Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([C:14]#[N:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:16])[C@H:10]([C:14]#[N:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](C#N)C1
Reactant: CI
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Temperature: 50 °C

Procedure:
80.2 A suspension of (3S,4S)-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (212 mg) in 10 ml of THF and 2.32 g of Ag2O and 0.62 ml of CH3I was heated in a sealed tube to 50° C. for 16 h. The suspension was filtered and the filtrate chromatographed on silica (heptane/AcOEt, 3:1) to give 161 mg of (3S,4S)-3-cyano-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless oil. MS 171.4 ([M-isobutene+H]+)
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([NH2:22])=[N:3]1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([N:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3]1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: CN(C)Cc1cccc(OCCCNc2nc(N=Cc3ccccc3)nn2C)c1
Yield: 94.4 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (6.08 g) and benzaldehyde (2.4 g) in dry benzene was heated under reflux during 12 hr in a Dean & Stark apparatus. The solvent was removed and the residue purified by column chromatography on silica using methanol to give the title compound as a yellow oil (7.4 g). TLC silica; methanol:ammonia (80:1) Rf 0.43. NMR (CDCl3) 0.85 s (1H); 2.05 m (2H); 2.5-3.0 m (4H); 3.0-3.3 m (3H); 5.35 t (1H); 5.88 t (2H); 6.39 q (2H); 6.42 s (3H); 6.62 s (2H); 7.77 s (6H); 7.83 m (2H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9]C)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][O:18][CH2:19][C:20]#[CH:21]>C(#N)C.C(OCC)C>[CH3:9][O:8][C:7]1[C:2]([C:21]#[C:20][CH2:19][O:18][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCOC
Reactant: CCOc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COCC#Cc1ncccc1OC
Temperature: 25 °C

Procedure:
To a solution of commercially available 2-chloro-3 ethoxy pyridine (1 eq.) in acetonitrile (1.9M) was added PdCl2(CH3CN)2 (0.015 eq.), Cs2CO3 (2.4 eq.) and 2-(dicyclohexylphosphino)-2′-6′-dimethoxy-1-1′-biphyl (S—PHOS; 0.044 eq.). The suspension was sonicated for 5 min then 3-methoxyprop-1-yne (1.7 eq.) was added. The final mixture was stirred 12 h at 100° C., cooled down to room temperature, diluted with diethylether. The organic fraction was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/Acetone 5% afforded the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([N:6]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])=[C:4]([F:13])[CH:3]=1
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: C#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 40.9 %

Procedure:
4-Chloro-2-fluoro-5-(2-propynyloxy)aniline (1.9 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.52 g) were dissolved in acetic acid (20 ml) and refluxed for 3 hours. The resultant mixture was allowed to cool to room temperature and poured into water, followed by extraction with ether. The extract was washed with water, dried over anhydrous sodium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 1.3 g of N-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]3,4,5,6-tetrahydrophthalimide (Compound No. 3). M.P. 136.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[NH:21][C:20]3[C:19](=[O:22])[NH:18][C:17](=[O:23])[N:16]([CH2:24][CH3:25])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:26](N(CC)CC)C.COS(OC)(=O)=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[N:21]([CH3:26])[C:20]3[C:19](=[O:22])[NH:18][C:17](=[O:23])[N:16]([CH2:24][CH3:25])[C:15]=3[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN(CC)CC
Reactant: CCn1c(=O)[nH]c(=O)c2[nH]c(C#Cc3ccc(OC)c(OC)c3)nc21
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c(=O)c2c1nc(C#Cc1ccc(OC)c(OC)c1)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-(3,4-dimethoxyphenylethynyl)-3-ethyl-3,7-dihydro-purine-2,6-dione (1.52 g, 4.4 mmol) in 10 ml of dimethylformamide (DMF) was added triethylamine (3 ml, 20 mmol) and dimethylsulfate (0.65 ml, 7 mmol). The mixture was stirred at room temperature for 0.5 h. The product was precipitated by addind water (40 ml), filtered under reduced pressure, washed with water and dried at 70° C. (310 mg, 20%).
Reaction SMILES: [OH:1][C@@H:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:27](OC(C)=O)([CH3:30])([CH3:29])[CH3:28]>Cl(O)(=O)(=O)=O>[C:27]([O:1][C@@H:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (S)-ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (560 mg, 1.42 mmol) in t-BuOAc (32.0 mL, 381 mmol) was added 4 drops (catalytic) of 70% HClO4 and the mixture allowed to stir at room temperature for 2 hrs. The mixture was quenched by dumping it into an icy solution of saturated NaHCO3. Extraction with EtOAc (3×20 mL), drying with sodium sulfate and subsequent chromatography on silica gel using EtOAc in Hexanes gave (S)-ethyl 2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CDCl3): δ 8.06-8.03 (m, 1H); 7.81-7.78 (m, 1H); 7.67 (s, 1H); 7.59-7.53 (m, 2H); 5.73 (s, 1H); 4.25-4.10 (m, 2H); 2.55 (s, 3H); 1.21 (s, 9H), 1.17 (t, 3H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CCCC)CCCC)CCC>>[C:3]1(/[CH:2]=[CH:1]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ccccc1
Reactant: C=Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: C(=C/c1ccccc1)\c1ccccc1

