Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([F:41])=[CH:22][N:21]=1>>[F:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(N)=O)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.013 g, 14%). MP: 98-140° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.92 (d, 1H, J=2.8 Hz), 7.40 (s, 1H), 7.25-7.17 (m, 2H), 6.64 (s, 1H), 6.56-6.54 (m, 1H), 6.53-6.49 (m, 1H), 5.52-5.41 (m, 1H), 3.93-3.84 (m, 10H, 3.16-3.10 (m, 6H), 2.90-2.82 (m, 4H), 2.76-2.68 (m, 4H). MS: 552.28 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29]C)=O)=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.[CH3:31][Mg]Br>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27](=[O:29])[CH3:31])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate (prepared in an analogous manner to Example 279, 1.00 g, 2.47 mmol) in anhydrous THF (30 mL) at −78 C was added methyl magnesium bromide (3M sol. in ether, 907 μL, 2.72 mmol) drop wise under an inert atmosphere. The resulting solution was stirred at −78 C for 1 h and then allowed to warm to room temperature where upon stirring was continued for a further 1 h. The reaction mixture was cooled again and quenched with acetone (1 mL) and a 10% citric acid aq. solution (5 mL). The reaction mixture was extracted with EtOAc (3×50 mL) and the resultant organics washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. 50 milligrams of the resulting crude material was purified by preparative HPLC-MS (Method C) to afford the title compound as an off white solid (21 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]I>>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[CH3:25])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: CI
Product: CN(Cc1ccc(OCc2ccccc2)cc1)c1ccc(C#N)cc1
Yield: 52.7 %

Procedure:
The procedure of Preparation Example 38 was repeated, except that 314 mg of 4-[N-(4-benzyloxybenzyl)amino]benzonitrile was used in place of 4-[N-(3-pyridyl)amino]benzonitrile, and 142 mg of methyl iodide was used in place of 4-benzyloxybenzyl chloride. The resulting crude product was purified by TLC (using a 2:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 173 mg of 4-[N-(4-benzyloxybenzyl)-N-methylamino]benzonitrile.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[C:5]([Cl:13])=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=O.O>CCOCC>[Cl:13][C:5]1[C:4]([Cl:3])=[CH:12][C:8]([C:9](=[O:11])[CH3:1])=[CH:7][N:6]=1
Reactant: [Li]C
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
62 ml of a 1.6 M solution (100 mmol) of methyllithium in ether are added to a solution of 9.6 g (50 mmol) of 5,6-dichloronicotinic acid in 250 ml of absolute ether at 0° C. When the addition has ended, the mixture is subsequently stirred at 0° C. for a further 30 minutes and 200 ml of water are then added, while cooling with ice. The phases are separated and the aqueous phase is extracted once more with 50 ml of ether. The combined organic phases are dried over sodium sulphate and evaporated. 9 g (95% of theory) of 2,3-dichloro-5-acetylpyridine, melting point 80° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][C:36]([O:23][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:13]1[C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:37]
Reactant: CC(C)CCCC(=O)Cl
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OC(=O)CCCC(C)C)nc2n1
Yield: 60.3 %

Procedure:
The procedure is as in Example 7, but starting with 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.8 g) in methylene chloride (100 cc), triethylamine (10.1 g), 5-methylhexanoyl chloride (6.4 g) and 4-dimethylaminopyridine (50 mg). The residue obtained after treatment is purified by chromatography on silica gel (0.063-0.2 mm; 100 g) contained in a column 2.8 cm in diameter (eluant: methylene chloride), collecting 30-cc fractions. Fractions 19 to 94 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After the residue obtained has been recrystallized in heptane (75 cc), 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-methylhexanoate (5.6 g), m.p. 105° C., is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[N:22]=[C:23]([CH2:26]O)[S:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[N:22]=[C:23]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[S:24][CH:25]=1
Reactant: OCc1nc(Br)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4nc(Br)cs4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-bromo-1,3-thiazol-2-yl)methanol (76 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (45 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:8][C:9]([NH:21][C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[CH:19][N:18]=2)=[O:11])[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccnc(NC(=O)Cn2cc(C)c(=O)[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid (75 mg, 0.4 mmol), 4-methylpyridin-2-amine (44 mg, 0.4 mmol), HBTU (151 mg, 0.4 mmol) and 0.1 mL of Et3N in DMF (5 mL) was stirred at room temperature for 2 hours to provide the title compound, which was then purified by HPLC. 1H NMR (400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 10.97 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.58 (s, 2H), 2.33 (s, 3H), 1.77 (s, 3H). [M+H] calc'd for C13H14N4O2, 275; found, 275.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:11](=[O:18])[O:10][CH:9]1[CH2:19][O:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](/[C:8](=[CH:9]/[CH2:19][O:20][CH3:21])/[CH2:17][C:12]1([C:11]([OH:18])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCC1OC(=O)C2(CCCC2)CC1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: COC/C=C(\CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of the product from stage b) above (6.11 g, 20.49 mmol) in toluene (50 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 ml, 24.58 mmol), and the resultant solution was then heated at reflux under nitrogen for 5 h. The solution was then cooled to room temperature and the solvent was removed under reduced pressure. To the resultant residue was then added deionised water (100 ml) and the mixture was then extracted with tert-butyl methyl ether (30 ml). The phases were then separated and the aqueous phase was acidified to pH 2 with hydrochloric acid (15 ml of a 2 M solution) and then extracted with tert-butyl methyl ether (2×30 ml). The combined organic extracts were then washed with water (30 ml) and then brine (30 ml) and dried over magnesium sulfate. The solvent was then removed under reduced pressure to give the crude title compound (6.29 g), which was then crystallised from heptane (15 ml) at 0° C. The resultant solid was collected by filtration was then washed with ice-cold heptane (2×5 ml) to give the title compound as a white solid (1.79 g, 6.0 mmol, 29%, E-isomer assigned on basis of chemical shifts); 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 1.45-1.70 (m, 6H), 2.05-2.10 (m, 2H), 2.74 (s, 2H), 3.36(s, 3H), 4.09 (d, 2H), 6.75 (t, 1H); 13C NMR (100 MHz, CDCl3) δ: 23.9, 28.0, 34.1, 35.0, 55.0, 58.6, 69.2, 80.8, 132.7, 139.1, 167.1, 183.3.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:12]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[C:21]1[CH3:29])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCCCCCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Yield: 35.2 %

