Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])=[CH:10][C:5]2=[CH:4][C:3]=1[C:29]([O:31][CH3:32])=[O:30].[H-].[Na+].I[CH2:36][CH3:37].O>CN(C)C=O.C(OCC)(=O)C>[CH2:36]([N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[C:3]([C:29]([O:31][CH3:32])=[O:30])[CH:4]=[C:5]2[CH:10]=[C:9]1[C:11](=[O:28])[NH:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:14]([F:15])([F:16])[F:17])[CH3:37]
Reactant: CCI
Reactant: COC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2nc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)OC)c(C)nc21
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Methyl 6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.58 g, 3.44 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (35 ml). Sodium hydride (60%; 0.165 g, 4.12 mmol) was added and the mixture was stirred with ice cooling for 2 h. Iodoethane (0.643 g, 4.12 mmol) was added and the reaction mixture was thawed with stirring over 18 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (3/1) and gave 1.15 g (66% of theory) of methyl 1-ethyl-6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. HPLC-MS: log P=6.27; mass (m/z): 488.1 (M+H)+; 1HNMR (D6-DMSO): δ 1.20 (t, 3H), 2.83 (s, 3H), 3.87 (s, 3H), 4.59 (q, 2H), 6.30-6.34 (m, 1H), 7.42 (s, 1H), 7.70-7.84 (m, 2H), 8.06 (d, 1H), 7.93-7.97 (m, 1H), 8.21 (s, 1H), 8.67 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:5])[CH3:4].[C:6]([OH:14])(=S)[CH2:7][O:8][CH2:9]C(O)=O.[S:15]([O-:20])(O[O-])(=O)=[O:16].[K+].[K+]>CO.O>[CH3:9][O:8][C:7](=[S:15](=[O:20])=[O:16])[CH2:6][O:14][CH2:4][C:3]([OH:2])=[O:5]
Reactant: COC(C)=O
Reactant: O=C(O)COCC(O)=S
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(COCC(=O)O)=S(=O)=O

Procedure:
Thiodiglycolic acid monomethyl ether (Indian J. Chem. 25B, 880 (1986)) in a methanol/water mixture is oxidised with potassium peroxomonosulfate at approximately 25° C. to yield the title compound, which is further used.
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][N:8]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]2[N:8]([NH2:7])[C:9]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:11]=2)[CH:14]=1
Reactant: C[Si](C)(C)CCOC(=O)Nn1c(-c2cccnc2)ccc1-c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nn1c(-c2cccnc2)ccc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2,5-di-pyridin-3-yl-pyrrol-1-yl)-carbamic acid 2-trimethylsilanyl-ethyl ester (1 g, 2.6 mmol) is treated with a 1M solution of TBAF in THF (5.2 ml, 5.2 mmol). The resulting solution is stirred overnight under Ar at rt, then quenched with glacial acetic acid (0.3 ml, 5.2 mmol) and diluted with toluene. The resulting solution is passed through a short plug of silica gel and concentrated in vacuo to afford 2,5-Di-pyridin-3-yl-pyrrol-1-ylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[S:9]([CH2:12][C:13](OC)=[O:14])(=[O:11])=[O:10].Cl.[NH2:31][OH:32]>CO>[OH:32][NH:31][C:13](=[O:14])[CH2:12][S:9]([N:8]([CH3:7])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)(=[O:11])=[O:10]
Reactant: NO
Reactant: COC(=O)CS(=O)(=O)N(C)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(Cc1ccc(-c2ccccc2)cc1)S(=O)(=O)CC(=O)NO
Yield: 87.7 %

