Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[S:19][CH:20]=2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:15][O:14][C:9]1[C:8]2[C:7]([C:16]3[CH:17]=[C:18]([C:21]([NH2:23])=[O:22])[S:19][CH:20]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Temperature: 25 °C
Yield: 54.7 %

Procedure:
4-(1-tert-Butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (150 mg) obtained in Step C of Example 129 was dissolved in a mixed solvent of trifluoroacetic acid (20 mL)/water (2 mL), and the mixture was heated with reflux for 24 hr. The reaction mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate to ethyl acetate) to give the title compound (68.1 mg).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][PH:8](=[O:10])[CH3:9]>C(OCC)(=O)C>[CH3:7][P:8]([CH3:9])([CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[O:10]
Reactant: O=CC(=O)O
Reactant: C[PH](C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CP(C)(=O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
14.8 g (0.2 mol) of glyoxylic acid hydrate in 80 ml of ethyl acetate are added dropwise to a solution of 15.6 g (0.2 mol) of dimethylphosphine oxide in 80 ml of ethyl acetate. During this addition, the temperature rises slightly. The mixture is stirred at 25° C. for 24 hours and the product is filtered off with suction and washed with a little ethyl acetate to give, after drying, 20.2 g (66.5%) of the desired product of melting point 206°-208°.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])=[CH:4][C:3]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:4]=1)=[O:8])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,1-dimethylethyl {(2S)-2-({[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (crude from part a) was dissolved in TFA-DCM (3 mL, 1:2) and stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (5% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH3:9][C:10]1([CH3:22])[CH2:14][C:13]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:12]=2[O:11]1>C(OC(=O)C)(=O)C>[CH3:9][C:10]1([CH3:22])[CH2:14][C:13]2[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[C:18]([N+:5]([O-:8])=[O:6])[C:12]=2[O:11]1
Reactant: Cc1cc2c(c(C)c1C)CC(C)(C)O2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c([N+](=O)[O-])c1C)OC(C)(C)C2
Yield: 9.8 %

Procedure:
The mixed solution of acetic anhydride (5 ml) and acetic acid (5 ml) was cooled and nitric acid (5 ml) was added cautiously with stirring. Then, a solution of 2,2,4,5,6-pentamethyl-2,3-dihydrobenzofuran (2.9 g, 13.9 mmol) in acetic anhydride (5 ml) was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 9:1) and crystallized from methanol to obtain the desired compound (0.35 g, yield: 9.8% yield), m.p. 100°-101° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:34]CCl.Cl>C(O)C>[ClH:34].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (1.7 g, 4.1 mmol) was dissolved in ethanol (15 ml) and a 4 N sodium hydroxide solution (3.5 ml) was added. The mixture was stirred vigorously at room temperature for 5 h. Dichloromethane (300 ml) was added followed by a 4 N hydrochloric acid solution until pH 1. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated twice with acetone, once with ethyl acetate and once with diethyl ether to give 1.7 g of the title compound as a solid which was recrystallized from acetone.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Si:22]([O:29]C1CCCCC(O)CCCC1)(C(C)(C)C)([CH3:24])[CH3:23].[C:41]([CH:45]1[CH2:54][CH2:53][CH2:52][CH2:51][C:50]([O:56][SiH](C)C)(O)[CH2:49][CH2:48][CH2:47][CH2:46]1)([CH3:44])([CH3:43])[CH3:42].CCOCC>ClCCl>[C:41]([CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][C:50](=[O:56])[CH:51]([O:29][SiH:22]([CH3:24])[CH3:23])[CH2:52][CH2:53][CH2:54]1)([CH3:42])([CH3:43])[CH3:44]
Reactant: C[SiH](C)OC1(O)CCCCC(C(C)(C)C)CCCC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCCC(O)CCCC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[SiH](C)OC1CCCC(C(C)(C)C)CCCCC1=O
Temperature: 25 °C

