Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1(=O)[O:35][C:33](=[O:34])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:33](=[O:34])[C:32]3[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:30]2=[O:35])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (177.9 mg) and triethylamine (98 μL) in THF (2.94 mL) was added phthalic anhydride (105 mg). The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic anhydride (3 mL), and the mixture was stirred at 80° C. for 5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (252.7 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])C1C=CC=CC=1.C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:42]([CH:39]4[CH2:38][CH2:37][CH:36]([C:34]([OH:35])=[O:33])[CH2:41][CH2:40]4)=[O:43])[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)nc2)c1

Procedure:
4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid was prepared from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and trans-1,4-cyclohexane dicarboxylic acid monobenzyl ester in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentanecarboxylic acid above. HRMS m/z calcd for C28H36N4O4 [M+H]+: 493.2810. Found: 493.2807.
Reaction SMILES: C([C:5]([Br:17])(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)CCC.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:29]([O-])([O-:31])=[O:30].[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[S:29](=[C:5]([Br:17])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S([O-])[O-]
Reactant: CCCCC(Br)(CCCC)c1ccc(F)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)=C(Br)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 8.5 g (25 mmol) of sulfide obtained from Step 3 in 200 mL of CH2Cl2 at 0° C. was added 15.9 g (60 mmol) of mCPBA (64% peracid). The resulting solution was stirred cold for 10 min, then was allowed to stirred ambient temperature for 5 hours. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed several times with saturated Na2CO3, dried (MgSO4), and concentrated in vacuo to give 10.2 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.91 (t, J=7.05 Hz, 6H), 1.03-1.4 (m, 8H), 1.65-1.82 (m, 2H), 1.90-2.05 (m, 2H), 3.54 (s, 2H), 5.01 (s, 2H), 7.04-7.23 (m, 1H), 7.30 (dd, J=8.87, 2.42 Hz, 1H), 8.03 (dd, J=8.86, 5.64, 1H), 9.49 (s, 1H).
Reaction SMILES: C=O.[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:28])[N:17]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:18]4=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:5]=1.[CH3:29]C([O-])=O.[Na+]>CC(O)=O.O>[CH2:29]=[C:22]1[C:18]2=[N:19][C:20]3[C:15]([C:16](=[O:28])[N:17]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:14][CH:13]=[C:12]([C:10]([NH:9][C:7]1[S:8][C:4]([CH3:3])=[CH:5][N:6]=1)=[O:11])[CH:21]=3
Reactant: CC(=O)[O-]
Reactant: Cc1cnc(NC(=O)c2ccc3c(=O)n4c(nc3c2)CCCCCC4)s1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=C1CCCCCn2c1nc1cc(C(=O)Nc3ncc(C)s3)ccc1c2=O
Yield: 144 %

