Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([N+:22]([O-:24])=[O:23])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[K+].Cl.[CH2:29]([OH:31])[CH3:30]>O>[CH2:29]([O:31][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[CH:13]=2)[N:8]=1)[CH3:30]
Reactant: CCOC(=O)c1c(Cl)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc2ccc([N+](=O)[O-])cc2c(-c2ccccc2)c1C(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of 2-chloro-6-nitro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (10 mg, 0.028 mmol) was suspended in ethanol and treated with 3N KOH (0.1 ml, 10.7 Eq). The mixture was warmed to 80° C. for 24 h, then further 3N KOH (0.1 ml, 10.7 Eq.) was added and stirring at 80° C. was continued for further 24 h. The mixture was diluted with water and acidified to pH 1 with HCl 1N. The slurry was extracted with dichloromethane and the extracts were evaporated to yield the title compound (7.6 mg, 82%) as a white powder. MS (ESI): 339.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:22])[C:9]2[C:17]3[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25].I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[F:1][C:2]1[C:7]([C:8]([C:9]2[C:17]3[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[NH:11][CH:10]=2)=[O:22])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26]
Reactant: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncnc(NC(C)C)c23)c1F
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncnc(NC(C)C)c23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To propane-1-sulfonic acid {2-fluoro-3-[hydroxy-(4-isopropylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-amide (78, 102 mg, 0.242 mmol) in 1 mL of dimethylsulfoxide, stabilized 2-iodoxybenzoic acid (181 mg, 45%, 0.29 mmol) is added and the reaction is stirred at room temperature for 1 hour. The reaction is poured into water and stirred for 30 minutes, and the precipitate is collected by filtration. The resulting solid is dissolved in 2 mL of tetrahydrofuran and purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to give the desired compound (P-1106, 34 mg). MS (ESI) [M+H+]+=420.0.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([O:48][CH3:49])=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[S:43][C:42]2[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=2[CH:40]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-].[C]>[S:43]1[C:39]([C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([NH2:10])[C:12]=3[O:48][CH3:49])[N:16]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:15]=2)=[CH:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]1=2
Reactant: COc1c(NC(=O)OCc2ccccc2)ccc2c1c(-c1cc3ccccc3s1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(N)ccc2c1c(-c1cc3ccccc3s1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
A total of 939 mg of (3-benzo[b]thiophen-2-yl-4-methoxy-1-trityl-1H-indazol-5-yl)-carbamic acid benzyl ester obtained in Production Example II-39-a was dissolved in 20 ml of a 2:1 solvent mixture of ethyl acetate and methanol. 300 mg of 20% palladium hydroxide-carbon was added thereto, and the mixture was subjected to catalytic hydrogenation at room temperature and at normal atmospheric pressure in the presence of. The reaction mixture was filtrated through Celite, and the solvent was removed, to give 458 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)=[CH:4][C:3]=1[F:16].[NH2:17][C@@H:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C@@H:19]1[OH:27]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[C:10]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[O:12])=[CH:4][C:3]=1[F:16]
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)c(F)c1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(F)c1)C(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution containing ethyl 2-(4-chloro-3-fluorophenylamino)-2-oxoacetate (1) (1.73 g, 7.05 mmol) in 20 mL dioxane in a round-bottom flask was added (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (1.16 g, 7.76 mmol) and both a stir bar and a reflux condenser were equipped. The reaction was heated to reflux for 72 hours and then allowed to cool to room temperature. The crude reaction mixture was concentrated in vacuo. The solid was collected by filtration with a 1:1 mixture of hexanes and dichloromethane to give 2.04 g (83%) of TK-II-103 as an off-white flakey solid; [α]29D=−112.1° (c=0.48, DMSO): 1H NMR (500 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.36 (d, J=8.7 Hz, 1H), 7.97, (dd, J=2, 11.7 Hz, 1H), 7.77, (d, J=8.8 Hz, 1H), 7.59, (t, J=8.7 Hz, 1H), 7.28-7.18, (m, 4H), 5.46, (d, J=4.9 Hz, 1H), 5.25, (dd, J=5.2, 8.6 Hz, 1H), 4.52, (dd, J=4.6, 8.6 Hz, 1H), 3.14, (dd, J=4.9, 16.2 Hz, 1H), 2.88, (d, J=16.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.3, 158.8, 156.8, (d, JCF=242.5 Hz), 141.0, 140.8, 138.2, (d, JCF=10 Hz), 131.6, 127.7, 126.5, 125.0, 124.1, 117.5 (d, JCF=2.9 Hz), 114.5 (d, JCF=17.5 Hz), 108.6, (d, JCF=25 Hz), 71.6, 56.9. HRMS (ES+) m/z 371.0572 [(M+Na)+; calcd for C17H14ClFN2O3: 371.0575].