Procedure:
1.5 g of pyridinium dichromate was dissolved in 30 ml of dichloromethane, to the solution was added 0.77 g of 6-tert-butyldimethylsilyloxy-1-cyclodecanol prepared in above-described (a). The mixture was stirred at room temperature for one and a half hours. Then, another 2.5 g of pyridinium dichromate was added to the reaction solution and the reaction solution was stirred at room temperature for further three hours. To the reaction solution was added 50 ml of ether, followed by purifying by column chromatography on Florisil, and the eluate with ether was collected, to afford 0.73 g of the titled compound (b) as colorless liquid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH2:1]([C:3]1[C:12]([NH:13][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1ccc2cccnc2c1N
Agent: CN(C)c1ccncc1
Product: CCc1ccc2cccnc2c1NS(=O)(=O)c1ccccc1
Yield: 15.2 %

Procedure:
In a similar fashion using route 14 general procedure 27, 7-ethylquinolin-8-amine (Intermediate 63) (144 mg, 0.84 mmol), benzenesulfonyl chloride (170 mg, 1.01 mmol) and DMAP (cat.) gave the title compound (40 mg, 15%) after purification by column chromatography with n-hexane/ EtOAc (17:3) as the eluent.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CN(C=O)C>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][OH:16])[CH3:6]
Reactant: CCOC(CBr)OCC
Reactant: OCCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccccc1CCO)OCC
Temperature: 80 °C

Procedure:
2-bromo-1,1-diethoxyethane (5.13 g) was added to a stirred mixture of cesium carbonate (8.49 g) and 2-(2-hydroxyethyl)phenol (3.00 g) in DMF (20 mL). After 5 minutes the reaction mixture was heated at 80° C. 16 h, the reaction mixture was allowed to cool and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water (×3) then evaporated. Purification by silica gel chromatography eluting with ethyl acetate:iso-hexanes, 1:3 gave the subtitle compound as a green oil. Yield 3.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:9]([O:24]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:13])=[O:14])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:7]2
Reactant: COc1c(S(=O)(=O)NCc2ccc(Cl)cc2)cc(Cl)c2ccc(C(C)(C)C)nc12
Agent: BrB(Br)Br
Product: CC(C)(C)c1ccc2c(Cl)cc(S(=O)(=O)NCc3ccc(Cl)cc3)c(O)c2n1

Procedure:
The title compound is prepared from 5-Chloro-N-[(4-chlorophenyl)methyl]-2-(1,1-dimethylethyl)-8-methoxy-7-quinolinesulfonamide, which is the second title compound of Preparation 9, and 6 equivalents of BBr3 according to the procedure described in Example 18. Crystallization from Et2O/hexane affords 0.035 g of the title compound as a dark tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[CH2:31]([N:33]([CH2:37][CH3:38])[C:34](Cl)=[O:35])[CH3:32]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:34]([N:33]([CH2:37][CH3:38])[CH2:31][CH3:32])=[O:35])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N(CC)CC)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (648 mg, 2 mmol) in dichloromethane (5 mL) and pyridine (1 mL, 12 mmol) was added a solution of diethylcarbamyl chloride (0.28 mL, 2.2 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(3,3-diethyl-ureido)-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (846 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H33N3O3 (M+H)+: 424.56, observed: 424.2.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 58.4 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (50 mg, 0.168 mmol) and 1-butanesulfonyl chloride (158 mg, 1.01 mmol) affords 41 mg (58%) of the title compound as a colorless oil. MS (ES) 440 (M+Na); HPLC shows 99% purity.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[CH:11].[C:12]([O:16][C:17](=[O:21])[CH:18]=[N+:19]=[N-:20])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([C:18]1[NH:19][N:20]=[C:10]([CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CCOCCOCCOC
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Product: COCCOCCOCc1cc(C(=O)OC(C)(C)C)[nH]n1
Temperature: 70 °C