Procedure:
In a manner similar to that described in part A of Example 1 hereinabove, 7.4 g (0.05 mole) of phthalic anhydride, 16.0 g (0.053 mole) of 76.5 percent active 1-n-octyl-2-methylindole, and 13.3 g (0.1 mole) of aluminum chloride were interacted in 50 ml of benzene to obtain 6.9 g of 2-[(1-n-octyl-2-methyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 =R3 =Y1 =H; R5 =CH3 ; R6 =(CH2)7CH3), as a pink-colored powder which melted at 121°-123° C. The nuclear magnetic spectrum was in agreement with the structure and a significant maximum occurred at 1717 cm-1 (C=O; s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1)N1CCN(c2ccncn2)CC1
Reaction time: 20 h
Yield: 30 %

Procedure:
4-[1-(4-Pyrimidinyl)piperazin-4-ylcarbonyl]piperidine (385 mg) in dichloromethane (20 ml) was stirred at room temperature as a solid suspension and treated dropwise with 4-bromophenylsulphonyl chloride (385 mg) and triethylamine (0.4 ml) in dichloromethane (15 ml). The resulting clear yellow solution was stirred at the same temperature for a further 20 h and treated with saturated NaHCO3 solution (40 ml). The mixture was extracted twice with dichloromethane and the combined organic extracts washed twice each with water and brine dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid was chromatographed through a 10 g silica bond elut prepacked column, eluting with 1% methanol, 1% ammonium hydroxide and 98% dichloromethane to give 1-(4-bromophenylsulphonyl)-4-[1-(4-pyrimidinyl)piperazin-4-ylcarbonyl]piperidine (209 mg; 30% yield based on the amine), as a colourless solid, mp 171-174° C.;
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)(O)[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)=[CH2:9])=[CH:6][N:7]=1
Reactant: CSc1ccc(C(C)(O)c2ccc(F)nc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(c1ccc(SC)cc1)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.7 %

Procedure:
1-(6-Fluoropyridin-3-yl)-1-(4-(methylthio)phenyl)ethanol (1.261 g, 4.789 mmol) was dissolved in DCM (30 mL) and trifluoroacetic acid (1.0 mL, 13 mmol) was added, turning the solution dark green. The reaction was stirred at room temperature for 45 min and then was treated with saturated sodium bicarbonate (15 mL). The reaction was stirred for about 5 min, and then the layers were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under high vacuum to give 2-fluoro-5-(1-(4-(methylthio)phenyl)vinyl)pyridine (1.183 g). 1H NMR (CDCl3, 400 MHz) δ 8.23 (d, J=2.35 Hz, 1H), 7.71 (td, J=8.12 Hz, 2.54 Hz, 1H), 7.26-7.21 (m, 4H), 6.91 (dd, J=8.51 Hz, 2.64 Hz, 1H), 5.55 (s, 1H), 5.43 (s, 1H), 2.51 (s, 3H). m/z (ESI, +ve ion) 246 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:17])[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[C:8]([OH:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]1=[O:26])[CH3:2].[OH-:29].[K+]>CC(O)(C)C>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:17])[CH:11]=[C:12]([C:15](=[O:29])[NH2:16])[CH:13]=2)[C:8]([OH:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]1=[O:26])[CH3:28]
Reactant: [OH-]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#N)cc21
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C(N)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-cyanooxindole (462.6 mg, 1.06 mmol) dissolved in anhydrous t-BuOH (30 mL) at 50° C. was added powdered KOH (1.2 g, 20 eq). The resulting solution was stirred for 1 hour and then cooled to room temperature. Ice was added and the mixture extracted with EtOAc (3×20 mL). The extracts were combined and dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to give a light brown solid. Purification was carried out by column chromatography (silica gel, eluting EtOAc:EtOH:Et3N, 80:20:2) to yield the title compound as a white solid (346.5 mg, 69%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:24](=[O:28])[CH2:25][CH2:26][CH3:27])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:24]([C:5]1[C:4](=[O:3])[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH2:14][O:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)[NH:7][CH:6]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)C(=CNc1ccc(COC(=O)c2ccccc2)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2ccc(COC(=O)c3ccccc3)cc2c1=O
Yield: 89.9 %

