Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH:9]([C:11](=[O:33])[NH:12][C:13]1[CH:18]=[C:17](Br)[C:16]([Cl:20])=[C:15]([C:21]#[C:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][C:43]=2B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[C:1]([O:5][C:6](=[O:34])[N:7]([C@H:9]([C:11](=[O:33])[NH:12][C:13]1[CH:18]=[C:17]([C:43]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:44]=2[N:36]([CH3:35])[N:37]=[CH:38]3)[C:16]([Cl:20])=[C:15]([C:21]#[C:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C(=O)Nc1cc(Br)c(Cl)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cn1ncc2cccc(B(O)O)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[Si](C#Cc1nc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)cc(-c2cccc3cnn(C)c23)c1Cl)(C(C)C)C(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.03 mmol) is added to a mixture of tert-butyl-N-{1-[(4-bromo-5-chloro-6-{2-[tris(propan-2-yl)silyl]ethynyl}-pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate C2 (82 mg, 0.14 mmol), (1-methyl-1H-indazol-7-yl)boronic acid (24 mg, 0.14 mmol), Na2CO3 (44 mg, 0.42 mmol), dioxane (0.8 ml) and water (0.2 ml) under argon atmosphere and stirred at 100° C. for 4 h. The mixture is diluted with water (10 ml) and extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 25 mg (28%). HPLC-MS: M+H=624; tR=1.94 min (METHOD—1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[C:25]([OH:29])(=[O:28])[CH:26]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:26][C:25]([OH:29])=[O:28]
Reactant: O=CC(=O)O
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CC(=O)O)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with glyoxylic acid.
Reaction SMILES: [O:1]=[C:2]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=O.C(N=C=NCCCN(C)C)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:24]([N:26]([CH2:27][CH3:28])[C:3](=[O:5])[C:2](=[O:1])[CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[CH3:25]
Reactant: CCNCC
Reactant: O=C1CCC(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Compound 13 was synthesized starting from treating oxo-(4-oxo-cyclohexyl)-acetic acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 eq.) and 4-dimethylaminopyridine (catalytic amount) in DMF. After stirring at room temperature for approximately 10 min., the reaction mixture was cooled in an ice-bath and diethylamine (1.5 eq.) was added. The resulting mixture was stirred at room temperature for 5 hours with TLC monitoring. The solvent was removed by evaporation. The residue was diluted with EtOAc and washed with H2O twice. The aqueous then was extracted with EtOAc and the organic layer was dried over Na2SO4. The desired intermediate N,N-diethyl-2-oxo-2-(4-oxo-cyclohexyl)-acetamide was obtained after purification through a combiflash chromatography system using a silica gel cartridge and CH2Cl2/MeOH gradient eluent, which further condensed with 3-hydroxybenzaldehyde (2.5 eq.) by following the same procedure described above to get the desired product as a yellow solid ESI MS m/z: 406.51 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ: 7.54 (s. 2H, benzylidene CH═), 7.25 (t, 2H, J=7.8 Hz, aromatic ring H), 6.93-6.89 (m, 4H, aromatic ring H), 6.81-6.78 (m, 2H, aromatic ring H), 3.23 (q, 4H, J=7.2 Hz, —NCH2CH3), 2.95 (m, 4H, 4-oxo-cyclohexyl-H-2, 6), 2.54 (m, 1H, cyclohexyl-H-1), 0.94 (m, 6H, —NCH2CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[CH2:35]([O:34][C:32]([C:31]1[N:23]=[C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:13]3[CH2:14][C:15](=[O:17])[NH:16][C:10]4[CH:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:28]=[CH:27][C:11]=4[N:12]=3)[CH:19]=2)[S:22][CH:30]=1)=[O:33])[CH3:36]
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (39 mg, 0.1 mmol) and ethyl bromopyruvate (29 mg, 0.15 mmol) in ethanol (0.5 mL) was heated at reflux for 7 h. The solution was cooled to 0° C., stirred for 0.5 h, and the title compound was isolated by filtration as light yellow solid (29 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][C:24]([NH:26][OH:27])=[NH:25])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:28]1([C:31](O)=O)[CH2:30][CH2:29]1>>[CH:28]1([C:31]2[O:27][N:26]=[C:24]([CH2:23][CH:11]3[CH2:10][CH2:9][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]3[S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[N:25]=2)[CH2:30][CH2:29]1
Reactant: O=C(O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)N2C(CC(=N)NO)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(Cc3noc(C4CC4)n3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=442.3 (M+H+) was prepared in accordance with the general method of example 13 from (2RS,5SR)-2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-N-hydroxy-acetamidine and cyclopropyl-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:31][C:32]1[C:40]2[C:35](=[CH:36][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:39]=2)[NH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:36]=[C:35]4[C:40]([C:32]([CH3:31])=[N:33][NH:34]4)=[CH:39][CH:38]=3)[C:3]=12
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1n[nH]c2cc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4ccccc4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 20.8 %