Procedure:
To a solution containing approx. 2.5 g 3-[2-(2-Methoxy-ethoxy)-ethoxy]-propyne, 2.8 g Diazo-acetic acid tert-butyl ester were added and the mixture was heated to 70° C. for 5 days. Then the solution was concentrated under reduced pressure and directly purified by chromatography on silica eluting with a n-heptane/ethyl acetate gradient. Yield: 1.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:6]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1CNC(=O)C(C)C
Reactant: Nc1ncc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)c(C(=O)Nc2ncc[nH]2)cc1CNC(=O)C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a mixture of 2-chloro-4-methyl-5-[(2-methylpropanoylamino)methyl]benzoic acid (75.0 mg, 0.28 mmol, 1.0 equiv) and 2-aminoimidazole monosulfate (51.4 mg, 0.28 mmol, 1.0 equiv) in DMF (0.56 mL), add DIEA (0.204 mL, 1.17 mmol, 4.2 equiv) and BOP (152 mg, 0.33 mmol, 1.2 equiv). Stir at 60° C. for 5 h and isolate the resulting precipitate by filtration. Triturate with 9:1 dichloromethane:methanol (800 mL), and filter through a pad of silica gel. Concentrate the filtrate under reduced pressure to furnish the title compound as a white solid (57 mg, 61% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.76 (br s, 2H), 8.20 (t, 1H, J=6.0 Hz), 7.33 and 7.33 (s and s, 1H and 1H, isochronous), 6.75 (br s, 2H), 4.21 (d, 2H, J=5.7 Hz), 2.42 (sep, 1H, J=6.8 Hz), 2.28 (s, 3H), 1.00 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 335/337 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:11]=1
Reactant: CC(C)(C)c1cc(CCCOc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(CCCOc2ccccc2N)cc(C(C)(C)C)c1O

Procedure:
To a suspension of 4-[3-(2-nitrophenoxy)propyl]-2,6-di-t-butylphenol (1.03 g) in ethanol (30 ml) was added a catalytic amount of 10% palladium/carbon to carry out catalytic reduction under 3-4 arms at 40° C. for 10 hrs. After filtering off the catalyst, the solvent was distilled off to give 4-[3-(2-aminophenoxy)propyl]-2,6-di-t-butylphenol. This compound was dissolved in dichloromethane (20 ml), to which diisopropylamine (0.75 ml) was added. Phenyl chloroformate (0.84 g) was added dropwise under ice-cooling. After stirring the mixture at room temperature overnight, the reaction solution was washed with water and then saturated saline and dried over anhydrous MgSO4. After distilling off the solvent, the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=15:1) to give 1-(1-benzyl-4-piperidyl)-3-[2-[3-(3,5-di-t-butyl-4-hydroxyphenyl)propoxy]phenyl]urea (1.23 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].C(NC(C)C)(C)C.[Li].[C:19](=[O:21])=[O:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[C:6]([CH:7]=1)[C:19]([OH:21])=[O:20]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: O=C=O
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 1-bromo-2,3,4-trifluorobenzene (1) (5.0 mL, 41.7 mmol) in THF (120 mL) was added lithium diisopropylamine (2.0 M solution, 21 mL, 42 mmol) at −78° C. After stirring for 1 hour at −78° C., the mixture was added to a solution of CO2 in THF (1 L). The dry-ice bath was removed and the reaction mixture stirred overnight at room temperature. The reaction mixture was quenched with 10% aqueous HCl (835 mL), concentrated, and washed with ether (250 mL). The combined organics were washed with 5% aqueous NaOH (300 mL) and water (100 mL, pH 12). The aqueous layer was acidified (pH 0) with concentrated HCl. The resulting suspension was extracted with ether (2×300 mL), dried over MgSO4, filtered, concentrated under reduced pressure to afford 7.70 g (72% yield) of the desired product (2).
Reaction SMILES: C[Mg]Br.N#N.[O:6]=[C:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9]([CH:10]=[CH:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:27])=[CH:8]1.[CH2:39]1COCC1>CCOCC.Cl[Cu]>[CH3:39][CH:11]1[CH:10]=[C:9]2[C@:22]([CH3:25])([CH2:23][CH2:24][C:7](=[O:6])[CH2:8]2)[C@@H:21]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][CH2:20]2)([CH3:18])[C@@H:16]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:36])([F:37])[F:38])=[O:27])[CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Agent: Cl[Cu]
Agent: C[Mg]Br
Agent: N#N
Solvent: CCOCC
Product: CC1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)Nc4ccccc4C(F)(F)F)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3.0 M methylmagnesium bromide (2.35 mmol) in ether under a stream of N2 was added 6.0 mL degassed THF. The solution was cooled to 0° C., then CuCl (0.03 g, 0.300 mmol) was added. The mixture was stirred for 5 min. A solution of the compound from Step A (5-2) (0.25 g, 0.55 mmol) in 6.0 mL degassed THF was added. The reaction was warmed to room temperature overnight. It was quenched by slow addition of 2.0 mL degassed water, then diluted with 10% KHSO4 solution and EtOAc. The organic phase was washed with 10% KHSO4 solution, saturated NaHCO3 solution, and brine. After removal of the solvent, the residue was purified by preparative HPLC (C18; 70% MeOH with 5 to 30% MeCN-water) to provide 5-5.
Reaction SMILES: OO.C1(=O)OC(=[O:7])C=C1.[Cl:10][C:11]1[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N:14]=[C:13]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:12]=1>C(Cl)Cl.C1C=CC=CC=1>[Cl:10][C:11]1[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N+:14]([O-:7])=[C:13]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:12]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)n1
Agent: OO
Solvent: ClCCl
Solvent: c1ccccc1
Product: COC(=O)Nc1cc(Cl)nc(NC(=O)OC)[n+]1[O-]

