Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([OH:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([O:22][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([Br:28])=[CH:30][CH:31]=3)=[CH:20][C:19]3[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Reactant: BrCc1ccc(Br)cc1
Product: COC(=O)c1ccc(C(=O)c2cc3c(cc2OCc2ccc(Br)cc2)C(C)(C)CCC3(C)C)cc1
Yield: 60 %

Procedure:
The 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7) was alkylated with 4-bromobenzylbromide as described for Example 60 to give 4-[(3-(4-bromobenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (60%): 1H NMR (400 MHz, CDCl3) δ 8.03 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.80 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.46 (s, 1H, ArH), 7.29 (1/2ABq, 2H, J=8.4 Hz, ArH), 6.87 (s, 1H, ArH), 6.81 (1/2ABq, 2H, J=8.4 Hz, ArH), 4.87 (s, 2H, OCH2), 3.97 (s, 3H, OCH3), 1.70 (m, 4H, 2CH2), 1.30 (s, 6H, 2CH3), 1.27 (s, 6H, 2CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[S:16][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]=[C:33]=[O:34].O>C1COCC1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[NH:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[S:16][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1)=[O:34]
Reactant: COC(=O)c1cc(-c2cc(Oc3ccc(N)cc3)ccn2)cs1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 4-[4-(4-aminophenoxy)pyridin-2-yl]thiophene-2-carboxylate (500 mg, 1.53 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (255 mg, 1.68 mmol). The mixture was stirred at room temperature for one hour and poured into 200 ml of water. The resulting precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3-5% MeOH/CHCl3 to give methyl 4-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}thiophene-2-carboxylate as off-white solid. Yield: 560 mg, 76%.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28]O>S(=O)(=O)(O)O>[CH3:28][O:18][C:17](=[O:19])[CH2:16][C:14]1[N:15]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:12][CH:13]=1
Reactant: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid (prepared as in Example 18, 95.4 mg, 0.223 mmol) in methanol (1.1 mL) was treated with 1 drop of concentrated sulfuric acid. The reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with ethyl acetate (100 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/1 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (77.2 mg, 78%) as a yellow viscous oil: FAB-HRMS m/e calcd for C20H22Cl2N2O3S (M+H)+ 441.0807, found 441.0804.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)C(Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 8.2 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (300.2 mg) and ethyl 4-aminophenylacetate hydrochloride (202.2 mg) were condensed in THF (5 ml) in the presence of triethylamine (422.4 μl) and pivaloyl chloride (153.9 μl), and then the resulting crude product was recrystallized from ethanol to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (35.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:22]C(=O)C)[C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:22])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a solution of acetic acid (4-bromo-phenyl)-(4-trifluoromethyl-phenylcarbamoyl)-methyl ester (5.7 g, 13.7 mmol) in THF (20 mL) was added LiOH monohydrate (0.863 g, 20.5 mmol) in water (12 mL) dropwise at room temperature. After stirring an additional hour at room temperature, the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to obtain white solid (5.04 g, 98.8%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1cccc2c1CNCC2
Reaction time: 0.5 h

Procedure:
In a 10 dram vial, added 7-1 (292.5 mg, 0.958 mmol) to DCM (3831 μl) and TFA (958 μl). After 30 min at RT, concentrated to give a clear, colorless oil. Carried crude material forward to subsequent step.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH2:5][CH2:4][C@@H:3]4[NH:2][S:30]([CH3:29])(=[O:32])=[O:31])=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[O:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(C)(=O)=O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Prepared using General Procedure 12. To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (20 mg, 0.04 mmol) and TEA (14.7 mg, 0.14 mmol) in DCM (2 mL) was added methane sulfonylchloride (8.3 mg, 0.07 mmol) and the mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue purified by preparative HPLC to afford 12 mg (55%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide 33 as white solid. LCMS-ESI (m/z) calculated for C22H22N4O3S2: 454.1; found 455.1 [M+H]+, tR=3.48 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]#[N:19])[N:3]=1.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]([C:18]#[N:19])[N:3]=1)[CH3:21]
Reactant: N#Cc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)c1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1

