc32)c1
Yield: 26.2 %

Procedure:
A solution of 6-(2-furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine (400 mg, 1.12 mmol) in EtOH (10 mL) at 50° C. was treated with a solution of SnCl2.2H2O (808 mg, 3.58 mmol) in conc.HCl (1.8 mL, 21.42 mmol), stirred for 1.5 h, cooled, basified to pH 10 (1-M NaOH) and the resulting solid was filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with diethyl ether and filtered to give the title compound (90 mg, 22%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COCCCCCC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COCCCCCCN1CCCc2ccccc21

Procedure:
A solution of the above 1-(6-methoxyhexanoyl)-1,2,3,4-tetrahydroquinoline (2.7 g) in ether (200 ml) containing lithium aluminium hydride (9.9 g) was refluxed for 6 hours, then cooled and diluted with water. The ethereal solution was dried and evaporated and the residue was chromatographed on silica gel, eluting with 99:1 methylene chloride:methanol, so as to obtain the title compound as an oil.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(3-methylthiopropoxy)quinoline (0.31 g, 0.72 mmol) was dissolved in methylene chloride (10 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride: methanol 95:5 as the eluent gave 0.104 g (32%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](Cl)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.CN.[CH2:13]([N:15](CC)CC)C>C1COCC1>[CH3:13][NH:15][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: O=C(Cl)c1nccnc1Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of 3-chloropyrazine-2-carboxylic acid chloride (350 mg, 2.0 mmol) in THF (10 mL) was added methylamine (300 mg, 10 mmol) and triethylamine (303 mg, 3.0 mmol). The reaction mixture was stirred at RT for 3 h. The reaction solution was concentrated under reduced pressure to give the desired compound (200 mg, yield 100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][OH:19])=[C:4]([O:13][CH3:14])[C:5]([CH3:12])=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.Br[CH2:22][P:23](=[O:32])([O:28][CH:29]([CH3:31])[CH3:30])[O:24][CH:25]([CH3:27])[CH3:26].CC(C)([O-])C.[Li+]>CN(C=O)C>[CH:29]([O:28][P:23]([CH2:22][O:19][CH2:18][C:17]([CH3:20])=[CH:16][CH2:15][C:3]1[C:2]([OH:1])=[C:10]2[C:6](=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])[CH2:7][O:8][C:9]2=[O:11])(=[O:32])[O:24][CH:25]([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CO)C(=O)OC2
Reactant: CC(C)OP(=O)(CBr)OC(C)C
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Temperature: 70 °C
Yield: 30.4 %

