Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:26]([O:29][CH2:30]Br)(=[O:28])[CH3:27]>CN(C=O)C>[C:26]([O:29][CH2:30][O:18][C:17]([C:9]1[NH:10][C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])(=[O:28])[CH3:27]
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Stir at 50° C. for 10 min. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (1.27 g, 5 mmol) in DMF (25 mL), and add Cs2CO3 (1.63 g, 5 mmol). After 10 min. add bromomethyl acetate (0.95 g, 6.21 mmol) and one minute thereafter quench into aqueous NH4Cl solution. Extract with EtOAc and wash the extract with aqueous NaHCO3 solution. Dry the extract (MgSO4), filter and concentrate under vacuum to give a solid. Triturate the solid with EtOAc and obtain the title compound as a solid: MS 326(M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Mg].BrCCBr>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([OH:14])[CH2:33][C@H:34]([CH2:35][O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]([CH3:45])[CH3:46])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Reactant: CC(C)[C@H](CCl)COCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Alternatively, A solution of 27 g of aldehyde 7 in 30 mL of tetrahydrofuran is added to a room-temperature solution of the Grignard reagent prepared by refluxing 20 g of ((S)-2-chloromethyl-3-methyl-butoxymethyl)-benzene with 3.2 g of magnesium in 120 mL of tetrahydrofuran containing 1.3 g of 1,2-dibromoethane for 4 h. The reaction is stirred for 1 h at room temperature, then 100 mL of 2 N sulfuric add is added. The mixture is stirred until the excess magnesium has dissolved, then the phases are separated and the organic phase washed with 50 mL of 12% sodium chloride solution. The organic phase is concentrated in vacuum to give e.g. 42.6 g of the crude alcohol 8 as an oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]1)=O)#[N:2].[CH:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(O)C.[CH3:25][NH:26][NH2:27]>C(OCC)(=O)C>[CH3:25][N:26]1[C:1]([NH2:2])=[CH:3][C:4]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][NH:7]2)=[N:27]1.[CH:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: N#CCC(=O)C1CCCCN1
Reactant: CNN
Agent: O=COCc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(C2CCCCN2)cc1N
Yield: 66.2 %

Procedure:
Under nitrogen atmosphere, to a 250 mL three-neck reaction flask were added the compound of Example 11A (16.0 g, 55.9 mmol), ethanol (80 mL) and methylhydrazine (12 mL, 224 mmol). The mixture was refluxed for 5 hr. The reaction was stopped. Ethanol was removed by rotary-evaporation to obtain a crude product. The crude product was subject to column chromatography (eluant: petroleum ether:ethyl acetate=1:1) to give 11.7 g of the title compound. Yield: 66.6%. MS (ESI): m/z 315 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:28])[NH:11][CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:29])[CH:12]=[C:13]([C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)[C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1OCc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c(F)c(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoropyridin-2(1H)-one (24 mg, 0.065 mmol) in DMF (0.8 mL) was added Cs2CO3 (27 mg, 0.084 mmol) followed by a solution of MeI (10 mg, 0.071 mmol) in DMF (0.05 mL). After stirring at room temperature for 1 h the reaction mixture was filtered. Purification by preparative HPLC (10-80% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 22 mg (88%) of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoro-1-methylpyridin-2(1H)-one as a colorless glass. LC/MS (M−141)+ 296.2.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:13]=[N+:14]([O-:26])[C:15]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:12]2[N:13]=[N+:14]([O-:26])[C:15]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NCCCN1CCOCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCCC3
Yield: 99.7 %

Procedure:
3-(4-Morpholinyl)propylamine (314 mg, 2.18 mmol) was added to a stirred solution of chloride 176 (171 mg, 0.73 mmol) in DME (8 mL) and the solution stirred at reflux temperature for 30 min. The solution was cooled and partitioned in between EtOAc and aqueous Na2CO3 solution. The organic fraction was washed with water, dried and the solvent evaporated to give 1-oxide 179 (250 mg, 100%) as an orange solid: mp (EtOAc) 115-116° C.; 1H NMR δ 7.97 (s, 1H, H-10), 7.29 (s, 1H, H-5), 6.14 (br s, 1H, NH), 3.75 (t, J=4.6 Hz, 4H, 2×CH2O), 3.60 (q, J=6.2 Hz, 2H, CH2N), 2.86-2.95 (m, 4H, H-6, H-9), 2.45-2.56 (m, 6H, 3×CH2N), 1.80-1.88 (m, 6H, H-7, H-8, CH2); 13C NMR δ 158.7, 147.5 147.0, 136.0, 129.1, 124.9, 119.0, 67.0 (2), 57.3, 53.8 (2), 40.8, 30.0, 29.3, 25.3, 22.7, 22.5. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.8; H, 7.4; N, 20.3%.