Procedure:
Potassium carbonate (124 mg, 0.9 mmol) was added to a mixture of methyl 2-({methyl[(biphen-4-yl)methyl]amino}sulfonyl)acetate (100 mg, 0.3 mmol) and hydroxylamine hydrochloride (63 mg, 0.9 mmol) in methanol (3 ml). The mixture was heated to reflux for 18 hours. The mixture was cooled and partitioned between ethyl acetate and 0.1 M aqueous hydrochloric acid. The layers were separated, and the organic layer was dried (MgSO4), and the solvents were removed under reduced pressure. The residue was triturated with diisopropyl ether to give the titled compound as a colourless solid (88 mg).
Reaction SMILES: [C:1]1(=O)C2C(=CC=CC=2)C(=O)N1.[O:12]=[C:13]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)[CH2:14][C@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17].O=C(N1CC2C(=CC=CC=2)C1)C[C@@H](CC1C=CC=CC=1)C(O)=O.O=C(N1CC2C(=CC=CC=2)C1)CC(CC1C=CC=CC=1)C(O)=O>>[CH3:1][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH2:34][N:26]([C:13](=[O:12])[CH2:14][C@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17])[CH2:27]2
Reactant: O=C(O)[C@H](CC(=O)N1Cc2ccccc2C1)Cc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C(O)C(CC(=O)N1Cc2ccccc2C1)Cc1ccccc1
Agent: O=C(O)[C@@H](CC(=O)N1Cc2ccccc2C1)Cc1ccccc1
Product: Cc1ccc2c(c1)CN(C(=O)C[C@H](Cc1ccccc1)C(=O)O)C2

Procedure:
By reproducing this example using as starting material 1H-isoindole-1,3-(2H)-dione, it was possible to prepare γ-oxo-α(S)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoic acid, γ-oxo-α(R)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoic acid and γ-oxo-α(R,S)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]([C:29]2([CH3:42])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[S:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:17]2[N:18]=[C:19]([C:29]3([CH3:42])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=2)=[CH:4][CH:5]=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2sc(C3(C)CCNCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (98 mg, 0.160 mmol) in dichloromethane (DCM) (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to the title compound (26 mg). MS (ESI): 514.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[CH2:18]=[C:19]([CH3:21])[CH3:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[CH2:18][C:19]([CH3:21])([CH3:20])[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=3)[NH:8]2)[CH:15]=[CH:16][CH:17]=1
Reactant: C=C(C)C
Reactant: O=Cc1cccc(Br)c1
Reactant: Nc1ccc(Cl)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(Cl)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 4-chlorophenylamine (10.0 g, 78.4 mmol) and 3-bromobenzaldehyde (9.2 mL, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0-10% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (11.0 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 350.0 & 352.0.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.[CH2:32]=O>C(O)(=O)C>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH2:13][CH2:32][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:3]1
Reactant: C1COCCN1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
3α-Hydroxy-5α-pregnane-11,20-dione (1.0 g) in glacial acetic acid (20 ml.) was treated with morpholine (1.0 ml) and concentrated hydrochloric acid (1.0 ml). Paraformaldehyde (600 mg) was added to the stirred solution which was then heated in an oil-bath at 95°-100° for 1 hour. The solution was evaporated and dried in vacuo to a yellow oil (3.5 g.) which was partitioned between ethyl acetate and 0.1N hydrochloric acid. The colourless organic layer was extracted with more hydrochloric acid and the combined yellow aqueous layer was washed with ethyl acetate and basified with saturated sodium bicarbonate solution. The cloudy precipitate was extracted into ethyl acetate, and the extract washed with water, dried (Na2SO4) and evaporated to a pale yellow foam (1.05 g) which was purified by preparative t.l.c. in acetone to give title compound (534 mg) as a colourless foam, [α]D + 73° (c, 0.81).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH2:18]([O:20][P:21]([CH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:23][CH2:24][CH3:25])=[O:22])[CH3:19].O>CN(C)C1C=CN=CC=1.ClCCl>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:31]([C:30]2[CH:34]=[CH:35][C:27]([CH2:26][P:21](=[O:22])([O:20][CH2:18][CH3:19])[O:23][CH2:24][CH3:25])=[CH:28][CH:29]=2)=[O:32])=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: N#Cc1cc(Br)ccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Br)cc2C#N)cc1)OCC
Reaction time: 10 h
Yield: 32.6 %