Procedure:
A mixture of 7-hydroxy-6-(4-hydroxy-3-methyl-but-2-enyl)-5-methoxy-4-methyl-3H-isobenzofuran-1-one 1A (50 mg, 0.18 mmol, Pankiewicz et al., J. Med. Chem., 45, 703), diisopropyl bromomethylphosphonate (93 mg, 0.36 mmol) and lithium t-butoxide (1M in THF, 0.54 mL) in DMF (3 mL) was heated at 70° C. for 5 hours. The reaction was quenched with 1N HCl. The mixture was poured into 5% aqueous lithium chloride, extracted with ethyl acetate, and concentrated. The residue was purified by chromatography on silica gel, affording [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester 1B (25 mg, 32%); 1H NMR (300 MHz, CDCl3) δ1.25 (m, 12H), 1.79 (s, 3H), 2.05 (s, 3H), 3.37 (d, J=6.6 Hz, 2H), 3.58 (d, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 4.68 (m, 2H), 5.19 (s, 2H), 5.45 (t, J=6.6 Hz, 1H), 7.83 (s, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15]O)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:23])CC.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:15][F:23])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1COCC(CO)(c2cccc(Br)c2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1COCC(CF)(c2cccc(Br)c2)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 5-(3-bromo-phenyl)-5-hydroxymethyl-morpholin-3-one (2.6 g, 9.09 mmol) and 120 ml of dichloromethane was cooled to 0° C. DAST (1.26 ml) was added dropwise. The mixture was stirred overnight, poured onto 50 ml of 10% aqueous Na2CO3 solution and ice and extracted with dichloromethane. The extract was dried with sodium sulfate and evaporated. Chromatography on silica gel (EtOAc/hexane=1:1) gave the title compound in the form of a colourless solid. TLC (hexane/EtOAc=1:1): Rf=0.31; HPLC: RtH2=3.13 min; 1H-NMR (400 MHz, CD3OD): 7.71 (s, 1H), 7.56 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 4.77 (d, 2H), 4.20 (s, 2H), 4.11 (d, 1H), 3.95 (d, 1H); MS: 289, 291 [(M+H)+].
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][C:21]([C:23]([NH2:25])=[O:24])=[N:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][C:21]([C:23]([NH2:25])=[O:24])=[N:20][N:19]=1
Reactant: NC(=O)c1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Agent: [Pd]
Solvent: C1CCOC1
Product: NC(=O)c1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazole-2-carboxamide (0.14 g, 0.41 mmol) in THF (10 mL) was added 10% Pd/C (0.14 g). The mixture was stirred under H2 atmosphere at rt for 3 hrs then filtered and concentrated to provide 5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazole-2-carboxamide (103 mg, 100%), which was directly used in the next step. ESI-MS (EI+, m/z): 254 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3([CH3:25])OCC[O:21]3)[CH:15]=2)=[O:11])=[CH:5][CH:4]=1>C1COCC1>[C:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:12][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)=[O:11])(=[O:21])[CH3:25]
Reactant: CC1(c2cccc(CNC(=O)Nc3ccc(Cl)cc3)c2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(CNC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A 2N HCl solution was added to a solution of 22 (165 mg, 0.479 mmol) in THF (2 mL). The mixture was refluxed for several hours until the starting materials were consumed. The reaction mixture was allowed to cool to room temperature, quenched with solid NaHCO3, and then the volatiles were removed under reduced pressure. The residue was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography to give 23 (144 mg, 100%) 1H NMR (DMSO-d, 400 MHz) δ 4.44 (d, J=5.6 Hz, 2H), 5.37 (t, J=3.7 Hz, 1H), 6.83 (s, 1H), 7.20-7.26 (5H, m), 7.40 (t, J=7.6 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.85 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 27.45, 43.13, 119.85, 125.21, 127.11, 127.59, 129.13, 129.37, 132.61, 137.49, 140.07, 141.68, 155.73, 198.58; ESI-HRMS for C16H16N2O2Cl (M+H)+ calcd. 303.0900. found 303.0907.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: COc1ccccc1B(O)O
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: COc1ccccc1-c1ccc(C(C)CNS(C)(=O)=O)cc1
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To a degassed solution of 1.0 g (3.4 mmol) of material from Example 1, 0.8 g (5.1 mmol) of 2-methoxybenzeneboronic acid and 0.7 g (5.1 mmol) of potassium carbonate in 15 mL of dioxane and 5 mL of water was added 0.2 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with 10 mL of water and extracted three times with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (35% ethyl acetate/hexane) afforded 1.0 g (90%) of the title compound as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C)=[C:4]([NH2:15])[C:5](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]([OH:8])=[O:7].Cl.B(Br)(Br)Br.C(Cl)Cl>C(OCC)C>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([NH2:15])[C:5](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1c(Cl)cc(C(F)(F)F)c(C(=O)O)c1N
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1c(O)c(Cl)cc(C(F)(F)F)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
4-Chloro-3-methoxy-6-trifluoromethylanthranilic acid (5 mg, 0.019 mmol) was dissolved in diethyl ether (1 mL) and HCl (2M, 20 L) was added. The solution was evaporated and co-evaporated with toluene. The residue was dissolved in CH2Cl2 (2 mL), cooled to -60 C., and BBr3 (9 L, 0.092 mmol) was added followed by stirring at -60 C. for 3 min, 0 C. for 3 h and room temperature for 6 h. Additional BBr3 (4 L, 0.04 mmol) was added at -35 C. and the stirring was continued at room temperature for 2 h. The reaction mixture was cooled to -20 C. and added to ice-cold NaHCO3 (2 mL, sat.) followed by stirring for 1 h at room temperature. Methylene chloride (2 mL) was added and pH was adjusted to 5. The phases were separated and the H2O phase was washed with EtOAc (3). The combined organic layers were dried (Na2SO4), filtered and evaporated. The crude product was purified on a silica gel coloumn (EtOAc EtOAc-HOAc 100:1) and the title compound was isolated (3 mg). 1H NMR (CD3OD): 6.97 (s, 1H). MS (EI, 70 eV): m/z (rel. int.) 257/255 (M+, 0.16/0.54)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CCO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: Fc1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 4-fluorobenzylchloride (0.17 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH:32]=[N:33][OH:34])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:35])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH:32]=[N:33][O:34][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])=[O:22])=[CH:36][CH:37]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCC=NO)cc2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CON=CCOc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
To a mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(2-hydroxyiminoethoxy)phenyl]benzamide (255 mg) and potassium carbonate (78.5 mg) in N,N-dimethylformamide (10 ml) was added ethyl bromoacetate (94.9 mg) and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with ethyl acetate (30 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was purified by silica gel column (chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[2-(ethoxycarbonylmethoxyimino)ethoxy]phenyl]benzamide (245 mg) as a colorless amorphous.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:13])[CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH2:1]([NH:8][C:9](=[O:13])[C:10]([C:11]#[N:12])=[CH:16][N:17]([CH3:18])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)NCc1ccccc1
Product: CN(C)C=C(C#N)C(=O)NCc1ccccc1

