Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8]C(=O)OCC2C=CC=CC=2)=[CH:6][N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[N:5][CH:6]=1
Reactant: O=C(Nc1cnc(-c2ccccn2)nc1O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(-c2ccccn2)nc1O
Yield: 41.1 %

Procedure:
Benzyl 4-hydroxy-2-(pyridin-2-yl)pyrimidin-5-ylcarbamate (10-d) (1 g, 3.1 mmol) in methanol (20 ml) was hydrogenated under 1 atm of hydrogen in the presence of Pd/C (500 mg) overnight. The mixture was filtered and the filtrate was concentrated to provide the crude product, 10-e (240 mg).
Reaction SMILES: [S:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[N:15]([O-])=O.[Na+].O.[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[Na+]>Cl.O>[F:20][P-:21]([F:26])([F:25])([F:24])([F:23])[F:22].[S:1]([C:8]1[CH:14]=[CH:13][C:11]([N+:12]#[N:15])=[CH:10][CH:9]=1)([C:4]([F:5])([F:6])[F:7])(=[O:3])=[O:2]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 22.5 g (0.1 mole) of 4-triflylaniline in HCl/H2O (50:50) is cooled in an ice bath to about 10° C., and 6.9 g (1 mole) of sodium nitrite in a minimum amount of water is added slowly to the mixture, while maintaining the temperature below 10° C. The reaction then is warmed to room temperature and stirred for 15 additional minutes. Sodium hexafluorophosphate (16.7 g, 0.1 mole) is added in portions, and the mixture is stirred for 10 minutes more. The solid product is collected by vacuum filtration and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][CH2:13][O:14][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CCOc2cccc(Oc3ccc(Cl)cc3)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A solution consisting of 3-(2-hydroxy-ethyl)-azetidine-1-carboxylic acid tert-butyl ester (4.39 g, 21.8 mmol), 3-(4-chloro-phenoxy)-phenol (4.81 g, 21.8 mmol) and THF (40 mL) was cooled at 0° C., treated with polymer supported triphenyl phosphine (10.9 g, 32.7 mmol) then diisopropyl azodicarboxylate (6.62 g, 32.7 mmol) dropwise over 30 min. After stirring for 15 min at 0° C., the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered, the filtrate evaporated, and the residue purified (FCC) to give the title compound as a clear oil (6.39 g, 73%). MS (ESI+): calcd. for C22H26ClNO4, 403.16. m/z found, 426.2 (M+Na)+. 1H NMR (d6-DMSO): 7.43 (d, J=9.0 Hz, 2H), 7.28 (t, J=8.2 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.72 (dd, J=8.3, 1.5 Hz, 1H), 6.59-6.55 (m, 2H), 3.98-3.84 (m, 4H), 3.59-3.50 (m, 2H), 2.70-2.58 (m, 1H), 2.02-1.89 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1cc(Br)ccc1F
Product: O=C(O)c1cc(-c2ccc(F)cc2)ccc1F

Procedure:
5-Bromo-2-fluorobenzoic acid (250 mg, 1.14 mmol) was coupled to 4-fluoro-phenylboronic acid (192 mg, 1.37 mmol) using Method E to give the title compound. No chromatography was necessary.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1(O)[C:10]2[C:11]([CH3:31])=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=2[O:8][C:7]1([CH3:33])[CH3:32]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:10]2[C:11]([CH3:31])=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=2[O:8][C:7]1([CH3:33])[CH3:32]
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccco3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccco3)C(C)(C)O4)CC2)cc1
Yield: 67 %

Procedure:
Using 1-(3-(2-furyl)-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 42, the title compound was synthesized in the same manner as in Example 46. Yield 67%. mp. 110–111° C. (ethanol).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH2:13](O)[CH3:14].Cl>O>[OH:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]([O:8][CH2:13][CH3:14])=[O:7])=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)c1cc(C)c(O)c(C)c1

Procedure:
A mixture of 500 mg (3 mmol) of 4-hydroxy-3,5-dimethylbenzoic acid, 20 ml of absolute ethanol and a catalytic amount of anhydrous HCl was heated at reflux for 2 h. The mixture was then poured into excess cold water and the resultant precipitate was filtered. The precipitate was washed with water and dried in-vacuo to give the title compound as a white solid.
Reaction SMILES: [CH3:1][Si:2]([O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:11][CH2:10][CH2:9][N:8]([CH2:7][CH2:6][O:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30]
Reactant: C[Si](C)(C)OCCNCCO[Si](C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCN(CCO[Si](C)(C)C)S(=O)(=O)c1ccccc1
Yield: 88 %

