Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28](=[O:33])[CH2:29][C:30]([CH3:32])=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH4+:38]>C(C(C)=O)C(C)C>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[C:30]([CH3:32])=[N:38][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:33])[CH2:21][CH2:20]1
Reactant: N#Cc1cccc(C=CC(=O)c2ccccc2)c1
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)NCCN1CCOCC1
Agent: CC(=O)[O-]
Solvent: CC(=O)CC(C)C
Product: Cc1nc(-c2ccccc2)cc(-c2cccc(C#N)c2)c1C(=O)NCCN1CCOCC1
Reaction time: 4 h
Yield: 29.7 %

Procedure:
To a solution of 3-(3-cyanophenyl)-1-phenyl-2-propen-1-one (4.7 g) in methyl isobutyl ketone (50 ml) were added N-(2-morpholinoethyl)acetoacetamide (6.5 g) and ammonium acetate (2.3 g), and the mixture was stirred at 80° to 85° C. for 4 hours. After cooling, the reaction mixture was washed with water and dried over magnesium sulfate. To the filtrate containing 1,4-dihydro-3-(2-morpholinoethylcarbamoyl)-2-methyl-4-(3-cyanophenyl)-6-phenylpyridine and 3-(2-morpholinoethylcarbamoyl)-2-methyl-4-(3-cyanophenyl)-6-phenylpyridine was added manganese dioxide (20 g) and the resultant mixture was stirred at 80° to 85° C. for 1.5 hours. Manganese dioxide was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in diluted hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 8.0 with 20% aqueous solution of potassium carbonate, and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was subjected to a column chromatography on silica gel and eluted with a mixture of ethyl acetate and tetrahydrofuran (8:2 V/V). The fractions containing the desired compound were combined and concentrated in vacuo. The residue was recrystallized from diethyl ether to give 3-(2-morpholinoethylcarbamoyl)-2-methyl-4-(3-cyanophenyl)-6-phenylpyridine (2.55 g).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[O:1][C:42]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:43])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC(=O)N3CCOCC3)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 4-morpholine-carbonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH:8]3[CH:14]([NH2:15])[C:13]([CH3:16])([C:5]=2[CH:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH2:19](C12C(=O)C(CC3C=CC(OC)=CC=31)CCCC2)C>>[CH2:16]([C:13]12[C:14](=[NH:15])[CH:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=31)[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH3:19]
Reactant: COc1ccc2c(c1)C1(C)CCCCC(C2)C1N
Reactant: CCC12CCCCC(Cc3ccc(OC)cc31)C2=O
Product: CCC12CCCCC(Cc3ccc(OC)cc31)C2=N

Procedure:
Using a procedure analogous to that described in Example XXVIIA for the preparation of 6,7,8,9,10,11hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine there is obtained from 3.5 g. of 5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one, oxime 1.6 g. of the title product, b.p. 150-160° C. (0.5 mm.).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:27]=[C:26](F)[C:25]([Cl:29])=[CH:24][C:20]=2[C:21]([OH:23])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].CNC.C[N-]C>C1COCC1.CCCCCC>[C:5]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:27]=[CH:26][C:25]([Cl:29])=[CH:24][C:20]=2[C:21]([Cl:3])=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1)([CH3:7])([CH3:8])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)O)cc1
Agent: CNC
Agent: C[N-]C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1

Procedure:
Thionyl chloride (220 mL, 3.02 mol) was introduced to a 1 L round bottom flask fitted with a magnetic stir bar. 2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-4-fluoro-benzoic acid (22 g, 57.0 mmol) was added under rapid agitation and the mixture was heated at reflux under a nitrogen atmosphere. The reaction progress was monitored by the addition of a few drops of the reaction mixture into ˜1 mL of 2.0 M dimethylamine in THF, followed by LCMS analysis. Complete conversion to the dimethyl amide was observed at 1.25 h. The crude mixture was subsequently concentrated in vacuo to produce an orange oil. Hexane (50 mL) was added to the flask and the mixture concentrated again to afford 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-benzoyl chloride as an orange crystalline solid which was utilized direction in the next step.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][CH2:12]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([F:19])([F:18])[CH2:11][CH2:12][N:24]1[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[C:20]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCC(F)(F)COCc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC(F)(F)COCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-benzyloxy-2,2-difluoro-4-methanesulfonyloxybutane (63.44 g, 0.216 moles), potassium phthalimide (44 g, 0.238 moles) and dry DMF (500 mL), distilled from CaH2) is stirred and heated at 100° C. After a short time the mixture solidifies, and an additional dry DMF (500 mL) is added. Upon heating at 90°-100° C. for another 20 hours, salts are removed by filtration, and the DMF is distilled under vacuum (oil pump). The residue is dissolved in CH2Cl2 (800 mL) and washed with 1N KOH (twice) and 1N HCl (twice). Drying (Na2SO4) and evaporation yields N-(4-benzyloxy-3,3-difluorobutyl)-phthalimide as a yellow oil: 68.5 g (92%).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:19](OC)=[O:20])[CH2:17][OH:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3]O.[NH2:33][NH2:34].[OH2:35].CCOCC>CO>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:17]([NH:33][NH2:34])=[O:18])[CH2:19][OH:20])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:35]
Reactant: NN
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: O
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)NN
Reaction time: 18 h

