Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[NH:24][C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH:40]([CH3:42])[CH3:41])=[N:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]2[CH:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[N:24]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH:40]([CH3:42])[CH3:41])=[N:22]2)=[CH:19][CH:20]=1
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isobutyryl chloride (8.1 μL, 0.077 mmol) was added to a solution of triethylamine (10.8 μL, 0.077 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (30 mg, 0.071 mmol) in methylene chloride (3 mL). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were remove under reduced pressure and chromotagraphy of the residue over silica gel using 25% ethyl acetate in hexanes gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C28H29N2O2Cl2[(M+H)+]495.1601, observed 495.1606.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35]([OH:37])=O)[C:20]=3[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:37])[C:20]=3[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cnn2c(Nc3cccc4cccnc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4cccnc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 30 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-phenylpiperidine-1-carbonyl)-7-(8-quinolylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.08 mmol) obtained in step 2 and ethanesulfonamide (0.055 g, 0.5 mmol), the title compound (0.014 g, 30%) was obtained.
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])=[CH:5]1>C(Cl)Cl>[NH2:29][CH:14]([CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1)[CH2:15][NH:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmoles) was added to a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmoles) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[CH:5]=1.[H][H]>[Pd].CO>[NH2:11][C:7]1[C:8]([CH3:10])=[CH:9][C:4]([C:3]([N:2]([CH3:16])[CH3:1])=[O:15])=[CH:5][C:6]=1[CH3:14]
Reactant: Cc1cc(C(=O)N(C)C)cc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)N(C)C)cc(C)c1N

Procedure:
10% Palladium on carbon (100 mg) is added to a solution of N,N,3,5-tetramethyl-4-nitrobenzamide (1 g) in methanol (10 mL) and the mixture is hydrogenated for 3 hours under 2 bar hydrogen pressure. Then the catalyst is filtered off and washed with methanol. The combined mother liquors are concentrated to give the title compound. Yield: 1 g; LC (method 20): tR=2.75 min; Mass spectrum (ESI+): m/z=193 [M+H]+.
Reaction SMILES: ClC1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)C=1.[C:12]([O:16][C:17]([N:19]1CCC(=C)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:7][CH2:6][CH:5]([CH:4]2[O:10][CH2:8]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C2CO2)C1
Reaction time: 6 h
Yield: 56.8 %

Procedure:
3.54 g (0.0175 mole) of 85% m-chloroperbenzoic acid were added to a solution of 2.67 g (0.0146 mole) of 1-t-butoxycarbonyl-3-methylenepyrrolidine [prepared as described in Step (4) above] in 20 ml of chloroform, whilst ice-cooling, and the mixture was stirred at the same temperature for 6 hours and then stirred at room temperature overnight. At the end of this time, 1.8 g (0.073 mole) of 70% m-chloroperbenzoic acid were added, and the mixture was stirred at room temperature for 12 hours. At the end of this time, the mixture was extracted with toluene. The toluene extract was washed, in turn, with an aqueous solution of sodium bicarbonate, with an aqueous solution of sodium thiosulfate and with water, in that order, after which it was dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with a 1:9 by volume mixture of ethyl acetate and toluene, to give 1.77 g of 1-t-butoxycarbonyl-3 -(1,2-epoxyethyl)pyrrolidine as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12](Br)=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CN(C1C=CC=CN=1)[CH:26]=[O:27]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[N:11]([CH3:17])[C:12]([CH:26]=[O:27])=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1ccccn1