Procedure:
To a solution of Example 57b (0.350 g, 0.684 mmoles) in DMF (3.5 ml), ethanol (1.7 ml) and water (1.7 ml), 3-methyl-6-indazoleboronic acid pinacol ester 97 (0.353 g, 1.369 mmoles) and sodium carbonate (0.217 g, 2.05 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.040 g, 0.034 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.073 g, 21% yield). MP: 249-252° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.09(s,1H), 8.05(dd, J=8.0,1.6 Hz, 1H), 7.85(d, J=8.2 Hz, 1H),7.81(m,1H), 7.64(s,1H), 7.62(d, J=8.4 Hz, 1H), 7.51(t, J=7.3 Hz, 1H), 7.36(dd, J=9.3,1.0 Hz, 1H), 7.29(m,3H), 7.15(br s, 2H), 6.01(q, J=7.0 Hz, 1H),2.52(s,3H), 1.92(d, J=7.0 Hz, 3H). Mass: 514.18(M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17](OC)=[O:18])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].ClCCl>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]3[CH:15]=[C:16]([CH2:17][OH:18])[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(-c2ncc(N3CCN(C)CC3)cn2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
860 mg (2.75 mmol) of methyl 3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-benzoate are dissolved in 16 ml of THF, and 13.8 ml (13.8 mmol) of 1 M diisobutylaluminium hydride in THF are added dropwise at room temperature, and the reaction mixture is stirred at room temperature for 1 h. A further 13.8 ml 13 (13.8 mmol) of 1 M diisobutylaluminium hydride in THF are added dropwise, and the reaction mixture is stirred at room temperature for 1 h. 3 ml of saturated sodium sulfate solution are added to the reaction mixture with ice-cooling. Dichloromethane is added to the gelatinous mixture, which is then stirred for 30 min and filtered. The filtrate is dried over sodium sulfate and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
A solution of methyl 4-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamoyl)benzoate (128 mg, 0.286 mmol) in tetrahydrofuran (2.3 mL) at 25° C. was treated with a solution of lithium hydroxide monohydrate (24.0 mg, 0.573 mmol) in water (573 μL). The reaction was stirred at 25° C. for 24 hr. At this time, LC/MS indicated complete conversion to the desired acid. The reaction was diluted with water (30 mL) and was extracted with methylene chloride (1×50 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and then extracted with 90:10 methylene chloride-methanol (3×40 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the intermediate 4-((7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamoyl)benzoic acid (55.1 mg, 44%).
Reaction SMILES: Cl.Cl.NC1CCN(C[C@H]2N3C4N(C(=O)C=CC=4C=CC3=O)C2)CC1.[S:25]1[CH2:30][CH2:29][NH:28][C:27]2[N:31]=[C:32]([CH:35]=[O:36])[CH:33]=[CH:34][C:26]1=2.[N+](C1C=CC=CN=1)([O-])=O.O=C1CSC2C=CC(C=O)=NC=2N1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.CO>[S:25]1[CH2:30][CH2:29][NH:28][C:27]2[N:31]=[C:32]([CH2:35][OH:36])[CH:33]=[CH:34][C:26]1=2
Reactant: O=Cc1ccc2c(n1)NCCS2
Agent: Cl
Agent: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: O=Cc1ccc2c(n1)NC(=O)CS2
Solvent: ClCCl
Solvent: CO
Product: OCc1ccc2c(n1)NCCS2