Procedure:
3.94 Grams (20 millimoles) of 2-amino-5-bromo-benzonitrile, 2.22 g (22 millimoles) of triethylamine and 0.49 g (4 millimoles) of 4-dimethylaminopyridine were dissolved in 40 ml of dry dichloromethane, under ice-cooling there was added dropwise slowly 40 ml of dry dichloromethane solution of 5.81 g (20 millimoles) of 4-diethoxyphosphorylmethylbenzoyl chloride with stirring. The reaction was carried out at room temperature for 10 hours, to this reaction mixture was added 50 ml of water, then extracted with chloroform and the organic layer was dried over anhydrous sodium sulfate, next the solvent was removed by distillation under reduced pressure. Thus obtained residue was refined by means of a silica gel column chromatography (eluted with chloroform: ethyl acetate=1:2), recrystallized from benzen-n-hexane, there was obtained 2.94 g of diethyl 4-[N-(4-bromo-2-cyanophenyl)carbamoyl]benzylphosphonate as colorless crystals.
Reaction SMILES: O.O.[Sn](Cl)Cl.CN(C)C=O.[CH2:11]([O:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:23][C:22]([NH:33][C:34]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)=O)=[C:21]([N+:42]([O-])=O)[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[CH2:11]([O:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:23][C:22]2[NH:33][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)=[N:42][C:21]=2[CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1cc(Oc2ccccc2F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Oc1cc2[nH]c(-c3cnccn3)nc2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3.72 g of tin(II) chloride dihydrate was added to a dimethylformamide (16 ml) suspension of 1.52 g of N-(4-benzyloxy-5-(2-fluorophenoxy)-2-nitrophenyl)pyrazinecarboxamide, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain the entitled compound as a yellow solid.
Reaction SMILES: C([SH:3])C.[C:4]([N:9]=[C:10]=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6].Cl[CH2:13][CH2:14]Cl>>[C:4]([NH:9][C:10](=[S:3])[O:11][CH2:13][CH3:14])(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: CCS
Reactant: ClCCCl
Reactant: C=C(C)C(=O)N=C=O
Product: C=C(C)C(=O)NC(=S)OCC
Reaction time: 0.5 h

Procedure:
A solution of ethanethiol (1.24 g; 20 mmol) in 1,2-dichloroethane (12 ml) was dropwise added to a solution of methacryloyl isocyanate (2.22 g; 20 mmol) in 1,2-dichloroethane (14 ml) in 10 minutes under nitrogen stream while cooling with ice. After completion of the addition, the reaction mixture was stirred for 30 minutes. The solvent was removed by evaporation under reduced pressure to give ethyl N-methacryloylthiocarbamate (2.17 g) as a pale yellow liquid. Viscosity, 150 cp.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[S:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(I)ccc1N
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(I)ccc1N=C=S
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a stifling solution of 4-iodo-2-methylaniline (1.0 g, 4.2 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (490 mg, 4.2 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.05 g, 89%). δH (CDCl3) 7.75 (1H, d, J=1.2 Hz), 7.62 (1H, dd, J 1.2, 8.3 Hz), 7.15 (1H, d, J=8.3 Hz), 2.20 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(N)nc(OCc2ccccn2)c(C#N)c1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 317 (M+, 66), 92 (100), 65 (55).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:81][C:82](=[O:89])[NH:83][CH:84]1[CH2:88][CH2:87][NH:86][CH2:85]1)[CH2:78][CH2:79][CH3:80]>CN(C=O)C.C(OCC)(=O)C>[CH2:77]([O:81][C:82]([NH:83][CH:84]1[CH2:88][CH2:87][N:86]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH:32]3[CH2:33][CH2:34][CH2:35]3)=[O:24])[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:85]1)=[O:89])[CH2:78][CH2:79][CH3:80]
Reactant: CCCCOC(=O)NC1CCNC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)NC1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C1
Reaction time: 12 h

