Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([CH2:26]Br)=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]>C(COC)OC.CS(C)=O>[F:19][C:20]1[C:25]([CH2:26][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-hydroxyphthalimide (8.15 g, 0.05 mol) was dissolved in a mixture of dry dimethoxyethane (40 ml) and dry dimethyl sulphoxide (10 ml). To this solution was added, in one portion, potassium carbonate (3.46 g, 0.05 mol). An orange suspension resulted. The pentafluorobenzyl bromide (10.8 g, 0.05 mol) in dry dimethoxyethane (10 ml) was added dropwise over 1 h at room temperature. The reaction mixture was stirred at room temperature for 64 h and then quenched by pouring into water (1 l). The resulting slurry was filtered, the crystals washed with water and dried in vacuo to give N-(pentafluorobenzyloxy)phthalimide as white crystals (15.9)g.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3]2.[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[ClH:13].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:14])[CH2:12][S:25][C:23]1[CH:22]=[C:21]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]([OH:30])=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[CH:24]=1)[CH2:3]2
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C(CCl)NC1CN2CCC1CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1cc(SCC(=O)NC2CN3CCC2CC3)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving the product of Example 17 (2.0 g, 0.0084 mole) and 2,6-bis (1,1-dimethylethyl)-4-mercaptophenol (1.99 g, 0.0084 mole) in acetonitrile (25 ml). Triethylamine (5 ml) was added to the mixture and the mixture stirred at room temperature for 12 hours then refluxed for 72 hours. The hot mixture was filtered and the solvent removed on a rotary evaporator. The residue was triturated with hexane and dissolved in hot ethyl acetate and allowed to cool. After filtering, the solvent was removed by a rotary evaporator and the residue recrystallized from ethyl acetate-methanol-ethyl ether to give a tan solid. The structure was confirmed by mass spectroscopy M+ 404.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[O:18][C:19]=2[CH3:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[OH:26][C:27]1[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH:32]([C:31]1[C:27]([O:26][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[O:18][C:19]=3[CH3:20])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[N:28][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=[O:33]
Reactant: COC(=O)c1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a mixture of methyl 5-(chloromethyl)-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (1.16 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.12 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as colorless crystals (1.07 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: Cc1ccsc1C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sccc4C)C3)cc21
Reaction time: 18 h

Procedure:
A 3.64 g portion of 2-(3-methyl-2-thienyl)piperazine was added to 10 ml of pyridine followed by 1.35 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. The mixture was placed in a pressure bottle, under argon, sealed and heated at 120°-130° C., with stirring for 18 hours. The solvent was removed and the residue purified by chromatography, eluting with chloroform:methanol (9:1), giving 135 mg of the desired product, mp 252°-255° C. (dec.).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[NH2:17][C:18]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:44])[CH2:19][NH:20][C:21](=[O:43])[CH2:22][N:23]1[C:27](=[O:28])[N:26]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[N:24]1>ClCCl>[C:10]([NH:17][C:18]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)([CH3:44])[CH2:19][NH:20][C:21](=[O:43])[CH2:22][N:23]1[C:27](=[O:28])[N:26]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[N:24]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
