Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[CH2:2]1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].OP([O-])(O)=O.[K+]>CN(C=O)C>[CH2:24]([O:23][C:21]([CH2:20][N:12]1[C:13]2[CH2:1][CH2:2][CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of 2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (0.40 g, 1.86 mmol) in dry DMF (4 ml) is added NaH (0.16 g, 4.1 mmol, 60% in mineral oil) in one portion. After gas evolution has ceased, the reaction mixture is kept stirring at rt for 1 h. Then, ethyl bromoacetate (0.21 ml, 1.9 mmol) is added and stirring is continued overnight. Saturated KH2PO4 solution is added and the mixture is extracted with dichloromethane. The organic layers are combined and washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue is purified by flash chromatography on silica gel (hexane/EtOAc 3:1) to afford pure title compound as an off-white solid (0.34 mg) in 61% yield. tR (LC-3) 2.05 min; ESI-MS (positive ion): m/z 324.15 [M+Na]+ (calcd 301.13 for C17H19NO4). 1H-NMR (DMSO-d6): 1.13 (t, J=7.0 Hz, 3H); 1.79 (m, 11-1); 2.14 (m, 1H); 2.64 (m, 4H); 2.86 (dd, J=14.3 Hz, 4.8 Hz, 1H); 4.05 (q, J=7.0 Hz, 2H); 4.88 (s, 2H); 6.90 (dd, J=7.6 Hz, 7.0 Hz, 1H); 6.97 (dd, J=7.6 Hz, 7.0 Hz, 1H); 7.23 (d, J=8.1 Hz, 1H); 7.3 (d, J=6.8 Hz, 1H); 12.08 (s br, 1H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH:31]1C=CC=C[CH:32]=1.C(O)C>S(=O)(=O)(O)O.O>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:31][CH3:32])=[O:2]
Reactant: CC(C)(C)c1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(C(C)(C)C)cc3)cccc2o1

Procedure:
1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane (10.7 g), benzene (100 ml), ethanol (5 ml) and sulphuric acid (10 drops) were heated under reflux in a Dean and Stark separator until no more water passed over (about 6 hours). After cooling, the solution was washed with saturated sodium bicarbonate solution, and then water. The solvent was removed under reduced pressure to give a very viscous brown oil, from which solid material separated on standing. This solid was filtered off and washed several times with ether to give 1-(2-carbethoxy-chromon-5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane, 6.1 g, as a cream solid. A portion recrystallized from aqueous ethanol afforded almost colorless flakes m.p. 99°-101.5°.
Reaction SMILES: [F:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.P(Br)(Br)([Br:15])=O.CN(C)C=O.C(=O)(O)[O-].[Na+]>>[Br:15][C:3]1[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: Oc1ncc(C(F)(F)F)cc1F
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C(F)(F)F)cnc1Br
Temperature: 130 °C

Procedure:
A mixture of 3-fluoro-5-(trifluoromethyl)pyridin-2-ol (1.0 g, 5.5 mmol, Matrix) and phosphoric tribromide (1.6 g, 5.5 mmol) in N,N-dimethylformamide (2.9 mL, 38 mmol) was heated to 130° C. for 70 minutes. After cooling to room temperature, the mixture was poured onto a mixture of ice and sodium bicarbonate solution (final pH=8). The product was extracted with diethyl ether. The extract was washed with water (twice), followed by brine, dried and solvent removed in vacuo. Flash chromatography, eluting with a gradient from 0-10% ethyl acetate in hexanes afforded product as a colorless oil (0.59 g, 44%). 1H NMR (400 MHz, CDCl3): δ 8.53-8.50 (m, 1H), 7.66 (dd, 1H).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:42]2[C@H:43]([CH3:66])[C@H:44]3[C@@H:61]([C@H:62]([OH:64])[CH3:63])[C:60](=[O:65])[N:45]3[C:46]=2[C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[N:16]1([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:6][CH:5]([S:4][C:42]4[C@H:43]([CH3:66])[C@@H:44]5[C@@H:61]([C@H:62]([OH:64])[CH3:63])[C:60](=[O:65])[N:45]5[C:46]=4[C:47]([O:49][CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N+:57]([O-:59])=[O:58])=[CH:55][CH:56]=4)=[O:48])[CH2:8]3)[S:10][CH:11]=2)=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CCCC5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To a solution of 3-acetylthio-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (235 mg, 0.84 mmol) (obtained as described in Reference Example 26) in dimethylformamide (12 ml) was added hydrazine acetate (103 mg, 110 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 3 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (499 mg, 0.84 mmol) in acetonitrile (25 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.56 ml, 3.36 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (240 mg, yield 46%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCOC(C)=O>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: Nc1ccc(O)cc1F
Reaction time: 4 h
Yield: 96.7 %

