Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:37](=[O:38])[CH2:36][O:35][CH3:34])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: COCC(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, methoxyacetyl chloride (0.22 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 100:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-methoxyacetamide (0.44 g, 66%) as a white solid: mp 196-198° C.; 1H NMR (DMSO-d6) δ d 11.14 (s, 1H), 8.49 (t, J=6.1 Hz, 1H), 7.86-7.79 (m, 2H), 7.68-7.65 (m, 1H), 5.19-5.12 (dd, J=5.3 and 12.5 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 3.92 (s, 2H), 3.36 (s, 3H), 2.96-2.83 (m, 1H), 2.64-2.49 (m, 2H), 2.09-2.04 (m, 1H); 13C NMR (DMSO-d6) δ d 172.71, 169.78, 169.58, 167.52, 166.94, 139.09, 134.70, 133.00, 131.51, 127.08, 121.82, 71.46, 58.70, 48.86, 37.47, 30.91, 21.95; Anal. Calcd. For C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 57.02; H, 4.87; N. 11.36.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(NC(=O)c2cc(Br)ccc2O)cc(OC)c1
Yield: 40.3 %

Procedure:
Using 5-bromosalicylic acid and 3,5-dimethoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[CH2:20]1)=[O:18]>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH3:25])[CH2:20]1)=[O:18]
Reactant: CCOC(=O)n1c(C(=O)C2CCCC(C)C2)c(N)c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1CCCC(C(=O)c2[nH]c3cc(Cl)ccc3c2N)C1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-1-ethoxycarbonyl-2-(3-methylcyclohexylcarbonyl)indole (step 2). m.p.: 140-142° C. (hexane/ethyl acetate)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CC(O)C>[C:1]1([CH2:7][CH2:8][CH:9]([NH:20][OH:21])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(C)O
Product: ONC(CCc1ccccc1)CCc1ccccc1
Reaction time: 0.17 h
Yield: 30.6 %

Procedure:
A solution of 0.37 g (1.55 mmol) of 1,5-diphenyl-3-pentanone in 20 ml of 2-propanol was treated with 0.22 g (3.1 mmol) of hydroxylamine hydrochloride and 0.31 g (4.7 mmol) of anhydrous sodium acetate. After being stirred for 10 min, the mixture was treated with 0.20 g (3.2 mmol) of sodium cyanoborohydride and stirred at ambient temperature for 16 h. After concentration in vacuo, the residue was taken up in ethyl acetate, washed sequentially with aqueous NaHCO3 and saturated brine, dried over MgSO4, and concentrated. Flash chromatography using 40% ethyl acetate in chloroform gave 121 mg (31%) of the desired compound (Rf 0.16, 30% ethyl acetate in chloroform) as a white solid, m.p. 54°-55° C. 1H NMR (CDCl3) δ 1.7-1.85 (m, 2H), 1.85-2.0 (m, 2H), 2.6-2.75 (m, 4H), 2.90 (pentet, J=6 Hz, 1H), 5.22 (br, 2H), 7.1-7.35 (m, 10H). Mass spectrum (M+H)+ =256.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]([CH3:35])=[CH2:34]>C1COCC1.C(OCC)(=O)C>[C:8]1([C:7](=[N:6][CH:5]([CH2:34][C:33]([CH3:35])=[CH2:32])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C(C)CBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of N-(diphenylmethylene)glycine ethyl ester (available from Aldrich Chemical Co., Milwaukee, Wis.) (50.0 g, 187 mmol) in dry THF (200 mL) at −78° C. under argon was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (Li HMDS; 210 mL, 0.2 mol) in THF over a period of 45 min (“1.A, Scheme A). After 0.5 hour at −78° C., 3-bromo-2-methylpropene (18.91 mL, 187 mmol) was added dropwise to the orange-yellow suspension. After the addition was complete, the reaction mixture was stirred for an additional 0.5 hour at 0° C. and then allowed to warm to room temperature. After 1 hour the reaction mixture was concentrated under reduced pressure to give an orange-colored oil. The crude material was dissolved in ethyl acetate (EA) (600 mL), washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to give the desired compound (60 g, 99%), which was used for the next step without further purification.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.Br[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH3:24])=[C:14]([CH2:25][O:26][CH3:27])[CH:13]=1.[C:28](=[O:30])=[O:29]>CCOCC.CCOCC.CCOC(C)=O>[CH3:27][O:26][CH2:25][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH3:24])[C:28]([OH:30])=[O:29]