Procedure:
As for Example 1, N-benzyl-2-cyanoacetamide, m.p. 122°-123° C., is heated with N,N-dimethylformamide dimethylacetal to give N-benzyl-2-cyano-3-dimethylaminoacrylamide as colorless needles, m.p. 160.5°-161° C.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCCN=C=NCC.ON1[C:32]2[CH:33]=[CH:34][CH:35]=C[C:31]=2[N:30]=[N:29]1.NN1CCCCC1>C(Cl)Cl>[N:30]1([NH:29][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH:9]=2)=[O:15])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN1CCCCC1
Solvent: ClCCl
Product: O=C(NN1CCCCC1)c1cnc(-c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 59.1 %

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (150 mg, 075 mmol) in DCM (10 mL) is added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (158 mg, 0.83 mmol) and N-hydroxybenzotriazole (112 mg, 0.83 mmol) at rt and the mixture is stirred for 10 min. 1-Aminopiperidine (150 mg, 1.5 mmol) is added. The mixture is stirred at rt overnight. The mixture is washed with 2 N aqueous HCl (5 mL), saturated aqueous NaHCO3, (5 mL), and water (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid piperidin-1-ylamide (125 mg) as a solid. MS: 290 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1)[CH3:31]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:43])=[CH:35][CH:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Product: CCOC(=O)c1ccc(NC(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-Isocyanato-benzoic acid ethyl ester according to the procedure of Example 65. HRMS: calcd for C33H24F3N3O4, 583.1719; found (ESI, [M+H]+), 584.1801.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[S:16]1[C:20]([CH2:21][CH:22]([OH:25])[C:23]#[CH:24])=[CH:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]1=2.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.ClCCl>[S:16]1[C:20]([CH2:21][CH:22]([O:25][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[C:23]#[CH:24])=[CH:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]1=2
Reactant: C#CC(O)Cc1cc2ccccc2s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(Cc1cc2ccccc2s1)O[Si](C)(C)C(C)(C)C
Reaction time: 17 h
Yield: 69.9 %

Procedure:
DMAP (2.306 g, 18.9 mmol), TBSCl (11.502 g, 76.3 mmol) and triethylamine (5.25 mL, 37.7 mmol) were added to a solution of 9-4 (7.67 g, 37.9 mmol) in dichloromethane (120 mL). After 17 h, 150 mL of saturated NH4Cl solution was added and the layers were separated. The aqueous layer was extracted with dichloromethane (3×100 mL) and the combined organic solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (4% ethyl acetate/hexanes) gave 9-5 (8.38 g, 26.5 mmol, 70%).
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.[Br:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl.C(N(C(C)C)CC)(C)C.CN(C)C=O>O.C(Cl)Cl>[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[Br:21])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Reactant: Cc1cccc(Br)c1CCl
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(Br)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Temperature: 50 °C
Reaction time: 48 h
Yield: 9.3 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (1.0 g, 5.0 mmol), 2-bromo-6-methylbenzylchloride (45%)(3.0 g, 5.0 mmol) and diisopropylethylamin (2.2 g, 17 mmol) were added to dimethylformamide (50 ml) and stirred at 50° C. for 48 h. Methylene chloride and water were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue twice by column chromatography on silica gel using methylene chloride:methanol (10:1) and ethylacetate as eluent gave 0.18 g (1%) of the desired product.