Procedure:
2.00 Grams of Z-Ser-Leu-Ser-OCH3 was dissolved in 40 ml of methanol, then 1.10 ml of 100%-NH2NH2.H2O was added to the solution under ice-cooled condition, and the reaction mixture was allowed to stand at a room temperature for 18 hours. After completion of the reaction, the solvent was removed by distillation under a reduced pressure, and the residue obtained was solidified by adding ether, then an excess of NH2NH2.H2O was removed by adding water, then reprecipitated from methanol-ethyl acetate to obtain 1.91 g of the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH2:6][OH:7])[CH2:4][OH:5].CO[C:17](OC)([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C=O)C.C(OCC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[OH:1][CH2:2][C:3]1([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:6][O:7][C:17]([CH3:19])([CH3:18])[O:5][CH2:4]1
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)C(=O)NC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO)(NC(=O)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
A solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (15.7 g, 130 mmol) and di-tert-butyl dicarbonate (31.1 g, 143 mmol) in methanol (400 mL) and water (40 mL) was stirred at ambient temperature for 72 h. The contents of the flask were evaporated and the resulting white solid dissolved in minimal hot ethyl acetate and allowed to recrystallise overnight. The crystals were filtered and washed with petroleum ether to give N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)pivalamide (26.5 g, 130 mmol, 100%) as fluffy, white needles. To a solution of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)pivalamide (9.50 g, 42.0 mmol) and 2,2-dimethoxypropane (16.0 mL, 129 mmol) in DMF (100 mL) was added pyridinium para-toluenesulfonate (0.540 g, 2.15 mmol) at RT. The reaction was stirred at ambient temperature for 15 h. after which time the reaction was complete by TLC (petroleum ether:ethyl acetate, 4:1, visualised with Erlichs). The reaction mixture was diluted with diethyl ether, washed three times with aqueous sodium bicarbonate, once with brine, dried over magnesium sulphate, filtered and evaporated. The resulting semi-solid was recrystallised from minimal hot petroleum ether to give N-(5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-yl)pivalamide (7.32 g, 65%) as white crystals. 1H NMR (CDCl3) δ 5.31 (br s, 1H, NH), 4.18 (br s, 1H, OH), 3.85 (d, J=11.5 Hz, 2H), 3.80 (d, J=11.5 Hz, 2H), 3.70 (d, 6.6 Hz, 2H), 1.46 (s, 12H), 1.44 (s, 3H). 13C NMR (CDCl3) δ 154.0, 98.8, 80.5, 64.8, 64.5 (2C), 53.4, 28.3 (3C), 26.9, 20.3.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=1)[CH:15]=[O:16]>CS(C)=O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:15]2[CH2:2][O:16]2)[CH:17]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Brc1cncc(C2CO2)c1
Yield: 31.1 %