Reactant: Cn1c(Br)c(Br)cc(OCc2ccccc2)c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1c(C=O)c(Br)cc(OCc2ccccc2)c1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
To a −78° C. solution of 3-(benzyloxy)-5,6-dibromo-1-methylpyridin-2(1H)-one (1.5 g, 4.02 mmol) in THF (20 mL) was added 2 M isopropylmagnesium chloride in THF (4.02 mL, 8.04 mmol) dropwise. This mixture was stirred at −78° C. for 15 minutes under nitrogen, and N-methyl-N-pyridin-2-ylformamide (1.4 mL, 12.06 mmol) was added. The mixture was allowed to slowly warm to room temperature overnight. Volatiles were removed under reduced pressure, and the resulting residue was partitioned between dilute aqueous hydrochloric acid and ethyl acetate. The aqueous layer was removed and discarded. The organic layer was collected, dried over anhydrous magnesium sulfate, and purified by silica gel chromatography to afford 5-(benzyloxy)-3-bromo-1-methyl-6-oxo-1,6-dihydropyridine-2-carbaldehyde (1.09 g, 3.38 mmol, 84% yield). ES-MS (M+H)+=323.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:30])[O:3]1.CCN(C(C)C)C(C)C.[CH:41]1([CH2:46][CH2:47][C:48](Cl)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42]1.Cl>C(Cl)Cl>[CH:41]1([CH2:46][CH2:47][C:48]([N:12]([CH2:13][C:14]2[CH:29]=[CH:28][C:17]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[CH:16][CH:15]=2)[C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:31])([CH3:1])[O:3][C:4](=[O:30])[C:5]=3[CH:11]=2)=[O:49])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C(=O)OCc4ccccc4)cc3)ccc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)OCc4ccccc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a cold (0° C.) solution of benzyl 4-{[(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}benzoate (430 mg) and DIEA (146 mg) in anhydrous DCM (5 nm) was added a solution of 3-cyclopentylpropanoyl chloride (182 mg, 1 M in DCM). The mixture was stirred 1 h at 0° C. then 3 h at rt. An aqueous solution of HCl (1N, 50 mL) was added and the resulting mixture was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over MgSO4, filtered and evaporated under vacuum to give a light orange oil. Purification by chromatography (SiO2, DCM/c-Hex) gave the title compound as a colorless oil (499 mg, 89%). 1H NMR (CDCl3) δ 8.00 (d, J=8.3 Hz, 2H), 7.69 (d, J=2.3 Hz, 1H), 7.49-7.32 (m, 5H), 7.27 (d, J=7.5 Hz, 2H), 7.11-7.03 (m, 1H), 6.91 (d, J=8.6 Hz, 1H), 5.37 (s, 2H), 4.93 (s, 2H), 2.13-2.05 (m, 2H), 1.85 (s, 6H), 1.71-1.37 (m, 9H), 1.06-0.89 (m, 2H). M+(ESI): 542.3.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][SH:5].Cl[C:11]1[C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=[CH:13][N:12]=1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:5][C:11]1[C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=[CH:13][N:12]=1
Reactant: SCc1ccccc1Cl
Reactant: Cn1cnc2c(Cl)nccc21
Solvent: CCO
Product: Cn1cnc2c(SCc3ccccc3Cl)nccc21
Reaction time: 16 h

Procedure:
2.76 g of Na is dissolved in 180 ml of ethanol; 19.1 g of o-chlorobenzylmercaptan and 16.76 g of 4-chloro-1-methyl-1H-imidazo(4,5-c)pyridine are added; the mixture is boiled for 16 hours and evaporated; and the residue is worked up in the customary manner to give 4-o-chloro-benzylthio-1-methyl-1H-imidazo(4,5-c)pyridine of m.p. 152°-155° (from ethanol).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@H:9]3[C@@:14]([CH3:17])([CH2:15][CH2:16][C@@:7]2([CH:31]=[O:32])[CH2:6][CH2:5]1)[C@:13]1([CH3:30])[CH2:18][CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[CH:23]=[CH:22][C@:21]2([CH3:29])[C@H:12]1[CH2:11][CH2:10]3)=[CH2:3].OO.[O-:35]Cl=O.