Reaction SMILES: [CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[OH:3].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[C:7]([O:6][C:4]([N:2]([CH3:1])[O:3][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CN(O)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Product: CN(OC(=O)CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of N-methyl-N-boc hydroxylamine 3 (536 mg, 3.65 mmol) in ichloromethane (8 mL) were added DMAP (134 mg, 1.10 mmol) and succinic anhydride (548 mg, 5.48 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was poured into a saturated solution of ammonium chloride (10 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layer was washed with water (20 mL) and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by silica flash column chromatography using 45% EtOAc/hexane as eluent to give the corresponding acid as a white solid (693 mg, 2.81 mmol, 77%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.42 (s, 9H), 2.65-2.70 (m, 4H), 3.17 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 58.5 %

Procedure:
To a solution of 6-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile 0.75 g (1.70 mmol) dissolved in CH3CN (50 mL) was added 0.56 mL (4.14 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo) and the crude was dissolved in AcOH (30 mL) before a total of 0.45 g of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.36 g (60%) of the title compound as a colorless oil. ES-MS m/e: 362.3 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.Cl>CN(C=O)C>[Cl:21][C:20]1[C:15]([O:7][C:8]2[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=2)=[N:16][CH:17]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:19]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Temperature: 60 °C
Yield: 75.6 %

Procedure:
Potassium carbonate (7.60 g, 55.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (4.90 g, 50.0 mmol) and 2,3-dichloro-5-trifluoromethylpyridine (10.8 g, 50.0 mmol) in DMF (50 ml) at room temperature, and the mixture was stirred under heating at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/2), to give a white solid of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (10.5 g, yield: 76.0%). mp: 93-95° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.32 (s, 3H), 5.90 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 8.33 (m, 1H), 10.80-11.60 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([O:17]CC)=[O:16])[CH2:11][C@H:10]1[CH:12]1[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CO.O.O[Li].O>O>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([OH:17])=[O:16])[CH2:11][C@H:10]1[CH:12]1[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]1(NC(=O)OC(C)(C)C)C[C@H]1C1CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-cyclopropylcyclopropanecarboxylate (0.578 g, 2.15 mmol), was dissolved in 10 mL mixed solvent of THF:MeOH:water (2:2:1 v/v), followed by addition of LiOH—H2O (0.270 g, 6.44 mmol) in one portion at rt. Stirred it at rt over 2 days. After removal of most solvent, the white solid reaction residue was taken up in water (30 mL) and washed with ether (30 mL). The aqueous layer was then acidified with 1N HCl until pH reached 2. It was then extracted with EtOAc (2×50 mL), and the combined organic extract was washed with brine and dried over Na2SO4, giving the acid, (1R,2S)-1-(tert-butoxycarbonylamino)-2-cyclopropylcyclopropane carboxylic acid, as a white fluffy solid (0.48 g, 93%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:20]=O)[S:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][NH2:23].CO.CO>O1CCCC1>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH2:20][NH:23][CH3:22])[S:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1cc(-c2cccnc2F)c(Sc2ccccn2)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(2-fluoropyridin-3-yl)-5-[(pyridin-2-yl)thio]thiophene-2-carbaldehyde (270 mg) in tetrahydrofuran (2 mL) were added 40% methylamine-methanol solution (0.9 mL) and methanol (2 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (3 mL), and sodium tetrahydroborate (222 mg) was added at 0° C. The mixture was stirred at room temperature for 1 day and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield 286 mg, yield quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[Br:11]