Reactant: COCc1cc(Br)ccc1N1CCCCC1C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A 1.5M solution of tert-butyllithium in pentane (64 mL, 95 mmol) was added into anhydrous Et2O (130 mL) cooled at −78° C. A solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine (13.0 g, 43.5 mmol) in anhydrous Et2O (20 mL) was added slowly. After 40 minutes, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min. The mixture was diluted with Et2O/EtOAc (1:1, 800 mL) and washed with water (200 mL, pH=4-5 adjusted with a 5N aqueous solution of HCl). The aqueous layer was extracted with EtOAc (400 mL). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give a yellow oil, which was triturated in iPr2O (˜20 mL) and pentane (˜20 mL). The precipitate was filtered off, washed with pentane and dried under reduced pressure to give the title compound as a beige powder. HPLC (Method A), Rt: 1.6 min (purity: 93.5%). HPLC/MS, M+(ESI): 264.2, M−(ESI): 262.2. 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 3.02 (m, 1H), 2.63 (m, 1H), 1.88-1.65 (m, 4H), 1.55-1.40 (m, 2H), 0.88 (d, J=6.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[C:20]([Cu])#[N:21]>CN1CCCC1=O>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17])#[N:21]
Reactant: N#C[Cu]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A suspension of N-(4-chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (8.36 g, 28.5 mmol) and CuCN (4.33 g, 65.5 mmol) in anhydrous N-methylpyrrolidinone (85 mL) was refluxed for 38 h. After cooling to rt, the suspension was poured into ice water with stirring. The resulting solid was filtered, washed with water and dried to yield an 85:15 mixture (7.55 g) of compound 841C and 841D. The resulting mixture was used in the next step.
Reaction SMILES: [Br-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:10])[C:4]=1[CH2:18][CH3:19].[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CCOCC>C(O)(=O)C>[Br-:1].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:5]2[CH:6]=[CH:7][N+:3]([N:2]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([N:21]([CH3:30])[CH3:20])=[CH:23][CH:24]=3)=[C:4]2[CH2:18][CH3:19])=[CH:12][CH:13]=1
Reactant: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1n(CC(=O)c2ccc(Cl)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension consisting of 1.72 g (5 mmol) of 1-amino-3-(p-chlorophenacyl)-2-ethylimidazolium bromide and 0.74 g (5 mmol) of 4-dimethylaminobenzaldehyde in 15 ml of glacial acetic acid is stirred at room temperature for 48 hours, treated with ether and filtered. The filtered-off crude product is chromatographed on 30 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (9:1 v/v) and then recrystallized from methylene chloride/methanol/ether. There is obtained 3-(p-chlorophenacyl)-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium bromide of melting point 252°-253°.
Reaction SMILES: [CH3:1][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:20])([F:19])[C:15]([F:16])([F:18])[F:17])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(SC)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1c(C(F)(F)C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 25 °C

Procedure:
530 mg (1.69 mmol) of methyl 2-methyl-3-(methylthio)-4-(pentafluoroethyl)benzoate were introduced into 10 ml of methanol and admixed with 0.5 ml of 20% strength aqueous sodium hydroxide solution. The contents were stirred at RT until a check on the reaction by thin-layer chromatography indicated complete conversion. The mixture was freed from the solvent, and the residue was taken up in a little water. The mixture was acidified with 1M hydrochloric acid, then stirred for 5 minutes and finally filtered. The residue obtained was 470 mg of clean product.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH:25]1[CH:30]=[CH:29][N+:28]([CH2:31][C:32]([NH:34][NH2:35])=[O:33])=[CH:27][CH:26]=1.[Cl-:36].CS(C)=O>C(#N)C>[Cl-:36].[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:35][NH:34][C:32](=[O:33])[CH2:31][N+:28]3[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NNC(=O)C[n+]1ccccc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NNC(=O)C[n+]1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.172 g (0.9166 mmol) of Girard's reagent P were placed into a 10 ml round bottom flask with 2 ml dimethylsulfoxide and a magnetic stirring bar. The solution was heated to 70° C. with stirring. As the solution began to warm up, the solids began to dissolve and the solution became progressively green in color. After about 30 minutes, the solution was completely homogeneous. The solution was allowed to react at 70° C. for four hours and was allowed to cool to room temperature. 10 ml acetonitrile was added and a white precipitate formed immediately. The solution was filtered and washed with acetonitrile and ether. The solid was allowed to dry but it absorbed H2O from the atmosphere. The hygroscopic effect could either be due to residual dimethylsulfoxide or the product itself.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]([CH3:22])[CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:12]1=O>C1COCC1>[N:11]1([CH2:10][CH2:9][N:8]([CH3:22])[CH3:7])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)CCN1C(=O)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCN1CCCc2ccccc21