Procedure:
Paraformaldehyde (10 mg), N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide (60 mg, 0.16 mmol) and NaOAc (3 mg, 0.0365 mmol) in 5 mL HOAc was stirred at 120° C. overnight in a sealed tube. The completion was monitored by TLC and LC-MS. The sealed tube was then placed in water until cool. The suspension was diluted with water (30 mL) and adjusted pH to 8, then extracted with ethyl acetate (3×50 mL). The organic phase was concentrated to give crude product and 20 mg of the desired product was obtained by column chromatography. MS (ESI): 381 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.45-8.42 (d, J=8.22 Hz, 1H), 8.27 (s, 1H), 8.04-8.00 (dd, J=8.39, 1.61 Hz, 1H), 7.28 (s, 2H), 5.52 (s, 1H), 5.30 (s, 1H), 4.39-4.33 (m, 2H). 2.72-2.59 (m, 2H), 2.42 (s, 3H), 1.96-1.88 (m, 2H), 1.72-1.68 (m, 2H), 1.56-1.51 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[CH2:20]([O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
Prepared according to the method described in Example 33a) from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.97 g, Example 40a), 3-(benzyloxy)benzeneboronic acid (1.0 g, Example 93b), tetrakis(triphenylphosphine)palladium(0) (0.09 g), toluene (7.5 ml), ethanol (2 ml) and aqueous sodium carbonate (2 M, 3.5 ml) with heating at 120° C. for 2 hours 30 minutes. After work up the residue was purified by column chromatography over silica eluting with methanol:dichloromethane (5:95) to give the title compound as a white solid (1.07 g).
Reaction SMILES: [C@H:1]([OH:10])([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].N[C@@H](C(O)=O)C(S)(C)C>>[C:7]([OH:9])(=[O:8])[C@@H:1]([C@H:2]([C:3]([OH:5])=[O:4])[OH:6])[OH:10]
Reactant: O=C(O)[C@@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(S)[C@@H](N)C(=O)O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
Via chiral HPLC the absolute amounts of D-, L-, and meso-tartaric acid were determined (Column used: Chirex 3126 (D)-penicillamine (ligand exchange)) (see Table 2).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:11]=[CH:12][C:13]2[C:18]([I:19])=[CH:17][N:16]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[C:14]=2[N:15]=1.N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Si:1]([O:22][CH2:21][C:20]([N:16]1[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:18]([I:19])=[CH:17]1)([CH3:24])[CH3:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)n1cc(I)c2cnc(Cl)nc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
t-Butyldimethylsilyl chloride (78.8 g, 518 mmol) was added to 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-1-ol (140 g, 398 mmol) (see Preparation 43) and imidazole (67.8 g, 996 mmol) in DMF (996 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. The mixture was poured into saturated aqueous sodium bicarbonate (1500 mL) and extracted with heptane:EtOAc (1:1, 1500 mL). The organic extract was washed with brine (2×900 mL) then dried over magnesium sulfate and evaporated in vacuo to afford the title compound as a brown gum in 96% yield, 178.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:25][O:24][C:20](=[O:23])[CH2:21][O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: COC(=O)CO
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To a solution of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (prepared as in Example 1, 150 mg, 0.535 mmol) in THF (2 mL) was added methyl glycolate (82.5 μL, 1.07 mmol) followed by DBU (160 μL, 1.07 mmol). The reaction was stirred for 5 h, diluted with 3/6/1 ethyl acetate/hexane/dichloromethane, and passed through a plug of SiO2 using 4/5/1 ethyl acetate/hexane/dichloromethane. The filtrate was concentrated, and the resulting solids triturated with dichloromethane/hexane to afford 95.1 mg (58% yield) of the titled ester as a white solid. ESI-MS m/z 306 (MH+), 304 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=O)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:37][NH2:38]>C(O)C>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][C:11]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([NH:37][NH2:38])=[O:24])=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 80 °C
Yield: 103.9 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinate (Example 43) (0.2 g, 0.43 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.1 mL, 2.1 mmol). The reaction mixture was heated to reflux at 80° C. for 16 h. The ethanol was evaporated under reduced pressure and the residue was dissolved in DCM and washed with water. The organic layer was dried and concentrated to provide 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinohydrazide (0.2 g, crude), which was used without further purification. LCMS Method E: retention time 1.8 min; [M+1]=447.50.
Reaction SMILES: C1(CC[N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])CC1.N1C2C(=CC=CC=2)C(=O)C1=O.O1C2C=CC(O)=CC=2OC1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>>[Br:38][C:39]1[CH:40]=[CH:41][C:42]([OH:45])=[C:43]([C:8]2([OH:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:6][C:7]2=[O:16])[CH:44]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: O=C1Nc2ccccc2C1=O
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1Nc2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with isatin, 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (71%) as a yellowish solid: MS (ES+) m/z 319.4 (M+1), 321.4 (M+1).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[CH2:30]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:15]2[NH:14][C:13]([C:10]3[CH:11]=[N:12][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][CH:9]=3)=[CH:17][N:16]=2)[CH2:19]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCCNC4)n3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCCC(c3ncc(-c4cnc(-c5ccccc5)nc4)[nH]3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution consisting of (±)-2-phenyl-5-(2-(piperidin-3-yl)-1H-imidazol-4-yl)pyrimidine (Example 22, 40 mg, 0.13 mmol) in dimethylformamide (2 mL) was added cesium carbonate (85 mg, 0.26 mmol) followed by benzyl bromide (27 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for one hour and diluted with water and the organic material was extracted twice with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane/ethyl acetate and chromatographed on silica (4 g) eluted with 1:9 v/v ethanol-ethyl acetate. The purified material was diluted with toluene and concentrated. Solidification of the product was promoted with scratching under dichloromethane and hexane to afford the title compound (20 mg) as a colorless solid; melting point 179° C.; Rf 0.19 with 1:9 v/v ethanol-ethyl acetate; 1H-NMR (400 MHz; DMSO-d6) δ 12.1 (s, 1H), 9.18 (s, 2H), 8.2-8.4 (m, 2H), 7.8 (s, 1H), 7.4-7.6 (m, 4H), 7.22-7.35 (m, 4H), 7.18-7.22 (m, 4H), 3.4-3.6 (m, 2H), 2.9-3.0 (m, 2H), 2.7-2.9 (m, 1H), 2.02-2.1 (M, 1H), 1.9-2.1 (m, 2H), 1.62-1.8 (m, 1H), 1.5-1.62 (m, 2H); MS (ESI+) m/z 396 (M+1); H-PGDS FPBA IC50: 0.6 μM.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:7]=1[O:8][CH2:15][CH2:16][O:17][CH3:18])[C:1]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C(=O)OC)cc1OC
Yield: 99.8 %