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (0.075 g, 0.201 mmol) in dichloromethane (5 ml) and methanol (1 ml) at rt under argon was treated with 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (prepared by (1) reduction of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 301(d)) with LiAlH4 to give 3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-ylmethanol and then (2) oxidation with MnO2)) (0.036 g, 0.201 mmol), sodium bicarbonate (0.150 g, 1.786 mmol) and sodium sulfate (0.300 g, 2.112 mmol) and stirred at rt for 5 h. The solution was then treated with sodium triacetoxyborohydride (0.128 g, 0.603 mmol) and stirred over weekend for 65 hours. The solution was evaporated, taken up in CH3OH, adsorbed onto silica gel and chromatographed on silica (0-15% CH3OH in DCM (with 1% NH4OH)) to give the title compound as the free base (59 mg, 63%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([O-:29])=O)=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.O=S(Cl)[Cl:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([Cl:33])=[O:29])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: O=C([O-])c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
A solution of 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate acid (400 mg, 0.91 mmol) in 20 mL of SOCl2 was heated at 80° C. for 3 h. Concentration gave 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=O)N(CCC2C=CC=CC=2)C1=O.[CH2:28]1[CH:35](N2C(=O)C3C(=CC=CC=3)C2=O)C(=O)O[C:30](=O)[CH2:29]1.C(N)CC1C=CC=CC=1>>[CH2:12]([N:3]1[C:4](=[O:11])[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]1=[O:1])[CH2:17][C:16]1[CH:15]=[CH:30][CH:29]=[CH:28][CH:35]=1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCc1ccccc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)O1
Agent: NCCc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1
Temperature: 177 °C
Reaction time: 2 h

Procedure:
1,3-Dioxo-2-(1-phenethyl-2,6-dioxopiperidin-3-yl)isoindoline (8) was specifically prepared and isolated as follows. A mixture of N-phthaloyl-DL-glutamic anhydride (300 mg, 1.13 mmol) and phenethylamine (139 mg, 1.13 mmol) was stirred in a 177° C. oil bath for two hours. The reaction mixture was cooled down and purified by column chromatography, first using petroleum ether/dichloromethane (1:5) as an eluent to afford N-phenethyl phthalimide as a pale yellow solid [1H NMR (CDCl3) δ 7.78-7.77 (m, 2H), 7.65-7.62 (m 2H), 7.22-7.16 (m, 5H), 3.83 (t, 2H), 2.92 (t, 2H)], and then using dichloromethane as an eluent to afford N-phenethyl thalidomide as a syrup that was then recrystallized from ether to provide white crystals [(139 mg, 34%): mp 122-123° C.; 1H NMR (CDCl3) δ 7.84-7.81 (dd, J=3.1 Hz, J=5.4 Hz, 2H), 7.72-7.69 (dd, J=3.1 Hz, J=5.4 Hz, 2H), 7.20-7.14 (m, 5H), 4.89 (dd, J=5.4 Hz, J=12.5 Hz, 1H), 4.01-3.92 (m, 2H), 2.90-2.63 (m, 5H), 2.06-2.02 (m, 1H); Anal. Calcd for C21H18N2O4: C, 69.60; H, 5.01; N, 7.73. Found: C, 69.40; H, 5.13; N, 7.74].
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([SH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([S:20][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1cccc(Cl)c1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2cccc(Cl)c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and 3-chlorobenzenethiol (0.353 g, 2.45 mmol). The title compound was obtained as a yellow solid (0.476 g, 62% yield). 1H NMR (300 MHz, CDCl3) δ: 8.08 (1H, s), 7.68 (1H, m), 7.45-7.60 (3H, m), 2.49 (3H, s).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.Br[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:40])[CH2:24][O:25][CH2:26][C:27]([NH:29][C:30]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:19]=[CH:20][CH:21]=1>>[Cl:39][C:36]1[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[CH2:26][O:25][CH2:24][C:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[CH:13]=[CH:12][O:11][CH:10]=3)[CH:17]=2)=[O:40])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 5-(i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 75%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][N:11]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[CH3:9][C:4]1[CH:3]=[C:2]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(Br)ccc1N
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(-c2cnn(C)c2)ccc1N
Temperature: 80 °C
Yield: 21 %

Procedure:
To a solution of 4-bromo-2-methylaniline (500 mg, 2.69 mmol) in EtOH (10 mL), toluene (10 mL) and water (10 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (671 mg, 3.22 mmol), sodium carbonate (570 mg, 5.37 mmol) and Pd(PPh3)4 (373 mg, 0.322 mmol). The reaction mixture was heated to 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL), washed with water (30 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM to give the title compound (106 mg, 21%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][O:28][CH3:29])=[C:21]4[O:30][CH2:31][O:32][C:20]=34)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].FC(F)(F)C(O)=O.[F:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(C(C)C)CC)(C)C.[I-].[Na+].[ClH:62]>C(Cl)Cl.C(OCC)C.COCCO>[ClH:1].[ClH:62].[C:16]([C:11]1[CH:12]=[N:13][C:14]2[C:9]([C:10]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][O:28][CH3:29])=[C:21]3[O:30][CH2:31][O:32][C:20]=13)=[CH:8][C:7]([O:33][CH3:34])=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:48]1[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][F:42])[CH2:46][CH2:47]1)[CH:15]=2)#[N:17]
Reactant: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: FCCN1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: COCCO
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCN(CCF)CC4)c(OC)cc23)c2c1OCO2
Temperature: 100 °C