Procedure:
4-Chloro-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (10 mg) dimethylamine (18 ul) and triethylamine (50 ul) were stirred at room temperature in acetonitrile (500 ul) for one hour. After removal of solvent under reduced pressure, the residue was purified by preparative LCMS to give 4-diethylamino-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (2.5 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=1.[K+].[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25]>>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:15]([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])=[CH:16][CH2:17]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2N)CC1
Agent: [K+]
Product: CC1(C)CC=C(c2cc(C3CCC(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-cyclohexanone (as prepared in the previous step) and 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) according to the procedure in Example 1, step (f). Mass spectrum (APCI, m/z): Calcd. for C31H42N4O3Si, 547.3 (M+H), found 547.0.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])=[N:27][CH:28]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[C:66]([O:69][CH2:70][CH3:71])(=[O:68])[CH3:67]>O>[CH2:70]([O:69][C:66](=[O:68])[CH2:67][O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[N:27][C:26]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:13][CH2:14]1)[CH3:71]
Reactant: CCOC(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)c2ncnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(5-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile (0.42 g), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.1 mL) and tetrahydrofuran (20 mL) was stirred at 70° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (20 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.31 g) was added, and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), sodium borohydride (0.016 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution (10 mL) of the obtained residue in toluene was added dropwise ethyl diazoacetate (0.14 mL) in the presence of rhodium(I) acetate (0.0012 g) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.06 g, 15%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O-:14].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: Fc1c(Br)cccc1C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(Br)cccc1C(F)(F)F
Temperature: 150 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzotrifluoride (1.0 g, 4.1 mmol) in methanol (5 ml) was added a solution of sodium methoxide in methanol (30%, 0.73 ml, 4.1 mmol). The mixture was heated under microwave radiation to 150° C. for 10 min. The reaction mixture was poured into water and extracted with ethylacetate (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.89 g). MS m/z (rel. intensity, 70 eV) 256 (M+, 87), 254 (M+, 89), 239 (26), 211 (24), 132 (bp).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1Cl
Solvent: CCO
Product: CC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of 3-chloro-2-methylaniline (9.0 g, 63.56 mmol) in EtOH (75 mL) was treated with acetic anhydride (7.2 mL, 76.31 mmol) and the resulting mixture was stirred at rt for 3 h. Concentration was followed by crystallization from hexanes/EtOAc (1:3) to afford 11.2 g of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.30-7.23 (m, 2H), 7.17-7.13 (m, 1H), 2.18 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH:3]=[CH:4][C:5]([OH:7])=O.[CH:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:19][C:5](=[O:7])[CH:4]=[CH:3][CH:2]([CH3:1])[CH3:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCCc2ccccc21
Reactant: CC(C)C=CC(=O)O
Product: CC(C)C=CC(=O)NC1CCCc2ccccc21

Procedure:
Prepared in a similar manner as described in example 4 from 4-methyl-pent-2-enoic acid and 1,2,3,4-tetrahydro-naphthalen-1-ylamine. MS (M+H, 244.2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].I[CH2:18][CH3:19].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:19]
Reactant: CCI
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
Step A To a solution of methyl 3-hydroxy-4-nitrobenzoate (Aldrich) (3 g, 15.2 mmol) in anhydrous DMF (25 mL) were added NaH (Aldrich, 60%) (0.91 g, 22.8 mmol) and iodoethane (2.61 g, 16.7 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h. Water was added. The mixture was extracted with ethyl acetate. The organic extract was washed with water, brine, dried over MgSO4, and concentrated to give methyl 3-ethoxy-4-nitrobenzoate as a light yellow solid (1.0 g, 29%).
Reaction SMILES: Br.C([N:9]1[C:13]2=[C:14]([N+:29]([O-:31])=[O:30])[C:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[C:16]([CH3:19])[C:17](=[O:18])[N:12]2[CH2:11][CH2:10]1)C1C=CC=CC=1.C(OC(=O)C)C>C(O)(=O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]2[C:14]([N+:29]([O-:31])=[O:30])=[C:13]3[NH:9][CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]=2[CH3:19])=[C:22]([F:28])[CH:23]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
HBr in acetic acid (20 mL) was added to 1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (I-1f: 1.4 g) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (65% ethylacetate in hexane) afforded 600 mg of the product (54.5% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][O:16][P:15](OC3C=CC=CC=3)[O:14][CH2:13]2)[CH2:11][O:10][P:9]1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([C:36]1[CH:41]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:39]=[CH:38][C:37]=1[OH:46])([CH3:35])([CH3:34])[CH3:33].C[O-].[Na+]>>[CH2:1]([N:8]1[C:12]2([CH2:17][O:16][P:15]([O:46][C:37]3[CH:38]=[CH:39][C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:41][C:36]=3[C:32]([CH3:35])([CH3:34])[CH3:33])[O:14][CH2:13]2)[CH2:11][O:10][P:9]1[O:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]([CH3:7])([CH3:3])[CH3:1])=[CH:30][C:31]=1[C:12]([CH3:17])([CH3:13])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2P(Oc3ccccc3)OCC23COP(Oc2ccccc2)OC3)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)c1ccc(OP2OCC3(CO2)COP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)N3Cc2ccccc2)c(C(C)(C)C)c1