At RT, 12 μl (68 μmol) of N,N-diisopropylethylamine and then 6 μl (62 μmol) of acetic anhydride were added to a solution of 38 mg (62 μmol) of the compound of Example 53A in 0.96 ml of dichloromethane, and the mixture was stirred for 1 h. The volatile components were then removed on a rotary evaporator. Since LC/MS analysis of the crude product indicated additional formation of an O-acetylated byproduct, the residue was dissolved in 2 ml of methanol and 800 μl of 2 N aqueous sodium hydroxide solution were added. After 72 h, the mixture was acidified with 1 N hydrochloric acid and separated by preparative HPLC [Method 8]. In this step, the two product diastereomers were obtained in separated form. This gave 6 mg (16% of theory) of the title compound (Diastereomer 1) and 7 mg (19% of theory) of the second diastereomer (see Example 39).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=1.[CH3:20][CH:21]([O:23][C:24](=[O:49])[NH:25][CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]([C:45](=[O:47])[CH3:46])[CH:28]([CH3:48])[CH2:27]1)[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][CH:21]([O:23][C:24](=[O:49])[NH:25][C@H:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]4[C:17](=[O:18])[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[C:10]4=[O:19])[CH:6]=3)[CH:34]=2)[N:29]([C:45](=[O:47])[CH3:46])[C@@H:28]([CH3:48])[CH2:27]1)[CH3:20]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(NC(=O)OC(C)C)CC1C
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cnn(CCN4C(=O)c5ccccc5C4=O)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
2-[2-(4-bromo-1H-pyrazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 28) (80 mg, 0.250 mmol) and 1-methylethyl[1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (Intermediate 12, 150 mg, 0.360 mmol) were mixed with potassium carbonate (69.1 mg, 0.500 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.44 mg, 0.012 mmol), dissolved in ethanol (1 mL) and toluene (1 mL) and stirred under nitrogen at 90° C. for 1 hour. The mixture was partitioned between distilled water (20 mL) and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (60 mL) and the organic fractions were combined, washed (brine, 30 mL), dried (MgSO4), filtered and evaporated to dryness to give a yellow solid which was loaded on to a 12+M Biotage silica column and eluted with cyclohexane:ethyl acetate (3:1 to 1:2). Product-containing fractions were evaporated to dryness to give a solid (39 mg). LCMS (Method C): Rt=0.95, MH+=530
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]([F:27])[F:26])=[CH:21][CH:22]=3)[C:17]([C:28]3[N:29]=[C:30]4[C:36]([C:37]([NH:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][N:34](COCC[Si](C)(C)C)[C:31]4=[N:32][CH:33]=3)=[N:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[C:40]([NH:39][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[C:20]([O:24][CH:25]([F:27])[F:26])[CH:19]=4)[N:15]([CH2:14][CH:10]4[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9]4)[N:16]=3)[N:29]=2)[NH:34][CH:35]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Reaction time: 15 h
Yield: 76.3 %

Procedure:
To a stirred solution of 2-(1-((4-benzylmorpholin-2-yl)methyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 55.6 μmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrate. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-[1-(4-benzyl-morpholin-2-ylmethyl)-5-difluoromethoxy-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (25 mg, 76%). MS (M+H)+=590; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.39 (s, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.88 (d, J=4.0 Hz, 1H), 7.36-7.41 (m, 1H), 7.29-7.33 (m, 5H), 7.22-7.27 (m, 1H), 6.98-7.21 (m, 1H), 4.54-4.68 (m, 2H), 3.96-4.03 (m, 1H), 3.74 (d, J=11.0 Hz, 1H), 3.49 (s, 2H), 3.40-3.48 (m, 1H), 2.86 (d, J=11.3 Hz, 1H), 2.58 (d, J=12.3 Hz, 1H), 1.87-2.11 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-:11].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:5]([CH3:6])([CH3:4])[C:8]([OH:10])=[O:11])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: [OH-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
2-(p-Acetylphenoxy)-2-methylpropionic acid was prepared from 545 g. of p-hydroxyacetophenone, 960 g. of sodium hydroxide and 715 g. of chloroform in 11 liters of acetone according to the procedure described above in Example 1, part (d). The product was recrystallized from carbon tetrachloride and from isopropyl acetate to give 2-(p-acetylphenoxy)-2-methylpropionic acid as a pale cream solid, m.p. 108°-110°C.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[C:10]1=[O:24])(C)(C)C>C(OCC)(=O)C.C(Cl)(Cl)Cl>[ClH:1].[NH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=2)[C:10]1=[O:24]
Reactant: CC(C)(C)OC(=O)NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (1 mL) was added to a solution of tert-butyl[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]carbamate (134 mg) in chloroform (1 mL), and the reaction solution was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure to obtain 109 mg of the title compound. The property value of the compound is as follows.