Procedure:
Styrene (1.2 mmol), chlorobenzene (1 mmol), LDH-Pd0 (3 mol %), tri-n-butyl amine (222mg, 1.2 mmol) and NAIL (3.23 g, 10 mmol) were taken in a teflon vessel, closed and irradiated in a Miele Electronic M270 microwave oven at 400W and 130° C. for 0.5–1 h. After completion of the reaction, the LDH-Pd0 catalyst was filtered and washed with water and dichloromethane. After removing the solvent, the crude material was chromatographed on silica gel to afford the trans-stilbene.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:7]1=[O:33].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)[C:7](=[O:33])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (64 g) and trifluoroacetic acid (300 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (300 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (150 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (46.1 g, 100%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][CH:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]4[N:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]5=[N:27][CH:26]=4)=[O:24])[CH:16]=3)[N:11]=2)[CH2:7]1)(=O)=O.[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:34]1([CH:6]2[CH2:9][CH:8]([C:10]3[O:14][N:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23]([C:25]5[N:29]6[CH:30]=[CH:31][CH:32]=[CH:33][C:28]6=[N:27][CH:26]=5)=[O:24])[CH:16]=4)[N:11]=3)[CH2:7]2)[CH:38]=[CH:37][CH:36]=[N:35]1
Reactant: Cc1ccc(-c2noc(C3CC(OS(C)(=O)=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(C3CC(n4cccn4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 60 °C