[Na+]>CC#N.O.O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:14]([CH3:17])([CH2:15][CH2:16][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:13]1([CH3:30])[C@@H:12]([C@:21]2([CH3:29])[C@@H:20]([CH2:19][CH2:18]1)[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[CH2:23][CH2:22]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: [O-][Cl+][O-]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@@H](CC[C@@H]4[C@@]5(C)C=CC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The betulone aldehyde prepared from the last step is dissolved in a mixture of NaH2PO4.H2O (877 mg) and CH3CN—H2O (17 mL) and the suspension cooled to 0-5° C. 30% aqueous H2O2 (220 μL) and a solution of NaClO2 (200 mg) in water (16 mL) are then successively added, the mixture warmed to room temperature and stirred at this temperature for 1 h. The reaction is quenched by addition of Na2S2O5 (380 mg), and extracted with ethyl acetate. The organic extract is washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue is then subjected to column chromatography to afford betulonic acid (550 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[NH:10][CH:9]2[C:30]([OH:32])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[CH:39]=[CH:38][N:37]([CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])[N:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:43][C:41]([CH3:44])([CH3:42])[CH2:40][N:37]1[CH:38]=[CH:39][C:35]([NH:34][C:30]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:33])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[NH:10]2)=[O:32])=[N:36]1
Reactant: CC(C)(CCO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)C2NC(CC(C)(C)CCO)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Yield: 54.6 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid prepared in Example 116c (0.48 g, 0.78 mmol) was reacted with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (0.15 g, 0.9 mmol), HATU (0.6 g, 1.6 mmol) and iPr2NEt (0.41 mL, 2.4 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a white solid (0.27 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[C:4]([F:15])[C:5]([F:14])=[C:6]([O:8]C(OCC)=O)[CH:7]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[F:14][C:5]1[C:4]([F:15])=[C:3]([F:16])[C:2]([NH:1][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[OH:8]
Reactant: CCOC(=O)Oc1cc(N)c(F)c(F)c1F
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(O)c(F)c(F)c1F
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
1.27 g (5.40 mmol) of the above 5-amino-O-ethoxycarbonyl-2,3,4-trifluorophenol was dissolved in 5 mL of pyridine, 0.80 mL (6.5 mmol) of pivaloyl chloride was added under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. 1N hydrochloric acid was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 25 mL of methanol, 1.40 g (10.1 mmol) of potassium carbonate and 15 mL of water were added and the mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 2 by addition of 2N hydrochloric acid thereto and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1.20 g of 2,3,4-trifluoro-5-pivaloylaminophenol (two stage yield: 90%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([NH:28][C:29](=[O:37])[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:17]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([NH:28][C:18]2[N:17]=[C:16]([NH:15][C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=2)=[O:37])=[CH:35][CH:34]=1
Reactant: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3N)c2c1
Yield: 82.3 %

Procedure:
A solution of 120 mg of cis-N-tert-butoxycarbonyl-2-[2-(4-chlorobenzoylamino)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 5 mL of methylene chloride was combined with 2 mL of trifluoroacetic acid, and reacted at room temperature for 1 hour. The reaction solution was basified by addition of a saturated solution of sodium hydrogen carbonate, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 80 mg of the desirable compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[NH2:17].CCCCCC>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH3:23])=[C:14]([Br:13])[CH:15]=1)=[O:12])([O-:3])=[O:2]
Reactant: CCOc1ccc(N)cc1Br
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOc1ccc(NC(=O)Nc2ccccc2[N+](=O)[O-])cc1Br
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-Nitrophenyl isocyanate (3.34 g) in 100 mL of toluene was added 3-Bromo-4-ethoxyaniline (3.1 g). The mixture was stirred at 20° C. for 30 min. Hexane (300 mL) was added and the resulting solid was filtered and dried to yield N-(2-Nitrophenyl)-N'-(3-bromo-4-ethoxyphenyl)-urea as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C([Li])CCC.CCCCCC.[I:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:9])[CH2:10][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([I:25])=[CH:27][CH:28]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