Procedure:
Ethyl-2-butyryl-3-(4-benzoyloxymethylphenylamino)acrylate (50 g) was added portionwise to boiling diphenyl ether (500 ml) and hearing continued under reflux for 30 minutes. On cooling, crystals started to appear and the mixture was diluted with petroleum ether to give 3-butyryl-6-(benzoyloxymethyl)-4(1H)-quinolone (39.7 g, 96%) as light brown crystals, m.p. 220°-3° C.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]([F:11])([F:10])[F:9])([CH3:6])[C:3](=[O:5])[CH3:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([S:7][C:8]([F:10])([F:11])[F:9])[CH3:6]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)SC(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(SC(F)(F)F)C(=O)CBr
Temperature: 40 °C
Yield: 85 %

Procedure:
3-Methyl-3-trifluoromethylthio-butan-2-one was dissolved in chloroform and bromine was added dropwise at 20° C. at such a rate that decolorization occurred continuously. Addition was stopped when the color persisted, the reaction mixture was further stirred at 40° C. 1-Bromo-3-methyl-3-trifluoromethylthio-butan-2-one of boiling point 56° C./0.4 mbar was obtained in a yield of 85%. ##STR13##
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)c(F)c1)C(=O)OCC
Yield: 83.9 %

Procedure:
A solution of 4-bromo-3-fluoroaniline (56.6 g, 297.87 mmol) and 1,3-diethyl 2-(ethoxymethylidene)propanedioate (72.45 g, 335.06 mmol) in EtOH (560 mL) was stirred at 80° C. for 4 h. The reaction mixture was allowed to cool, the solids collected by filtration and dried in an oven to afford the desired material (90 g, 84%) as an off-white solid which was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18-7.25 (1H, m), 7.57 (1H, dd), 7.64-7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=360.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.CCN(C(C)C)C(C)C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:2]1)=[O:5])[CH3:8]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a mixture of Ethyl nipecotate (2 g, 12.72 mmol) in THF (25 ml, 0.5M) was added DIEA (4.79 ml, 27.99 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (2.5 g-15.76 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated to afford 1.15 g (33%) of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid ethyl ester as a colorless oil which can be used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19]C=[CH:17][C:16]=1COCOC>>[B:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[C:17]2[CH:16]=[CH:15][CH:20]=[CH:19][C:11]=2[CH2:12][O:13]1
Reactant: COCOCc1ccccc1Br
Reactant: N#Cc1cccc(B2OCCO2)c1
Product: N#Cc1cccc(B2OCc3ccccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[C:14]1(=[O:28])[N:18]([CH2:19][C:20](=O)[CH3:21])[C:17](=[O:23])[C:16]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:15]12.O>CN(C)C=O>[O:23]=[C:17]1[C:16]2[C:15](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14](=[O:28])[N:18]1[CH2:19][C:20]([CH3:21])=[CH:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=C(C)CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 80.7 %

Procedure:
A solution of methyl dimethylphosphonoacetate (21.5 g) in N,N-dimethylformamide (50 mL) was added dropwise to a suspension of sodium hydride (63%, 4.50 g) in N,N-dimethylformamide (100 mL) with stirring at 0° C. The mixture was stirred at 0° C. for 30 minutes. Then, a solution of phthalimidoacetone (20.0 g) in N,N-dimethylformamide (50 mL) was added dropwise thereto, and the mixture was heated to room temperature and stirred overnight. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the title compound (20.6 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:28][CH:27]=1)=[O:30])[CH3:33]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CCN(CC)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCCNC(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 63.7 %

Procedure:
DIPEA (130 μl, 1.0 mmol) was added to a solution of 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (100 mg, 0.34 mmol), 3-diethylaminopropylamine (49 mg, 0.37 mmol), HBTU (155 mg, 0.41 mmol) and HOBT (46 mg, 0.34 mmol) in DMF (1.0 ml). The reaction was stirred at room temperature for 66 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (5 ml) and water (5 ml) The organic phase was absorbed onto a silica flash column and eluted with DCM/ethanol/ammonia (100:8:1). The product fractions were concentrated under vacuum to give N-[3-(diethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (88 mg, 64%).