Procedure:
A mixture of 18.7 g (0.385 mol) of 70 percent hydrogen peroxide and 400 ml of methylene chloride, stirred under argon and cooled to about 0°, is treated with 49.0 g (0.5 mol) of maleic acid anhydride. The mixture is stirred at 0° for 5 minutes and subsequently treated dropwise over a period of 15 minutes with a solution of 13.0 g (0.05 mol) of dimethyl 6-chloro-2,4-pyrimidinedicarbamate in 1500 ml of methylene chloride in such a manner that the temperature does not exceed 2°. The cooling bath is removed, the mixture is stirred for a further 15.5 hours, cooled to 3° and filtered. The white solid residue is subsequently washed with 400 ml of semi-saturated ice-cold sodium carbonate solution and then with 100 ml of ice-water. The material obtained is taken up in 150 ml of benzene and evaporated. This procedure is repeated once more and then the residue is dried at 60° under vacuum. There is obtained dimethyl 6-chloro-2,4-pyrimidinedicarbamate 3-oxide as a white solid of melting point 224°-225°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][CH3:31]>O1CCOCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:30]([CH3:31])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4]
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CC(=O)c1cccc([N+](=O)[O-])c1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(3-nitrophenyl)ethanone (2 g, 8.23 mmol, 1.00 equiv), triethylamine (3.4 g, 4.00 equiv), (2,4-dichlorophenyl)-N-methylmethanamine (1.9 g, 10.05 mmol, 1.20 equiv), 1,4-dioxane (50 mL). The resulting solution was stirred for 2 h at room temperature at which time it was judged to be complete by LCMS. The mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100˜1:50). This resulted in 1.5 g (50%) of 2-((2,4-dichlorobenzyl)(methyl)amino)-1-(3-nitrophenyl)ethanone as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][C:36]1([CH3:45])[CH2:41][CH:40]([NH2:42])[CH2:39][C:38]([CH3:44])([CH3:43])[NH:37]1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([NH:22][C:20]1[CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH:40]3[CH2:41][C:36]([CH3:45])([CH3:35])[NH:37][C:38]([CH3:44])([CH3:43])[CH2:39]3)[N:7]=2)[CH:17]=[CH:18][C:19]=1[F:34])(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Yield: 29 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 2,2,6,6-tetramethyl-4-piperidinamine (0.30 g, 1.9 mmol) the title compound was obtained (0.035 g, 0.054 mmol, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.95-8.72 (m, 1H), 8.20 (d, J=4.9 Hz, 1H), 7.95-7.72 (m, 1H), 7.72-7.20 (m, 6H), 6.43-6.20 (m, 1H), 2.05 (d, J=12.8 Hz, 2H), 1.75-1.27 (m, 22H). MS (ESI): 645 [M+H]+.