Procedure:
To a solution of trimethylsulfoxonium iodide (7.10 g, 32.3 mmol) in DMSO (25 mL) were added, sodium hydride (0.774 g, 32.3 mmol, 95%) (portionwise) at ambient temperature, followed by 5-bromonicotinaldehyde (3.00 g, 16.1 mmol) in DMSO (15 mL). The reaction mixture was quenched by the addition of cold ice water (200 mL) and the resulting mixture extracted with ethyl acetate (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the residue which was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 40 g, 25% EtOAc/hexanes) to obtain 3-bromo-5-(oxiran-2-yl)pyridine (1.00 g, 31.0%). LCMS Condition B-26: retention time 1.83, [M+2]=202.2. 1H NMR (400 MHz, CDCl3) δ 2.79 (dd, J=2.4 Hz, J=5.2 Hz, 1H), 3.20 (dd, J=4.0 Hz, J=5.2 Hz, 1H), 3.87 (dd, J=2.4 Hz, J=4.0 Hz, 1H), 7.69 (dd, J=1.6 Hz, J=2.0 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H).
Reaction SMILES: IC.[H-].[Na+].[C:5]([CH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])([CH3:8])([CH3:7])[CH3:6].[C:26](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:5]([CH:9]1[C@@:13]([CH3:26])([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]1[C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C[C@H](c1ccccc1)N1C(=O)CC(C(=O)O)C1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C(=O)C[C@](C)(C(=O)O)C1C(C)(C)C
Temperature: 30 °C
Yield: 33.7 %

Procedure:
Under a nitrogen gas atmosphere, iodomethane (26.0 mL, 59.28 g, 0.418 mol) and sodium hydride (oil content: 55%, 11.35 g, 0.260 mol) were sequentially added at room temperature to a solution of t-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (30.05 g, 0.104 mol) in N,N′-dimethylformamide (210 mL) with stirring. When the internal temperature reached to about 50° C., the mixture was cooled to 30° C. in an ice-water bath. Subsequently, the bath was changed to a water bath having an external temperature of 17° C., followed by stirring for 23 hours. The reaction mixture was poured into cold aqueous citric acid (a mixture of 10% citric acid (1 L) and ice (500 g)), followed by stirring for 30 minutes and extracting with ethyl acetate (800 mL, 500 mL). The organic layers were combined. The combined organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and filtration. The filtrate was evaporated to dryness under reduced pressure. The residue was purified through flash silica gel column chromatography (eluent; hexane:ethyl acetate=5:1 to 4:1), to thereby yield the title compound as white solid (10.63 g, 33.7%) as a high-polar isomer. In addition, t-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (14.91 g, 47.3%) was produced as a low-polar isomer.
Reaction SMILES: Cl.N[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+].O>C(OCC)C>[OH:15][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccccc1
Yield: 41.8 %