Reactant: CO
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccc1Br
Temperature: 25 °C

Procedure:
5-Amino-2-bromobenzoic acid (10.8 g, 50 mmol) was dissolved in methanol (100 mL). Conc. H2SO4 (2 mL) was added slowly and the reaction mixture heated to reflux for 4 h. The mixture was concentrated and the residue was allowed to cool to room temperature. It was poured over crushed ice. The organic product was extracted using diethyl ether (2×200 mL). The organic extract was washed with water, 10% aqueous NaHCO3, dried (anhydrous Na2SO4) and concentrated to get the title compound.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[C:10]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]([F:28])([F:27])[F:26])=[N:15]2)[CH:11]=[CH:12][CH:13]=1)([O-])=O>[Pd].C(O)C>[NH2:5][C:8]1[CH:9]=[C:10]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]([F:28])([F:27])[F:26])=[N:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Acetic acid (3 mL) and ethanol (2 mL) were added to 1-(3-nitrophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole (0.59 g, 1.77 mmol) and 5% palladium on carbon (0.06 g), and the mixture was hydrogenated at room temperature for 2 hours under hydrogen atmosphere. After the insoluble matter was filtered off, the residue obtained by evaporation under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (491.1 mg, 91.4%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH:8]=[O:9].[C:17]([O-])(O)=[O:18].[Na+].BrBr>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[NH:10][C:5]2=[N:6][C:7]=1[C:8]([O:18][CH3:17])=[O:9]
Reactant: CCCCc1nc2nc(C=O)c(Br)cc2[nH]1
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1nc2cc(Br)c(C(=O)OC)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
0.69 g (2.45 mmole) of the compound obtained in step 7 of Example 1 was dissolved in 10 ml of MeOH--H2O (9:1) and to the resulting solution was added 4.12 g (49 mmole) of NaHCO3. The resultant was stirred until NaHCO3 was dissolved and thereto was added 2.0 ml (4.9 mmole) of Br2. The resulting solution was stirred for 1 hour at room temperature and extracted with a mixture of water and ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure to obtain 0.75 g of the title compound (quantitative).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:57]1([CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([N:64]5[CH2:65][CH2:66][N:61]([CH2:60][CH:57]6[CH2:59][CH2:58]6)[CH2:62][CH2:63]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(CC3CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the general procedure for amide bond synthesis using HATU and 1-(cyclopropylmethyl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.07 (br. s., 2 H) 0.47 (br. s., 2 H) 1.55 (br. s., 5 H) 1.68 (br. s., 2 H) 1.90 (br. s., 2 H) 2.21 (br. s., 1 H) 2.40-2.48 (m, 3 H) 3.31 (s, 4 H) 3.32 (br. s., 3 H) 3.88 (s, 3 H) 4.03 (t, J=13.89 Hz, 2 H) 4.64-4.76 (m, 1 H) 6.96 (d, J=8.84 Hz, 1 H) 7.04 (s, 1 H) 8.00 (s, 1 H) 8.15 (d, J=7.83 Hz, 1 H) 8.23 (s, 1 H). [M+H] calculated for C29H37F2N7O3, 570; found 570.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of ethyl 4-benzyloxy-3-methoxyphenylacetate (32 g, 110 mmol), from Step 1, in ethanol (200 mL) and THF (20 mL) was added 200 mL of a 1M aqueous lithium hydroxide solution. The resulting mixture was stirred at ambient temperature for 4 hours and then 1M aqueous hydrochloric acid solution was added to precipitate the product. The solid was filtered, washed with water, taken up in diethyl ether, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow solid. The solid was recrystallized from methylene chloride/petroleum ether (b.p. 30°-60° C.) to give 19 g (58% yield based on ethyl 4-hydroxy-3-methoxyphenylacetic acid) of the title compound as a white solid; 1H NMR (CDCl3) δ 3.57 (s, 2H), 3.88 (s, 3H), 5.14 (s, 2H), 6.74 (dd, 1H, J=8.0, 2.7 Hz), 6.82-6.85 (m, 2H), 7.28-7.45 (m, 5H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:18])[CH2:16][CH3:17]