t-butylacetoacetate (1.5 mL, 9.2 mmol) was added dropwise over 2 minutes to a stirred suspension of sodium hydride (60% mineral oil suspension; 400 mg, 10.0 mmol) in tetrahydrofuran at 0° C. under nitrogen. After stirring for 10 minutes n-butyl lithium in hexane (1.6 M; 6.0 mL, 9.6 mmol) was added then stirring continued for a further ten minutes. The resulting solution was treated dropwise with a solution of 4-iodobenzyl bromide (2.97 g, 10.0 mmol) in tetrahydrofuran (4 mL) and then warmed to room temperature. The reaction was stirred for 40 minutes at room temperature and then quenched with 6 M HCl (5 mL). The resulting mixture was extracted with diethyl ether (3×50 mL). The organic phases were combined, washed with brine (50 mL) and dried (MgSO4) then the solvent evaporated under reduced pressure. The residue was purified via flash chromatography on silica gel (1:20 to 1:10 ethyl acetate/cyclohexane) to give the title compound (1.88 g, 54%) as a yellow oil. LC/MS: 3.66 min; z/e 375, calcd (M+1) 375. 1H NMR (400 MHz; CDCl3): 7.6 (2H), 6.93 (2H), 3.33 (2H), 2.85 (4H), 1.45 (9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(3-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 18 & 19, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: NC1C=CC(N2CCOCC2=O)=CC=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][C:16]1=[O:21].[H-].[Na+].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C:16]2=[O:21])=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1COCCN1
Agent: Nc1ccc(N2CCOCC2=O)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1

Procedure:
In contrast, WO-A 01/47919 also describes a preparation method for 4-(4-aminophenyl)-3-morpholinone (I). In this method, morpholin-3-one (V) is first deprotonated with sodium hydride and then reacted with 4-fluoronitrobenzene (VI) to give 4-(4-nitrophenyl)-3-morpholinone (VII). Catalytic hydrogenation of (VII) with hydrogen over palladium on activated carbon in tetrahydrofuran as a solvent affords 4-(4-aminophenyl)-3-morpholinone (I):
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:14]2[CH2:15][CH2:16][NH:17][CH2:18][C:13]2=[N:12][N:11]=1.[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)CCC>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:17]2[CH2:16][CH2:15][N:14]3[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[N:11][N:12]=[C:13]3[CH2:18]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: c1ccc2sc(-c3nnc4n3CCNC4)nc2c1
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCn3c(nnc3-c3nc4ccccc4s3)C2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine (prepared according to the method of Example 259, Step C, 170 mg, 0.66 mmol), (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 150 mg, 0.66 mmol), and triethylamine (0.28 mL, 1.98 mmol) in n-butanol (2.2 mL) was heated to reflux overnight, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 224 mg (76%) of the title compound of Example 259, Step D as a colorless solid. 1H NMR (CDCl3, 300 MHz) δ 8.37 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.57-7.43 (c, 2H), 6.53 (d, 1H), 5.71 (q, 1H), 5.09 (s, 2H), 4.82 (t, 2H), 4.33-4.26 (c, 2H), 2.42 (t, 2H), 1.78-1.64 (c, 2H), 1.61 (d, 3H), 0.99 (t, 3H); MS (APCI) 450 (MH+).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[Cl:21].C(OC([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=O)(C)(C)C.C(C1C=C(NC(=O)C2C=CC(N3CCNCC3)=C(F)C=2)C=CC=1)(C)(C)C>>[C:15]([C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:3]([Cl:21])[CH:4]=2)[CH:14]=[CH:13][CH:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(Cl)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(Cl)c2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-3-chloro-4-piperazin-1-yl-benzamide was synthesized from 4-bromo-N-(3-tert-butyl-phenyl)-3-chloro-benzamide and piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide above. LCMS calcd for C21H26ClN3O (m/e) 371, obsd 372 (M+H)