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([Cu])#[N:9].[Br:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15](N)=[C:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)[CH:13]=1.Cl>CS(C)=O>[Br:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:8]#[N:9])=[C:14]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[CH:13]=1
Reactant: N#C[Cu]
Reactant: CCc1ccc(Cc2cc(Br)c(OC)cc2N)cc1
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: CCc1ccc(Cc2cc(Br)c(OC)cc2C#N)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Tert-butyl nitrite (1.1 mL) is added to a 60° C.-warm solution of CuCN (0.36 g) in DMSO (3 mL). Then, a solution of 4-bromo-2-(4-ethyl-benzyl)-5-methoxy-phenylamine (1.0 g) in DMSO is added dropwise and the resulting solution is stirred for 1 h at 60° C. After cooling to room temperature, the solution is acidified by the addition of 5 N aqueous hydrochloric acid. The resulting mixture is extracted with ethyl acetate and the combined extracts are dried (Na2SO4). After removal of the solvent, the residue is purified by chromatography on silica gel (cyclohexane/dichloromethane 3:1->1:3) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][C:27](=[O:31])[CH2:26]2)=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:30][CH2:29][NH:28][C:27](=[O:31])[CH2:26]4)=[CH:23][N:24]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCNC(=O)C2)cn1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNC(=O)C4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 26-3 (22 mg, 0.1 mmol), 4-(6-aminopyridin-3-yl)piperazin-2-one 141-4 (19 mg, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (40 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (52 μL, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(3-oxopiperazin-1-yl)pyridin-2-yl)acetamide 141. MS m/z 402.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.53 (s, 1H), 8.49 (d, 1H), 8.05-8.01 (m, 2H), 7.94 (d, 1H), 7.75 (d, 2H), 7.57 (s, 1H), 7.48-7.48 (m, 3H), 7.41 (dd, 1H), 3.74 (s, 1H), 3.71 (s, 2H), 2.54-2.50 (m, 7H), 1.24 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])([O-])=O.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([C:25]2[NH:22][C:21]3[CH:20]=[CH:19][C:6]([NH:7][C:8]([C:10]4[NH:11][C:12]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][CH:13]=5)=[O:9])=[CH:5][C:4]=3[N:1]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cc2ccccc2[nH]1
Product: O=C(Nc1ccc2[nH]c(-c3ccccc3)nc2c1)c1cc2ccccc2[nH]1

Procedure:
Compound 203 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(indol-2-oyl)aniline and benzaldehyde. 1H NMR (500 MHz, CD3OD) δ 8.20 (d, J=1.5 Hz, 1H), 8.09 (dd, J=1.5, 8 Hz, 2H). 7.66 (d, J=8 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.57-7.52 (m, 4H), 7.48 (dd, J=0.5, 8 Hz, 1H), 7.34 (s, 1H), 7.25 (dt, J=1, 7 Hz, 1H), 7.09 (dt, J=0.5, 8 Hz, 1H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[O:5]([CH2:12][CH2:13][N:14]([CH2:15][CH2:16][CH3:17])[C:1]([Cl:4])=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCCNCCOc1ccccc1
Solvent: CCOC(C)=O
Product: CCCN(CCOc1ccccc1)C(=O)Cl

Procedure:
To 100 ml. of mechanically stirred, refluxing dry ethyl acetate was introduced a steady flow of phosgene gas followed by the dropwise addition of 22.4g. N-2-phenoxyethyl-N-propylamine in 100 ml. dry ethyl acetate over a period of 45 minutes. On completion of the addition, the reaction mixture was boiled under reflux with stirring, whilst continuing the flow of phosgene for a further three hours. The solvent was removed on the steam bath, the last traces being extracted under vacuum to give N-2-phenoxyethyl-N-propylcarbamoyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: ClCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc(OCCCCCCCl)ccc1O
Reaction time: 8 h
Yield: 83.2 %

Procedure:
A mixture of 2',5'-dihydroxyacetophenone (150 g), 1-bromo-6-chlorohexane (186 g), and potassium carbonate (186 g) in 2500 mL of 2-butanone was refluxed for 16 hours. The solvent was removed in vacuo and the residue was stirred with 1000 mL of methylene chloride. After filtration, the filtrate was washed with 10% KOH (250 mL), water (250 mL), and brine (250 mL). The solution was dried over magnesium sulfate and the solvent was removed to give an oil which solidified overnight to give 210 g of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone as a yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>C1(C)C=CC=CC=1>[CH2:3]1[CH2:2][O:1][C:6]2[CH:7]=[CH:8][C:9]([N:11]=[C:19]=[S:20])=[CH:10][C:5]=2[O:4]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: S=C=Nc1ccc2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To