Procedure:
To a dry flask purged with argon was added 10% Pd/C (80 mg) followed by a solution of 3-fluoro-4-nitrophenol (1.2 g, 7.64 mmol) in EtOAc (40 mL). The mixture was stirred under an H2 atmosphere for 4 h and filtered through a pad of Celite®. The filtrate was evaporated under reduced pressure to afford the desired product as a tan solid (940 mg, 7.39 mmol; 97% yield). 1H-NMR (DMSO-d6) δ 8.76 (s, 1H), 6.62 to 6.52 (m, 1H), 6.41 (dd, J=2.5, 12.7 Hz, 1H), 6.35 to 6.29 (m, 1H), 4.38 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:18][C:19](=[O:21])[CH3:20])([CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=[O:26])C>O.Cl[Cu].Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:18][C:19](=[O:21])[CH3:20])([CH2:14][CH2:15][C:16](=[O:26])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: C=CCCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: O
Product: CC(=O)CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl-4-acetoxy-4-(but-3-en-1-yl)piperidine-1-carboxylate (1 g, 3.36 mmol) in DMF (6 mL) and H2O (2 mL) was added CuCl (0.77 g, 7.73 mmol) and PdCl2 (0.16 g, 0.91 mmol) and the resulting suspension was stirred under an oxygen atmosphere at room temperature for 24 h. The insoluble materials were removed by filtration, and washed with ethyl acetate. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 16D (540 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.84 (br. s., 2H), 2.97 (t, J=12.1 Hz, 2H), 2.38-2.47 (m, 2H), 2.17-2.24 (m, 2H), 2.15 (s, 3H), 2.04 (s, 3H), 1.39-1.51 (m, 9H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C1COCC1>[CH2:16]([C:5]1[N:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC(=O)c1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1cccnc1Cc1ccccc1

Procedure:
NaH (300 mg; 60%) is added to the solution of methyl nicotinoylacetate (896 mg, 5 mmol) in THF (15 mL) at 0° C. under argon atmosphere. The reaction mixture is stirred for 15 minutes at the temperature and benzyl bromide (0.36 mL) is added. The reaction mixture is heated at reflux overnight. The reaction mixture is poured into iced 1N HCl and extracted with EtOAc three times. The combined organic extract is washed with brine and dried over MgSO4. Concentration under reduced pressure gives the residue which is purified over column chromatography to afford methyl 2-benzyl-nicotinoylacetate intermediate (389 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[CH2:25]([O:24][C:22]([C:21]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:8][CH:20]=1)=[O:23])[CH3:26]
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(-c2ccc(OC)cc2)n1
Temperature: 65 °C
Yield: 48.4 %

Procedure:
To an ice-cold solution of 4-methoxy-thiobenzamide (0.50 g, 2.98 mmol) in ethanol (25 ml) was added triethylamine (0.41 ml, 2.98 mmol) followed by dropwise addition of ethyl bromopyruvate (0.56 ml, 4.40 mmol). The reaction mixture was heated at 65° C. for 12 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure, water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 10% EtOAc-Hexane) to get the desired product (0.38 g, 48%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16](O)=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C[N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([NH2:28])=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(C(N)=O)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
To a round bottom flask was added 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (1.1 g, 2.8 mmol), DCM (35 mL), TBTU (3.6 g, 11.3 mmol), and TEA (3.0 mL, 21.5 mmol). The mixture was allowed to stir for 5 min at rt and then ammonia (0.5M in dioxane, 32 mL) was added. The resulting mixture was allowed to stir at rt overnight. The mixture was concentrated and the residue was washed with water to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxamide (0.96 g, 92%). LCMS (FA): m/z=371.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][NH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[CH2:7][C:8]1[C:12]([CH3:13])=[N:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=2)[C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccc(I)cc1
Reactant: Cc1n[nH]c(C)c1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(Cc2ccc(I)cc2)c(C)c1CC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 60.2 %

Procedure:
To a stirred solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid tert.-butyl ester (10 g) in dimethylformamid (50 ml) at room temperature is added 1-bromomethyl-4-iodobenzene (15.5 g) and potassium carbonate (8.0 g). After 15 h of stirring, water is added and the reaction mixture is extracted twice with ethyl acetate. The organic layer is washed several times with water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (4:1 to 3:2 cyclohexane:ethyl acetate) to yield 1-(4-iodobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (12.2 g). [M+H]=427; HPLC retention time 1.57 min (Method E).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[NH:21][CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH:36]=O)[CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[N:21]([CH2:36][CH:32]4[CH2:33][CH2:34][CH2:35][O:30][CH2:31]4)[CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CC1CCCOC1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1CC1CCCOC1
Reaction time: 0.33 h
Yield: 50.5 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropane-carboxamide (150 mg, 0.38 mmol) in anhydrous dichloromethane (2.3 mL) at room temperature under N2 was added tetrahydropyran-3-carbaldehyde (54 mg, 0.47 mmol). After 20 min of stirring, NaBH(OAc)3 (110 mg, 0.51 mmol) was added in one portion at room temperature. The reaction mixture was stirred for 6 h at room temperature before being purified by column chromatography on silica gel (5-20% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-((tetrahydro-2H-pyran-3-yl)methyl)indolin-5-yl)cyclopropanecarboxamide (95 mg, 50%). CDCl3 was added to the indoline and the solution was allowed to stir overnight at ambient temperature. The solution was concentrated to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-indol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 493.0.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:26][C:27](C)([O-:29])C.[K+].ClCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][OH:29])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Agent: OCCCl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCO)cccc2c1Nc1ccc(F)cc1C
Reaction time: 48 h