Procedure:
L-Phenylalanine hydrochloride (12.2 g, 60.5 mmol) was added to 183 ml of 5% sulfuric acid (sulfuric acid: 96.0 mmol) and the solution was treated with a mixture of 8.35 g (121 mmol) of sodium nitrite and 44.5 g of water at 0° C. for 3 hours. Thereafter, 100 ml of diethyl ether was added to the reaction mixture and, after stirring, the organic phase was separated (extract 1). Further, 50 ml of diethyl ether was added to the aqueous phase and, after stirring, the organic phase was separated (extract 2). The extracts 1 and 2 were combined. The combined extract (95.0 g) contained 4.2 g of (2S)-2-hydroxy-3-phenylpropionic acid (yield 42%, optical purity 92.6% ee). The proton concentration (normality) in the reaction of this comparative example was 1.4 mol/kg, the amount of the protonic acid was 4.0 equivalents (relative to L-phenylalanine), and the reaction temperature was 0° C.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][C:6]([C:9](=[N:27][O:28][CH3:29])[C:10]([NH:12][CH:13]2[C:25](=[O:26])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cnc(NC=O)s3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cnc(N)s3)[C@H]2SC1
Yield: 73.1 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.9 g) and conc. hydrochloric acid (1.36 g) in methanol (190 ml) was stirred at ambient temperature for 1.3 hours. After the reaction mixture was evaporated to dryness, the residue was suspended in water (35 ml) and then adjusted to pH 7-8 with 10% aqueous sodium hydroxide, followed by adjusting to pH 3 with 10% hydrochloric acid. The precipitated solid was collected by filtration, washed with water and then dried to give 7-[2-(2-aminothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.3 g), mp>250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl>C(Cl)Cl>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture consisting of 2-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid (1-38, 10 mmol), 4-t-butylbenzylamine (12 mmol) and EDC (12 mmol) in CH2Cl2 (20 mL) was stirred for 12 h at room temperature. The reaction mixture was filtered off and the filtrate was concentrated. the residue was purified by flash column chromatography on silica gel using EtOAc:hexanes as eluant to obtain N-(4-tert-butylbenzyl)-2-[3-fluoro-4-(metylsulfonylamino)phenyl]propionamide (1-51, KMJ-372) having following physicochemical properties:
Reaction SMILES: FC1C=CC=CC=1CN1C=C(C2C3C(=NC=C(C4C=C(NS(C)(=O)=O)C=CC=4)C=3)NC=2)C=N1.I[C:35]1[C:43]2[C:38](=[N:39][CH:40]=[C:41]([C:44]3[CH:45]=[CH:46][C:47]([O:55][CH3:56])=[C:48]([S:50]([NH:53][CH3:54])(=[O:52])=[O:51])[CH:49]=3)[CH:42]=2)[N:37]([S:57]([C:60]2[CH:66]=[CH:65][C:63]([CH3:64])=[CH:62][CH:61]=2)(=[O:59])=[O:58])[CH:36]=1.[F:67][C:68]1[CH:69]=[C:70]([CH:88]=[C:89]([F:91])[CH:90]=1)[CH2:71][N:72]1[C:76]([CH3:77])=[C:75](B2OC(C)(C)C(C)(C)O2)[C:74]([CH3:87])=[N:73]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:67][C:68]1[CH:69]=[C:70]([CH:88]=[C:89]([F:91])[CH:90]=1)[CH2:71][N:72]1[C:76]([CH3:77])=[C:75]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:44]4[CH:45]=[CH:46][C:47]([O:55][CH3:56])=[C:48]([S:50]([NH:53][CH3:54])(=[O:52])=[O:51])[CH:49]=4)[CH:42]=3)[N:37]([S:57]([C:60]3[CH:66]=[CH:65][C:63]([CH3:64])=[CH:62][CH:61]=3)(=[O:59])=[O:58])[CH:36]=2)[C:74]([CH3:87])=[N:73]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 77.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example 1, 5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (200 mg, 0.335 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (146 mg, 0.418 mmol) in sodium carbonate (100 mg, 1.0 mmol) Pd(PPh3)2Cl2 (11.7 mg, 0.011 mmol), Toluene/ethanol/water (20/10/2 ml) to afford 180 mg (77.9% yield) of the titled compound after purification by column (SiO2-eluted by 0.4 to 1.2% MeOH in CHCl3). MS: m/z=692.0 (M+1).
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[NH2:37][C:38]([NH:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:39]>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:44]2[CH2:45][CH2:46][CH:41]([NH:40][C:38]([NH2:37])=[O:39])[CH2:42][CH2:43]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: NC(=O)NC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(NC(N)=O)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-(aminocarbonyl)aminopiperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxy-benzyloxy) phenyl]-5-[4-(aminocarbonyl)aminopiperidin-1-yl]pentan-1-one hydrochloride, m.p. 220°-224° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([S:18][CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[O:26])[N:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[C:12]1([S:18]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[N:21]=2)=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)c2noc(CSc3ccccc3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2noc(CS(=O)c3ccccc3)n2)cc1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of 5.14 g of m-chloroperoxybenzoic acid (85%) in 125 ml CH2Cl2 was added dropwise to a solution of 7.5 g of 5-phenylthiomethyl-3-(4-toluoyl)-1,2,4-oxadiazole in 150 ml CH2Cl2 at -70° under N2. The temperature was maintained below -65° during the addition by controlling the addition rate and stirring was continued for 30 minutes after the addition while maintaining the temperature below -65°. The resulting mixture was poured directly into a separatory funnel containing 250 ml of 10% Na2S2O3 and 500 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 5.3 g (64%) of needles, m.p. 97°-99°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][C@H:10]1[CH3:14])=[O:25]
Reactant: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1C(=O)CCl

Procedure:
Protocol S was followed using 1-(4-Chloro-phenyl)-3-(R)-methyl-piperazine, Et3N, chloroacetyl chloride and methylene chloride. Column chromatography afforded the title compound
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl.CO>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:39]([NH:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:40])[CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: Fc1cccc2c1CCNC2c1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CCc2c(F)cccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluoro-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.27 g, 0.897 mmol) and diisopropylethylamine (0.2 mL, 0.919 mmol) in anhydrous dichloromethane (6 mL) was treated with 4-fluorophenyl isocyanate (0.105 mL, 0.934 mmol) and stirred at RT for 16 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product which was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give 5-fluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide as a colorless oil. MS (ESI pos. ion) m/z: 433 (M+H).