a mixture of 1,4-benzodioxan-6-amine (15.1 g; 100 mmol) and triethylamine (20.2 g; 200 mmol) in toluene (350 ml) was added dropwise over 10 min. thiophosgene (11.5 g; 100 mmol) in toluene (50 ml). The mixture was stirred at 80° C. for 30 min., cooled to room temperature and filtered. The filtrate was evaporated. The product was redissolved in toluene and concentrated in vacuo. The resulting oil was taken up in warm petroleum ether, which was filtered. The filtrate was concentrated to a small volume, which afforded 7.2 g of 3,4-ethylenedioxyphenylisothiocyanate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:24](OS(C)(=O)=O)[CH2:23][CH2:22][CH:21]1[CH3:30].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH:20]1[CH:21]([CH3:30])[CH2:22][CH:23]=[CH:24]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C(C)CCC2OS(C)(=O)=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2C=CCC2C)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
A 200 mL round bottom flask was charged with 66.56E (mixture of diastereomers) (0.59 g, 1.4 mmol), toluene (10 mL), and DBU (2.0 mL, 14 mmol). The resulting solution was stirred for 16 hours at 95° C., cooled to room temperature, and quenched with 1 N HCl. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated. The initial product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 66.56F (mixture of diastereomers) (0.31 g, 67% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(F)cnc1N1CC(Nc2ccc(F)cc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)ccc1NC1CN(c2ncc(F)cc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of methyl 5-fluoro-2-(3-((4-fluoro-2-methylphenyl)amino)azetidin-1-yl)nicotinate (D90) (150 mg, 0.450 mmol) in 1,4-dioxane/water (3 ml/1 ml), 1M NaOH (0.675 ml, 0.657 mmol) was added and the resulting mixture was stirred 2 h at 60° C. Organic solvent was evaporated. The remaining aqueous were washed with dichloromethane (5 ml) then acidified to pH2 by addition of 2M HCl and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation afforded the title compound (D135) (140 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][O:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[O:25])=[CH:19][CH:18]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:10]1([C:3]2[C:2]([NH:1][C:24](=[O:25])[CH2:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[C:6]([C:7]([NH2:9])=[O:8])[O:5][N:4]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: NC(=O)c1onc(C2CCCC2)c1N
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(CC(=O)Nc2c(C3CCCC3)noc2C(N)=O)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
12 g (61 mmol) of 4-amino-3-cyclopentyl-isoxazole-5-carboxamide (example VI) are dissolved in 50 ml of pyridine, and 12.48 g (67 mmol) of 4-methoxyphenylacetyl chloride and a spatula tip of DMAP are added. The reaction mixture is stirred at 60° C. for 5 hours and the solvent is then removed in vacuo. The residue is taken up in dichloromethane and the solution is shaken twice with 1N hydrochloric acid and twice with sodium hydrogencarbonate solution; it is then dried over sodium sulfate and the solvent is removed in vacuo. The residue is triturated with a little dichloromethane and then filtered; the filtrate is concentrated to dryness and the residue is purified by chromatography (cyclohexane/ethyl acetate=2:1).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4].[F:19][C:20]([F:32])([F:31])C1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:1][C:2]([CH3:18])([C:6](=[O:17])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:20]([F:32])([F:31])[F:19])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccccc1
Product: CC(C)(C(=O)O)C(=O)NS(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
2,2-dimethyl-3-oxo-3-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)propanoic acid was prepared in the same manner as 2,2-dimethyl-3-oxo-3-[(phenylsulfonyl)amino]propanoic acid starting from 4-(trifluoromethyl)benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1)[CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]([OH:7])=O.[NH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.O.CN(C=O)C>[F:17][C:14]([F:15])([F:16])[CH2:13][CH2:12][CH:11]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1)[C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:3][C:2]=1[CH3:1]
Reactant: CC(C)(C)C(O)CN