Procedure:
A solution of 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-hydroxyquinoline (3.2 g, 9.4 mmol) and potassium t-butoxide (1.83 g, 15 mmol) in tetrahydrofuran (75 ml) was warmed to reflux, 2-chloroethanol (1.3 ml, 20 mmol) added, and heating continued for 2 days. The solvent was evaporated, the residue taken up in dichloromethane, washed with water and brine, dried and evaporated. Chromatography (silica gel, 5% methanol in dichloromethane) gave initially recovered starting material, followed by product fractions which were recrystallised from ethyl acetate/petroleum ether, then from methanol to give 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline as a hygroscopic solid (0.82 g, 23%), m.p. 130°-133°.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[Li+].[OH-]>CO>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1ccccc1)C(=O)O

Procedure:
To a solution of 2-methyl-2-phenoxypropanoic acid from Step A (0.05 mmol) in methanol (200 mL) was added aqueous LiOH (150 mL, 1 mol). The reaction mixture was refluxed for 3 hours. After removal of the solvent, the residue was extracted with ethyl acetate (50 mL×2). The aqueous layer was adjusted to pH=2 with concentrated HCl and extracted with ethyl acetate (200 mL×4). The combined extracts were washed with brine, dried with sodium sulfate and concentrated to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.26˜7.30 (m, 2H), 7.06 (t, J=7.2 Hz 1H), 6.93-6.95 (m, 2H), 1.61 (s, 6H); LCMS (ESI+) m/z 181 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[C:33]([O:32][CH3:31])[CH:34]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)c1

Procedure:
In a manner similar to that of Example 37(e), by reacting 540 mg (1.2 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 300 μl (2 mmol) of 3-methoxybenzoyl chloride, and after purification, 400 mg (70%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-3-methoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 173° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCO)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCOS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 300 mg (1.61 mmol) 5-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid methyl ester in 10 mL DCM is added 0.90 mL triethylamine (6.44 mmol) and subsequently 312 μL (4.03 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and is diluted with 50 mL DCM. The organic phase is separated, washed three times with water and is dried over MgSO4. After filtration and evaporation of the solvent, the product is afforded.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>C(#N)C.C(OCC)(=O)C>[C:3]1([C@@H:2]([NH:9][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: C[C@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (S)-α-methylbenzylamine (3.87 mL, 0.03 mol) in acetonitrile (50 mL) was added diisopropylethylamine (5.23 mL, 0.03 mol), followed by methyl bromoacetate (2.84 mL, 0.03 mol). The reaction was stirred under nitrogen, at room temperature, overnight. The solution was concentrated and the residue partitioned between ethyl acetate and saturated NaHCO3. The aqueous layer was separated, and the product extracted three times with ethyl acetate. The ethyl acetate solutions were combined, washed three times with brine, dried over MgSO4, and concentrated to give a light yellow liquid. Chromatography was carried out on silica gel, using ethyl acetate as eluent, to give a colorless liquid; 4.97 g (86% yield). MS-APCI: M+1=194.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[H][H]>[Pt].C(O)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Agent: [Pt]
Solvent: CC(=O)O
Product: Nc1ccc(Br)c2ccncc12
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A mixture of Example 801A (500 mg, 2 mmol), 5% Pt/C and acetic acid (50 mL) was equipped with a balloon of hydrogen gas and stirred at room temperature. When the reaction was complete, the solution was filtered through Celite. The mixture was treated with 50% sodium hydroxide solution until pH reached 10. Filtration provided 267 mg (60%) of the desired product as a yellow solid. MS (ESI) m/e 223 (M+H)+.
Reaction SMILES: B([O-])O[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=CCCCCCC.B1C2CCCC1CCC2.[OH-].[Na+].Br[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:37](=[O:42])[CH2:36][CH2:35]2>C1COCC1>[CH2:3]([C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C:37](=[O:42])[CH2:36][CH2:35]2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: CCCCCCCCOB[O-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CCCCCCCCc1ccc2c(c1)CCC(=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
An octyl boronate intermediate is first generated by adding 1-octene (1.38 g, 14.1 mmol) to a solution of 9-BBN in THF (28.3 mL of a 0.5 M solution, 14.1 mmol). The reaction is stirred at room temperature overnight, then an aqueous solution of sodium hydroxide (5.0 mL of a 3.0 M solution) is added, followed by the addition of 6-bromo-2-tetralone (2.40 g, 10.0 mmol) and Pd[P(Ph)3]4 (0.310 g, 0.270 mmol). The reaction is brought to reflux and maintained for 12 hours under an inert atmosphere. The reaction is then cooled, filtered, concentrated in vacuo and the residue purified using silica gel chromatography with hexanes/ethyl acetate (75:25) as solvent to provide 6-octyl-2-tetralone (2.35 g, 8.5 mmol, 85%) as a clear liquid.