Procedure:
A mixture of 7-(3-chloropropoxy)-3-cyano-6-methoxy-4-[4-(3-methoxyprop-1-ynyl)-2,3-methylenedioxyanilino]quinoline (0.14 g), 1-(2-fluoroethyl)piperazine trifluoroacetic acid salt (0.158 g), diisopropylethylamine (0.189 g), sodium iodide (0.02 g) and 2-methoxyethanol (20 ml) was stirred and heated to 100° C. for 30 hours. The cooled mixture was evaporated and the resultant residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was dissolved in the minimum quantity of methylene chloride. The solution was diluted with diethyl ether and a solution of hydrogen chloride in diethyl ether (1M) was added. The resultant solid was isolated, washed with diethyl ether and dried. There was thus obtained the title compound (0.045 g); NMR Spectrum: (DMSOd6 and CF3CO2D at 100° C.) 2.22–2.31 (m, 2H), 2.98–3.1 (m, 6H), 3.1.6–3.21 (m, 2H), 3.25–3.31 (m, 4H), 3.36 (s, 3H), 3.99 (s, 3H), 4.3–4.34 (m, 4H), 4.6 (t, 1H), 4.72 (t, 1H), 6.08 (s, 2H), 6.9 (d, 1H), 6.98 (d, 1H), 7.49 (s, 1H), 7.96 (s, 1H), 8.69 (s, 1H); Mass Spectrum: M+H+ 576.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([O-])(=[O:10])C1C=CC=CC=1.[NH4+].[CH:13]1([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C=O>>[Zn:2].[CH:13]1([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:3]=[O:10]
Reactant: [Zn+2]
Reactant: O=C([O-])c1ccccc1
Agent: C=O
Agent: Oc1ccc(C2CCCCC2)cc1
Agent: [NH4+]
Solvent: Oc1ccccc1
Product: [Zn]

Procedure:
A mixture of 3.7 g of zinc oxide (JIS No. 1) and 15.0 g of ammonium benzoate was gradually added to 100 g of the above p-cyclohexylphenol/phenol/formaldehyde co-condensate kept at 170° C. with stirring, and they were reacted at 165° to 170° C. for 1.5 hours to give a pale yellow transparent zinc salt of the p-cyclohexylphenol/phenol/formaldehyde co-condensate.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=O)[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][N:19](C)C)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30]N>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][NH:19][N:30]=2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=C(C(=O)c1c[nH]c(C(=O)NCc2ccccc2)c1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C(NCc1ccccc1)c1cc(-c2n[nH]cc2-c2ccccc2)c[nH]1
Reaction time: 12 h

Procedure:
To a solution of compound 3 (1 equivalent) in ethanol, at ambient temperature, was added hydrazine hydrate (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by preparatory HPLC (reverse phase; 10→90% MeCN in water; 15 minutes) to afford the desired compound II-5. LC/MS (M+1) 343.3, (M−1) 341.2.
Reaction SMILES: O([CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)CC.B(Br)(Br)[Br:23]>C(Cl)(Cl)Cl>[Br:23][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrB(Br)Br
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Solvent: ClC(Cl)Cl
Product: Nc1nc(-c2ccccc2)c(CCBr)c2ncnn12
Temperature: 0 °C

Procedure:
To 2.8 g of 8-(2-ethoxylethyl)-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amine dissolved in 30 ml of chloroform was added 5 ml of boron tribromide (1 M solution in dichloromethane) at room temperature with stirring. After 8 hours the complex was decomposed by the addition of ice water. The phases were separated and the aqueous layer was adjusted to pH 8 with potassium carbonate, then extracted three times with chloroform. The chloroform extract was added to the original chloroform layer, and the resultant solution was washed with water and dried over sodium sulfate. Removal of chloroform followed by chromatography on Porosil afforded, in order of elution, title compound (m.p. 163°-164°), and title compound Example 1, (m.p. 193°-194°)