Reactant: O=C1NC2C=CC1C2
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCC(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
47 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (325 ml) and pyridine (41 ml) under nitrogen. At 12° C., 43.9 g of propionyl chloride were added dropwise over the course of 1 h. The reaction was then stirred at room temperature for 5 h. 145 ml of water were added to the mixture, and the acetonitrile was evaporated off in vacuo. The aqueous phase was extracted 3 times with 115 ml of ethyl acetate. The combined organic phases were washed with 1N HCl (140 ml), saturated NaHCO3 (40 ml) and NaCl (40 ml) solutions, dried with sodium sulphate and completely evaporated. The residue was purified by distillation. 55.8 g of title compound were obtained and solidified on leaving to stand. The yield was 81.6%.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[C:10]([O:12]C)[C:9]([O:14]C)=[CH:8][C:7]=1[S:16]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:18])=[O:17].P([O-])(O)(O)=O.[K+]>ClCCl>[F:5][C:6]1[CH:11]=[C:10]([OH:12])[C:9]([OH:14])=[CH:8][C:7]=1[S:16]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: COc1cc(F)c(S(=O)(=O)N2CCCCC2)cc1OC
Agent: BrB(Br)Br
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: O=S(=O)(c1cc(O)c(O)cc1F)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A 1M solution of boron tribromide in dichloromethane (58 mL) was added dropwise to a cooled solution of 1-(2-fluoro-4,5-dimethoxy-benzenesulfonyl)-piperidine (5.89 g, 19.42 mmol) in dichloromethane (100 mL), maintaining the temperature between 10 and 20° C. The mixture was stirred overnight at room temperature and poured into 1M aqueous potassium dihydrogenphosphate and ice. After stirring 1 h, the phases were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (10:1 dichloromethane/methanol eluant) to afford the title compound as a brown gum (4.17 g, 78%)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:14]=[C:15]([NH:22][C:23]([C:25]2([CH3:28])[CH2:27][O:26]2)=[O:24])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20]>>[OH:26][C:25]([CH3:28])([CH2:27][NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)[C:23]([NH:22][C:15]1[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:13]([CH3:12])[CH:14]=1)=[O:24]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]

Procedure:
2-Hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)-3-(4-trifluoromethylphenylamino)propionamide was prepared as described in Example 52 starting from 4-(trifluoromethyl)aniline and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.5% methanol). 1H NMR (400 MHz, DMSO-d6): 1.42 (3H, s), 2.51 (3H, s), 3.23 (1H, dd, J=13.3 Hz, J=5.0 Hz), 3.51 (1H, dd, J=13.3 Hz, J=7.0 Hz), 6.06 (1H, s), 6.18 (1H, m), 6.77 (2H, d, J=8.4 Hz)), 7.31 (2H, d, J=8.4 Hz), 7.79-7.83 (2H, m), 8.01 (1H, d, J=8.9 Hz), 10.02 (1H, s).
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][Br:13])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C([OH:20])C>COCCOC>[Br:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([OH:20])([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(Br)C(=O)c1ccc(CCBr)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)(O)C(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g, 0.105 mol) of 2-bromo-1-[4-(2-bromo-ethyl)-phenyl]-2-methyl-propan-1-one, 0.60 g (0.015 mol) of sodium hydroxide, 100 ml of ethanol and 50 ml of 1,2-dimethoxyethane is stirred at room temperature overnight. The reaction mixture is concentrated and the crude product is dissolved in ethyl acetate. The solution is washed with distilled water, dried over sodium sulfate and concentrated to give 3.4 g of 1-[4-(2-bromoethyl)phenyl]-2-hydroxy-2-methylpropan-1-one.