Procedure:
A stirring mixture of 3-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl methanesulfonate (81) (25 mg, 0.0535 mmol), 1H-pyrazole (7 mg, 0.0802 mmol) and cesium carbonate (26 mg, 0.107 mmol) in anhydrous DMF (1 mL) was heated at 60° C. for 1 hour. Then, the reaction was cooled to room temperature and filtered. The crude product was purified by reverse phase preparative HPLC to give N-(5-(5-(3-(1H-pyrazol-1-yl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F45). 1H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 9.54-9.51 (m, 1H), 8.71 (s, 1H), 8.10 (dd, J=1.6, 7.2 Hz, 1H), 7.89-7.85 (m, 3H), 7.70-7.66 (m, 1H), 7.54-7.50 (m, 2H), 7.33-7.29 (m, 1H), 6.28-6.25 (m, 1H), 5.04-4.96 (m, 1H), 3.82-3.73 (m, 1H), 3.10-2.85 (m, 4), 2.37 (s, 3H). MS m/z 440.18 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:30])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:29]=1.[CH3:31][NH2:32]>C(#N)C>[Cl:22][C:21]1[C:16]([N:15]2[C:11]([C:9]([NH:10][C:5]3[C:6]([C:7]([NH:32][CH3:31])=[O:28])=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[Cl:30])=[O:8])=[CH:12][C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[N:14]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Oc1cc(-c2nc3c(Cl)cc(Cl)cc3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: CN
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(OS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,8-dichloro-2-[1-(3-chloro-2-pyridinyl)-3-[(methylsulfonyl)oxy]-1H-pyrazol-5-yl]-4H-3,1-benzoxazin-4-one (i.e. the product of step D) (0.05 g, 0.10 mmol) in acetonitrile (3 mL) was added methylamine (2.0 M solution in THF, 0.5 mL, 1 mmol). The resulting solution was stirred at room temperature overnight. Thin layer chromatography showed the reaction to be incomplete. Methylamine (2.0 M solution in THF, 0.5 mL, 1 mmol) was added dropwise and the reaction stirred 1 hour at room temperature. Thin layer chromatography showed the reaction was complete. The reaction mixture was concentrated to dryness to yield 0.057 g of the title compound, a compound of present invention, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.BrN1C(=O)CCC1=O.[CH:19]1([CH2:22][N:23]2[C:31]3[N:30]=[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH3:40])=[CH:35][CH:34]=4)[NH:28][C:27]=3[C:26](=[O:41])[N:25]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:24]2=[O:50])[CH2:21][CH2:20]1.C(N(CC)CC)C>>[CH:19]1([CH2:22][N:23]2[C:31]3[N:30]=[C:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]([CH3:40])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][CH:9]=[N:10][C:2]=5[CH3:1])=[CH:37][CH:38]=4)[NH:28][C:27]=3[C:26](=[O:41])[N:25]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:24]2=[O:50])[CH2:21][CH2:20]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1ncccc1C(=O)O
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Product: Cc1ncccc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Yield: 34 %

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 2-methylnicotinic acid (Aldrich) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, N-bromosuccinimide was used in place of N-chlorosuccinimide, the reaction was performed using 0.66 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 1 equivalent of triethylamine was added as the final reagent to the reaction mixture. Purification was performed by chromatography using silica eluted with 95:5 ethyl acetate/methanol to give the product as a light brown solid (34%). MS, M+H)=553.2361.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=1.[C:14]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:14]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[CH:13]=[CH:12][C:7]4[N:8]=[CH:9][S:10](=[O:11])[C:6]=4[CH:5]=3)[CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=S1C=Nc2ccc(CCBr)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=S1C=Nc2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc21