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)O)cc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(C(=O)NCC(O)C(C)(C)C)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-4-(4,4,4-trifluoro-1-((4-(methoxycarbonyl)phenyl)amino)butyl)benzoic acid (725.6 mg), 1-amino-3,3-dimethylbutan-2-ol (430 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (704 mg), 1-hydroxybenzotriazole monohydrate (562 mg), N,N-diisopropylethylamine (0.962 mL), 4-dimethylaminopyridine (22.42 mg) and DMF (4.5 mL) was stirred at room temperature overnight, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CC1CCC([OH:16])CC1.C1(=O)CCCCC1.C1(O)CCCCC1>>[CH3:1][CH:2]1[CH2:3][CH2:4][O:8][C:5](=[O:16])[CH2:6][CH2:7]1
Reactant: CC1CCC(O)CC1
Reactant: CC1CCC(=O)CC1
Solvent: OC1CCCCC1
Solvent: O=C1CCCCC1
Product: CC1CCOC(=O)CC1
Yield: 45.6 %

Procedure:
The procedure of Example 25 was repeated, except that 4-methylcyclohexanone (2 mmol) and 4-methylcyclohexanol (20 mmol) were respectively used in stead of cyclohexanone and cyclohexanol. As a result, γ-methyl-ε-caprolactone was formed in yield of 45.6% (on 4-methylcyclohexanone basis).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:15][C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C1N=CN([C:48](N2C=NC=C2)=[O:49])C=1>C1COCC1>[O:49]=[C:48]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[S:13][C:12]([N:14]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:15][C@@H:16]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)=[N:11][N:10]=3)=[CH:3][C:2]=2[O:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc(N)c(O)c2)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc3[nH]c(=O)oc3c2)s1
Temperature: 70 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
tert-Butyl (S)-1-(5-(3-hydroxy-4-aminophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (200 mg, 328 μmol) was dissolved in 50 mL THF in a round bottom flask. To this flask was added CDI (213 mg, 1312 μmol). The mixture was stirred at 70° C. for 16 hours. After removing the solvent under reduced pressure, the remaining residue was mixed with 100 mL EtOAc. The organic solution was washed with water, saturated ammonium chloride twice and dried over sodium sulfate. After removing the solvent, the desired product (140 mg, 67%) was obtained as a tan solid. LCMS (API-ES) m/z (%): 636.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.23 (s, 9H) 1.58 (s, 9H) 2.82-2.96 (m, 1H) 2.95-3.08 (m, 1H) 4.12-4.27 (m, 1H) 4.32-4.43 (m, 2H) 7.15-7.25 (m, 1H) 7.49 (d, J=8.02 Hz, 2H) 7.60 (d, J=7.83 Hz, 2H) 7.70 (dd, J=8.12, 1.47 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: N(C1C=CC=CN=1)N.C([O-])([O-])(OCC)C.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[CH:25][C:26]3[N:27]([C:29]([CH3:32])=[N:30][N:31]=3)[CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:28][N:27]3[C:29]([CH3:32])=[N:30][N:31]=[C:26]3[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nnc2ccc(-c3cccc(F)c3)cn12
Agent: CCOC(C)([O-])[O-]
Agent: NNc1ccccn1
Product: Cc1nnc2n1CC(c1cccc(F)c1)CC2

Procedure:
A mixture of 3 g. of the above hydrazinopyridine and 30 ml. of ethyl orthoacetate is heated at reflux for 4 hours and filtered to remove a tan solid which is washed with hexane to give 2.15 g. of 6-(3-fluorophenyl)-3-methyl-1,2,4-triazolo[4,3-a]pyridine, m.p. 179°-182° C. Reduction of this product as in Example 1 gives the product of the Example.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:23]=[CH:24][CH:25]=5)[N:18]=4)[N:13](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:23]=[CH:24][CH:25]=5)[N:18]=4)[NH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)Nc1cccc(-c2cnc3c(n2)c(-c2cc4ccc(C)cc4[nH]2)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cc5ccc(C)cc5[nH]4)c3n2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of Compound 9 (20 mg, 0314 mmol) in chloroform was added trifluoro acetic acid. The reaction was stirred overnight at 45° C. The reaction was completely distilled and diluted with water, adjust the pH to 9-10 with 1 molar NaOH solution at 20-25° C. The aqueous layer was extracted with DCM (25 mL) twice. The organic layer was dried over sodium sulphate, filtered and concentrated to get the crude. The resulting oil was purified via silica gel chromatography using gradient of 50% Ethyl acetate:hexane afforded Compound 10. MS-ES +393.16; 1H NMR (400 MHz, DMSO-D6-d6) 10: 12.29 (d, 1H),11.17 (d, 1H), 10.39 (d,1H), 8.84 (d,1H), 8.54 (d,1H),7.94 (d, 2H),7.55 (d, 2H), 7.49 (d, 2H),7.26(d, 2H), 6.83 (d, 1H), 6.54 (d,1H), 6.36 (d, 1H) 5.81 (d, 1H), 4.45 (d, 3H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Reactant: COc1ccccc1Br
Product: COc1ccccc1N1N(C2CC3CCC2C3)C(=O)C1(C)C

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 78 and 1-bromo-2-methoxybenzene were used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.