Procedure:
To a solution of 303 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 34 μl DIPEA, 193 mg HATU and 103 mg pyrrolidin-3-yl-carbamic acid butyl ester. After stirring for 12 h the reaction mixture was diluted with ethyl acetate, washed with aqueous LiCl (4%) and saturated aqueous NaHCO3 solution. The solution was concentrated, dissolved in 2 ml dichloromethane and stirred in the presence of 384 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 229 mg MS (ES+): m/e=710.
Reaction SMILES: [C:1]([N:4]([C:17]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:13][OH:14])=[CH:8][C:7]=1[CH3:15])(=[O:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:32][C:33]1[CH:34]=[C:35]([C:41]([C:43]([F:46])([F:45])[F:44])=[CH2:42])[CH:36]=[C:37]([Cl:40])[C:38]=1[Cl:39].C(=O)([O-])O.[K+]>COCCOC.O>[C:1]([N:4]([C:17]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:42][C:41]([C:35]3[CH:36]=[C:37]([Cl:40])[C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:43]([F:46])([F:45])[F:44])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC(=O)N(C(=O)c1ccc(C=NO)cc1C)c1ncc(Cl)cn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
In a solution of 30 mg of N-acetyl-N-(5-chloro-2-pyrimidinyl)-4-hydroxyiminomethyl-2-methyl benzoic acid amide in 5 mL of 1,2-dimethoxyethane, 16 mg of N-chlorosuccinic acid imide was added and stirred at 40° C. for 30 minutes. Then the reaction mixture was left and cooled to room temperature, and 24 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 10 mg of potassium hydrogen carbonate and 1 drop of water were added, and continued to stir at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 11 mg of the aimed product as colorless resinous substance.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[CH3:39][NH:40][C:4](=[O:3])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Yield: 62 %

Procedure:
N-Methyl-3-(3-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXXII (386 mg, 62% yield) was prepared from 3-(3-methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XVIII (see Example 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:14][OH:15].CC([O-])=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[O:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#CCC(=O)c1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Br)c2)no1

Procedure:
To a solution of 3-(3-bromophenyl)-3-oxopropanenitrile (1.12 g; 5.00 mmol; Note 1) in EtOH (20 mL) was added a solution of hydroxylamine hydrochloride (1.74 g; 25 mmol) and NaOAc (2.46 g; 30 mmol) in water (20 mL). The mixture was heated under reflux for 1 h, cooled and concentrated in vacuo. The residue was slurried in 1N NaOH and extracted with Et2O (×1). The organic layer was washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a pale yellow solid which was used without further purification. LC/MS (method B) 2.21 min, m/z 239, 241 (Br isotopes).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([OH:28])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:7])[CH3:6].ClC(Cl)C.C(O)(=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[OH:28][C:3]([C:2]([F:30])([F:1])[F:29])([CH2:4][C:5]([CH3:6])([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:9]=1)[CH3:7])[CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1
Reactant: C1COCCN1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a solution of 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde (0.05 g, 0.12 mmol), dichloroethane (3.0 mL), and acetic acid (0.09 mL, 1.46 mmol) in an ice bath was added morpholine (0.26 μL, 3.00 mmol). The solution was warmed to room temperature and stirred for 0.5 hours. Triacetoxy sodium borohyride (0.06 g. 0.30 mmol) was added and the reaction stirred at room temperature. After 3.0 hours, the solution was partitioned between EtOAc and 3% NH4OH (3 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The product was eluted from a flash chromatography column with EtOAc/hexanes, and concentrated in vacuo to afford 1-[2-hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylpentyl]-1H-quinolin-4-one as a colorless solid (0.03 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]1[C:15]([CH3:16])=[C:14]([C:17](O)=[O:18])[C:13](=[O:20])[N:12]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:9][C:4]1[CH:3]=[C:2]([NH:1][C:17]([C:14]2[C:13](=[O:20])[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:11]([CH3:10])[C:15]=2[CH3:16])=[O:18])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(O)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a suspension of 4-amino-2-chlorophenol (4.0 g, 28.00 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (7.4 g, 30.11 mmol) in DCM (70 mL) were added EDCI (6.65 g, 30.11 mmol) and HOAT (0.76 g, 5.68 mmol). The mixture was stirred at 45° C. for 20 hours, then cooled to rt and filtered. The filter cake was washed with DCM (20 mL×3), and dried at 50° C. in a vacuum oven overnight to give the title product as a gray solid (7.1 g, 72.1%).