Procedure:
To a 100 ml round-bottomed flask with condenser and nitrogen inlet were added 1.0 gram (3.88 mmol) of 6-(2-bromoethyl)benzothiazolone, 822 mg (3.88 mmol) N-(1-naphthyl)piperazine, 410 mg (3.88 mmol) sodium carbonate, and 50 ml methylisobutlyketone. The reaction was refluxed for 24 hours, cooled, and evaporated. The residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated. The resulting solid was treated with hot ethyl acetate to afford a white solid, m.p. 198°-220° C., 540 mg (36%).
Reaction SMILES: Cl.C(O)(=O)C.C([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([O:33]CC)=[O:32])=[CH:18]2)[CH:14]=[CH:13][C:12]=1[F:36])(C)(C)C>O>[NH2:10][C:11]1[N:16]=[C:15]([N:17]2[C:26]3[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=3[Cl:27])[C:20](=[O:30])[C:19]([C:31]([OH:33])=[O:32])=[CH:18]2)[CH:14]=[CH:13][C:12]=1[F:36]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To 2 ml of mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 450 mg of ethyl 1-[6-(t-butyl-amino)-5-fluoropyridine-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 hours. After adding 1 ml of distilled water, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 342 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1>[Cl:23][CH2:24][C:25]([N:11]1[C@@H:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][CH3:15])=[O:13])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (2.76 g, 12.2 mmol) and triethylamine (2.13 mL, 15.3 mmol) in dry tetrahydrofuran (50 mL) at 0° C. was gradually added a solution of chloroacetyl chloride (0.97 mL, 12.2 mmol) in dry tetrahydrofuran (10 mL). After stirring at room temperature for 2 hours, the mixture was filtered. The solid cake was washed with THF, and the filtrate and washings were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue taken up in toluene and concentrated to dryness under reduced pressure to provide the titled compound. MS (CI) m/z 302 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:32][C:33]1[CH:34]=[N+:35]([O-:58])[CH:36]=[C:37]([Cl:57])[C:38]=1[CH2:39][C@@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH:43]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([S:18][CH2:19][C:20]([O:22][C@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:50])[F:51])=[C:44]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:43]=1)[CH2:39][C:38]1[C:37]([Cl:57])=[CH:36][N+:35]([O-:58])=[CH:34][C:33]=1[Cl:32])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)SCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetic acid (0.206 g, 0.491 mmol) in dry DCM (16 ml), EDC (0.157 g, 0.818 mmol) and DMAP (0.050 g, 0.409 mmol) were added followed by (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.172 g, 0.409 mmol), and the resulting solution was stirred overnight at RT. Additional EDC (0.080 g, 0.42 mmol) and DMAP (0.025 g, 0.20 mmol) were added, and the reaction was stirred at the same temperature for 24 hours. The mixture was partitioned between DCM and HCl 1N; the organic phase was washed with aqueous NaHCO3 and dried over Na2SO4. The solvent was removed and the crude was purified by preparative HPLC affording (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.082 g, 0.100 mmol, 24.4% yield, MS/ESI+ 821.1 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40]2.C(N(CC)CC)C>C(COC)OC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:42]3[CH:41]=[CH:40][C:39]4[C:44](=[CH:45][CH:46]=[C:37]([O:36][CH3:35])[CH:38]=4)[CH:43]=3)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2OS(=O)(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (2.15 g, 4.0 mmol), 6-methoxy-2-naphthylboronic acid (1.18 g, 6.0 mmol), and triethylamine (1.2 ml, 8.0 mmol) were dissolved in dimethoxyethane (40 ml) in a thick-wall tube. The reaction mixture was purged with N2 for 15 min. Catalyst Pd(PPh3)4 (350 mg, 8%) was added, and the test tube was heated in a microwave reactor to 100° C. for 15 min. The solvent was removed under reduced pressure, and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 0.5 NH4Cl2×, brine 2×, dried over Na2SO4, and filtered through a Celite pad. The crude product was purified by column chromatography (SiO2, 10-15% ethyl acetate in hexanes) to give ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as a dry film. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.96 (d, J=7.0 Hz, 3H); 3.95 (s, 3H); 4.37 (q, J=7.1 Hz, 2H); 5.59 (q, J=7.0 Hz, 1H); 6.65 (s, 1H); 7.17 (d, J=2.6 Hz, 1H); 7.20 (dd, J=2.6, 8.9 Hz, 1H); 7.28 (d, J=8.4 Hz, 2H); 7.29 (dd, J=1.8, 8.5 Hz, 1H); 7.30 (t, J=1.9 Hz, 1H); 7.63 (d, J=1.8 Hz, 1H); 7.67 (d, J=8.9 Hz, 1H); 7.76 (d, J=8.5 Hz, 1H); 7.80 (d, J=1.9 Hz, 2H); 7.99 (d, J=8.4 Hz, 2H); MS C31H26Cl2N2O3 Cald: 544.13; Obsd: 545.15.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21]C)=[O:20])([O-:3])=[O:2].O.[OH-].[Li+]>O1CCCC1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([OH:21])=[O:20])([O-:3])=[O:2]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinate 1.1g (1 g, 2.93 mmol, 1.00 equiv) in tetrahydrofuran/water (1:1) (20 mL), lithium hydroxide hydrate (1.26 g, 30.00 mmol, 10.23 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the aqueous layers combined. The solution was adjusted to pH 5 with hydrochloric acid. The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 0.8 g (83%) of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:13]([C:11]2[O:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH:23]=1)[CH3:17]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Product: CCOC(=O)COc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
Carboxylic acid (76)(53 mg, 0.26 mmol) was coupled to aniline (64)(56 mg, 0.26 mmol) using Method C to give the title compound.