Procedure:
A mixture of methyl vanillate (6.376 g, 35 mmol), 1-bromo-2-methoxyethane (5.56 g, 40 mmol), and K2CO3 (5.528 g, 40 mmol) in DMF (40 mL) were reacted according to the procedure described in Example 6A Step 1, to afford methyl 3-methoxy-4-(2-methoxyethoxy)benzoate as a solid (8.394 g, 99.8%). 1H NMR (300 MHz, CDCl3) δ 7.65 (dd, 1H), 7.54 (d, 1H), 6.92 (d, 1H), 4.23 (q, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.81 (t, 2H), 3.45 (s, 3H); LC-MS (ESI) m/z 241 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[CH2:16][C@H:15]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].[Br:36]Br.[OH-].[Na+]>C(O)(=O)C>[Br:36][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:17]2[C:12]=1[CH2:13][CH2:14][C@@H:15]([NH:18][C:19](=[O:30])[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)[CH2:16]2
Reactant: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Br)c3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
(R)-N-[8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-trifluoromethylbenzamide (80 mg, 0.19 mmol) and sodium acetate (200 mg) were dissolved in acetic acid (3 mL) and the mixture was stirred at room temperature. Bromine (34 mg, 0.21 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 2 h at ambient temperature. A 2 M sodium hydroxide solution (100 mL) was added and the mixture was extracted with diethyl ether (2×50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification on a silica gel column using methylene chloride/ethanol saturated with NH3 (94:6) as the eluent gave 80 mg (85% yield) of the title compound as a white solid: mp 229-230° C.; [α]21D−5.4° (c=1, chloroform); EIMS (70 eV) m/z (relative intensity) 495 and 497 (3, M+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[NH2:26]>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:26][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH3:19])[N:7]=[CH:6][N:5]=2)=[O:9])=[C:12]([CH3:18])[CH:13]=1
Reactant: CC1CCCCC1N
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: Cc1cc(O)ccc1NC(=O)c1cc(NC2CCCCC2C)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and 2-methylcyclohexylamine (Aldrich), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:21]=[C:22](Cl)OC(Cl)(Cl)Cl>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:22](=[O:21])[NH:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1cnc2ccc(Br)cc2n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]nc2cnc3ccc(Br)cc3n12

Procedure:
To the solution of 7-bromo-2-hydrazinylquinoxaline (200 mg, 0.83 mmol) in dichloromethane (5 mL) was added triethylamine (0.175 mL, 1.2 mmol), then the solution of diphosgene (0.055 mL, 0.46 mmol) in dichloromethane was added dropwise at 0° C. with stirring under nitrogen atmosphere. After stirring at r.t. for 5 h, the solvent was removed under vacuum, the residue was washed with water, and dried in vacuo to afford the title product 8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one as yellow solid in 82% yield (180 mg). m/z 265 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[SH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: Sc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=c1cnn(-c2ccc(C(Sc3ccccn3)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol) and 2-mercaptopyridine (0.04 mol) in THF (100 ml) was stirred overnight at RT. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mol) was added and the resulting reaction mixture was stirred for 3 hours. NaOH (1 N; 50 ml) was added. The mixture was stirred for 5 minutes, then extracted with EtOAc. The separated organic layer was washed with water, dried, filtered and the solvent evaporated. The aqueous layers were combined, then acidified (pH=6) with HCl (1 N). This mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/THF/CH3OH 94/5/1). The pure fractions were collected and the solvent was evaporated. The residue was stirred overnight in diethyl ether. The solvent was evaporated. The residue was dried, yielding 2.98 g (43%) (±)-2-[3-chloro-4-[(4-chlorophenyl)(2-pyridinyl-thio)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 93).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:13]([Cl:30])=[CH:14][C:15]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C@H:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1>C1COCC1>[CH:1]([NH:11][C:12]1[C:13]([Cl:30])=[CH:14][C:15]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C@H:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1)=[O:3]
Reactant: O=CO
Reactant: CN1CCc2cc(Cl)c(N)cc2[C@@H](c2ccccc2)C1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CN1CCc2cc(Cl)c(NC=O)cc2[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Formic acid (2.25 g, 95-97%) was added dropwise to acetic anhydride (4.10 g.) at 0° C. with stirring. The resulting solution was heated under nitrogen in a water bath at 50°-60° C. with stirring for 2 hours longer. The solution was cooled down to room temperature and diluted with 5 ml of THF. A solution of (R)-8-amino-7-chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (5.10 g, 0.018 mol) in 25 ml of THF was added dropwise with stirring to the above solution. The resulting solution was stirred at room temperature for 3.5 hours longer and left standing at room temperature for 24 hours. The THF was evaporated in vacuo and the residue was treated with ether and 1N Na2CO3. The dried ether solution was evaporated in vacuo. The residue crystallized from acetonitrile, m.p. 135°-136° C. [α]26D +72.6° C. (DMF, c=1).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:7]=1.[CH3:23]C1C(C)=CC=CC=1NC(=O)C.NC1C=CC(C)=C(NC(=O)C)C=1>>[CH3:22][C:5]1[C:4]([CH3:23])=[CH:3][CH:2]=[CH:7][C:6]=1[NH:8][C:9]1[O:10][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:12][N:13]=1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reactant: CC(=O)Nc1cccc(C)c1C
Agent: CC(=O)Nc1cc(N)ccc1C
Product: Cc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1C
Yield: 91 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(2,3-dimethylphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=91%.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(Nc2ccccc2)CCNCC1
Yield: 85 %

Procedure:
A mixture of 32.5 parts of methyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate and 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue solidifies on scratching in 2,2'-oxybispropane. The product is filtered off and dried in vacuo, yielding 20 parts (85%) of methyl 4-(phenylamino)-4-piperidinecarboxylate; mp. 139.1° C.