Procedure:
The product of Example 18 is reacted with two equivalents of 2,4-di-tert-butylphenol and sodium methoxide at reduced pressure and at an elevated temperature to afford the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26]Cl)[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>CS(C)=O>[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:1]#[N:2])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 0 °C
Yield: 98.2 %

Procedure:
Dimethyl sulfoxide (500 ml) and sodium cyanide (9.8 g) were added to 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (about 70 g) and the resultant mixture was stirred at 50° C. for 2 hr. Next, ice water (500 ml) was added to the reaction solution followed by vigorously stirring. The resulting crystals were collected by filtration, washed with water and air-dried at 80° C. to give the title compound (67 g) as a pale yellow powder (yield: 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[Br:20])[NH2:16]>>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[Br:20]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1cc(N)ccc1Br
Product: Cc1cc(Nc2ccccc2CC(=O)O)ccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methyl-4-bromoaniline to yield 2-[(3-methyl-4-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: C([N+](CC)(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[C:36](Cl)([Cl:39])([Cl:38])[Cl:37]>C(Cl)(Cl)Cl>[Cl:37][C:36]([CH:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[OH:33])([Cl:39])[Cl:38]
Reactant: COc1ccc(C=O)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Yield: 94.5 %

Procedure:
A 10 g quantity of tetraethyl ammonium salt of p-toluenesulfonic acid was dissolved in 60 ml of dimethylformamide containing 0.1 mole of chloroform. The solution was placed in a cathode chamber and in an anode chamber. Further 13.6 g (0.1 mole) of p-methoxybenzaldehyde and 0.01 mole of carbon tetrachloride was introduced into the cathode chamber. A glass filter was used as a diaphragm. Electrolysis was conducted at a constant current of 0.1 A. After current (2 F/mole) was passed, the reaction liquid was withdrawn from the cathode chamber. The carbon tetrachloride and chloroform were distilled off and the residue was extracted with methylene chloride. The methylene chloride was distilled off from the extract and the residue was distilled in a vacuum, giving trichloromethyl-4-methoxyphenyl carbinol. Yield 94.5%, b.p. 122°-124° C./1 mmHg.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43]Cl)=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C:7](=[N:8][C:9]([CH3:10])([CH2:43][C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[C:11]([O:13][CH3:14])=[O:12])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reactant: ClCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C(C)(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of methyl N-(diphenylmethylene)alaninate from Step A (9.78 g, 36.6 mmol) in 60 ml DMF at 0° C. was added a 1M solution of sodium bis(trimethylsilyl)amide in THF (45.72 ml, 45.72 mmol) over a 20 min period. After 30 min, a solution of 4-picolyl chloride hydrochloride (3.00 g, 18.29 mmol) in 40 ml DMF was added to the reaction via cannula over a 25 min period. The reaction was warmed to rt and stirred for 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 3M LiCl (2×) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-40% EtOAc/hexanes) afforded methyl 2-[(diphenylmethylene)amino]-2-methyl-3-pyridin-4-ylpropanoate as a white solid (5.28 g, 81%). LCMS [M+H]=359.2. 1H NMR (d4-MeOH) δ 8.51 (dd, J=4.5, 1.5 Hz, 2H), 7.56 (dd, J=8.4, 1.4 Hz, 2H), 7.40-7.37 (m, 4H), 7.34-7.30 (m, 2H), 7.26-7.23 (m, 2H), 7.10-7.07 (m, 2H), 3.33 (A of AB, d, J=13.0 Hz, 1H), 3.27 (s, 3H), 3.18 (B of AB, d, J=12.9 Hz, 1H), 1.32 (s, 3H).