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A solution of LiAlH4 (39.39 mL, 39.397 mmol, 1 M solution in THF) was treated with compound 2 (2.15 g, 9.849 mmol) in dry THF (25 mL) at 0° C. The reaction was brought to room temperature and stirred for over night (18 h). The reaction was quenched with water (1.5 mL), 2 N NaOH solution (1.5 mL) and water (1.5 mL). After stirring for 30 min. at room temperature, the reaction was filtered, washed with CH2Cl2 (4×20 mL). The combined organic layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) to obtain compound 3 (0.95 g, 47%) as a syrup. 1H NMR (DMSO-d6) δ 6.93 (t, 1H, J=8.1 Hz), 6.83 (d, 1H, J=7.2 Hz), 6.51 (d, 1H, J=8.1 Hz), 6.43 (t, 1H, J=7.8 Hz), 3.33-3.24 (m, 4H), 2.64 (t, 2H, J=6.3 Hz), 2.36 (t, 2H, J=7.5 Hz), 2.17 (s, 6H), 1.85-1.77 (m, 2H); ES-MS (m/z, %) 205 (MH+, 22), 160 (100), 132 (65).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:28]O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][CH2:19][C:20]([O:22][CH3:28])=[O:21])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
A mixture of 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionic acid (6.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionate (5.91 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 103–104° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)[C:7]([O:17][CH:18]([CH3:20])[CH3:19])=[N:8][C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[CH:30][C:29]4=[O:38])[CH2:24][CH2:23]3)[C:7]([O:17][CH:18]([CH3:19])[CH3:20])=[N:8][C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)nc3OC(C)C)CC2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1nc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(n2ccc(C(=O)O)cc2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A mixture of methyl 1-(1-((5-cyclopropyl-6-(4-fluorophenyl)-2-isopropoxypyridin-3-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (189 mg), a 1 M aqueous sodium hydroxide solution (1.5 mL), and ethanol (3 mL) was stirred at 70 C for 1 hour. The obtained reaction mixture was neutralized with 1 M hydrochloric acid and stirred overnight at room temperature. The resulting solid was collected by filtration and recrystallized (ethanol/ethyl acetate) to obtain the title compound (91 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:14]([O:16][C:17](=[O:22])[CH:18]=[C:19](Cl)[CH3:20])[CH3:15]>O1CCCC1>[CH2:14]([O:16][C:17](=[O:22])/[CH:18]=[C:19](/[O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)\[CH3:20])[CH3:15]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C=C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1
Temperature: 23 °C
Yield: 88.4 %

Procedure:
Potassium t-butoxide (11.9 g, 0.106 mol) was added to a stirred solution of phenol (7.86 g, 0.053 mol) in tetrahydrofuran (25 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-phenoxy-but-2-enoic acid ethyl ester (6.20 g, 89%) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=O)OC(C)(C)C)[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH:37]([OH:39])C>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][C@@H:23]([NH:26][CH2:27][CH2:37][OH:39])[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Reactant: CC(O)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCN[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.6 %

Procedure:
To a solution of tert-butyl {(3R)-1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidin-3-yl}carbamate (300 mg, 0.672 mmol) in anhydrous DMF (2.0 ml) was added 95% NaH (25.4 mg, 1.01 mmol). After stirring at R.T. for 10 mins, to the reaction mixture was added iodoethanol (288.9 mg, 1.68 mmol). After stirring at 70° C. for 16 h, to the reaction mixture was added iodoethanol (288.9 mg, 1.68 mmol). After stirring at 90° C. for 7 h, 105° C. for 32 h, the reaction mixture was quenched with water and filtered. The eluent was extracted with 2:1 EtOAc:toluene (2×30 ml). The organic layer was dried with K2CO3, filtered and concentrated. The resulting residue was dissolved in CH2Cl2 (10 ml) and TFA (0.5 ml) and MeOH (1 pipet drop) were added. After stirring at R.T for 16 h, the reaction mixture was concentrated. The resulting residue was purified via reversed phase column eluted with 0.1% TFA CAN: water to give the desired product (1.6 mg).
Reaction SMILES: Cl.NCCCCCC(N1C[C@@H](S)[C@H](NS(C2C=CC(OC3C=CC=CC=3)=CC=2)(=O)=O)C1)=O.Cl.[C:34]([N:41]1[CH2:45][C@@H:44]([S:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:43]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:42]1)(OC(C)(C)C)=[O:35].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.[C:86]([O:90][C:91]([NH:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98]C(O)=O)=[O:92])([CH3:89])([CH3:88])[CH3:87].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.CCCCCC>[C:86]([O:90][C:91]([NH:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][C:34]([N:41]1[CH2:45][C@@H:44]([S:46][C:47]([CH3:49])([CH3:48])[CH3:50])[C@H:43]([NH:51][S:52]([C:55]2[CH:60]=[CH:59][C:58]([O:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:57][CH:56]=2)(=[O:53])=[O:54])[CH2:42]1)=[O:35])=[O:92])([CH3:89])([CH3:88])[CH3:87]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NCCCCCC(=O)N1C[C@@H](S)[C@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCCCCC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)[C@H](SC(C)(C)C)C1
Temperature: 0 °C
Yield: 83.1 %

Procedure:
YHJ-7-52: (±)-N-(6-Aminohexanoyl)-trans-3-(4-phenoxybenzene-sulfonamido)-4-mercaptopyrrolidine Hydrochloride. To a stirred solution of 1.5 M HCl in ethyl acetate (1 mL) was added (±)-N-Boc-trans-3-(4-phenoxybenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (200 mg, 0.39 mmol) and stirring was continued at room temperature until no starting material was detected by TLC (50% ethyl acetate in hexane). The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The solution was cooled to 0° C. and triethylamine (60 μL, 0.43 mmol), HOBt.H2O (54 mg, 0.40 mmol), 6-(tert-butoxycarbonylamino)hexanoic acid (90 mg, 0.39 mmol) and DCC (80 mg, 0.39 mmol) were added. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (10 mL) and the organic layer was washed with 10% citric acid and sat. aq NaHCO3, then it was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (50% ethyl acetate in hexane) to give (±)-N-(6-(tert-butoxycarbonylamino)hexanoyl)-trans-3-(4-phenoxybenzenesulfonamido)-4-tert-butylmercaptopyrrolidine (201 mg, 84%): 1H NMR (300 MHz, CDCl3) δ 7.82 (dd, J=9, 3, 2H), 7.43 (t, J=8, 2H), 7.24 (t, J=7, 1H), 7.08 (m, 4H), 5.13 (br m, 1H, NH), 4.57 (br s, 1H, NH), 3.72-4.10 (m, 2H), 3.00-3.45 (m, 6H), 2.21 (t, J=7, 2H), 1.64 (m, 2H), 1.48 (m, 2H), 1.44 (s, 9H), 1.36 & 1.30 (s, 9H), 1.26 (m, 2H); HRMS (ESI) calculated for C31H45N3O6S2Na+ 642.2642. found 642.2654.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[O:14][CH:2]([CH3:4])[CH3:3]
Reactant: Oc1c(Cl)cc(I)cc1Cl
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(Cl)cc(I)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 2-iodopropane (3.7 g, 21.77 mmol, 1.00 equiv), 2,6-dichloro-4-iodophenol (5 g, 17.31 mmol, 0.80 equiv) and potassium carbonate (9.2 g, 66.09 mmol, 3.04 equiv) in N,N-dimethylformamide (50 mL) was stirred for overnight at 50° C. The resulting solution was diluted with 300 mL of ethyl acetate then washed with 3×100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether (100%) to give 4.6 g (64%) of 1,3-dichloro-5-iodo-2-isopropoxybenzene as a light yellow oil. 1H-NMR (300 MHz, CDCl3): δ 7.60 (s, 2H), 4.63-4.54 (m, 1H), 1.34 (d, J=5.1 Hz, 6H) ppm.