Procedure:
To a mixture of 4.97 g of bis(2-trimethylsilyloxylethyl)amine, 3.03 g of triethylamine and 50 ml of benzene, 3.21 g of benzenesulfonyl chloride was added at 0° C. under stirring. After the addition, the mixture was taken out of the cooling bath and stirred further for 2 hours. The reaction mixture was filtered, mixture was taken out of the cooling bath and stirred further for 2 hours. The reaction mixture was filtered, and the filtrate was subjected to vacuum distillation. The residue was passed through a silica gel column with the eluent varying from benzene to benzen-acetic acid (9:1). As a result, 6.23 g of the title compound was obtained as a colorless oily substance. NMRδ: 7.83 (2H,d,J=8.0 Hz),7.52 (3H,m), 3.72, 3.31 (each 4H,t,J=6.5 Hz), 0.09 (18H,s)
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.C1C=CC=CC=1>O>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 79 %

Procedure:
A mixture of 40 ml (R)-(−)-2,2 dimethyl-1,3-dioxolane-4-methanol, 55 grams of powdered potassium hydroxide and 109 ml hexadecyl bromide were added to 500 ml benzene, and the reaction mixture was stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 150 ml. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. Thereafter, 150 ml water was added, and the obtained mixture was extracted thrice with 150 ml diethyl ether. The combined organic phase was washed with 150 ml water and the solvent was then removed under reduced pressure. The residue was dissolved in 200 ml of a mixture of 90:10:5 (volume/volume) methanol:water:concentrated HCl, and the resulting solution was refluxed for 2 hours. After cooling to room temperature and adding 200 ml water, the product was extracted with 250 ml chloroform. The organic phase was washed consecutively with 250 ml water, 200 ml saturated aqueous solution of sodium carbonate, and again with 200 ml water. The solvent was removed under reduced pressure and the product was then crystallized from hexane (500 ml) to give 81.25 grams (yield 79%) of pure 1-hexadecyl-glycerol, which was dried in a desiccator under reduced pressure.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][CH2:5][C@@H:6]([C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])[CH3:7].O>>[CH2:1]([O:10][C:9](=[O:11])[C@H:8]([C@H:6]([CH2:5][CH3:4])[CH3:7])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH3:2]
Reactant: CCI
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC

Procedure:
The title compound was prepared by the method of Example 8 using ethyl iodide (0.4 mL, 5 mmol) instead of methyl iodide and BOC--L--Ile--OH--0.5 H2O (1.0 g, 4 mmol) instead of the title product of Example 1. Concentration afforded the title compound (1.1 g) as a water white liquid and the structure verified by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C@@H:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:13]([O:15]CC2C=CC=CC=2)=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]>CCO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C@@H:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(N[C@@H](Cc2cccc(C)c2)C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N[C@@H](Cc2cccc(C)c2)C(=O)O)c1
Reaction time: 1 h

Procedure:
A mixture of benzyl (S)-2-(3-methoxycarbonylphenylamino)-3-(3-methylphenyl)-propionate (0.25 g, 0.62 mmol) and 10% Pd/C (0.25 g) in EtOH (25 mL) is hydrogenated at 1 atm for 1 h. The mixture is filtered through celite and evaporated to yield (S)-2-(3-methoxycarbonylphenylamino)-3-(3-methylphenyl)-propionic acid, as a grey oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:38])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[F:37])[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[F:38][C:22]([CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1)=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[F:37])[CH2:25][CH2:26]1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(C(F)(F)F)cc2F)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(C(F)(F)F)cc2F)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 27.1 %

Procedure:
The method of Example 25 was updated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.26 g), tetrahydrofuran (2 ml) and magnesium (22 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (Example 21) (0.1 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: phenyl; solvent: methanol; flow rate: 2 ml/min) to afford 1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(2-fluoro-4-trifluoromethylphenyl)cyclopropane (38 mg, 27%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:21])([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH:23][C:24](=[O:36])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[C:26]=1[O:34][CH3:35])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:31][C:27]1[C:26]([O:34][CH3:35])=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:4]1[C:5]([CH3:22])=[CH:6][C:7]([C:9]([F:21])([C:17]([F:18])([F:19])[F:20])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:36]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1OC
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a solution of N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-methoxy-3-nitrobenzamide (Example I 4.1) (5.1 g, 9.57 mmol) in isopropanol (50 ml) was added tin chloride (6.5 g, 34.5 mmol) at ambient temperature. The mixture was cooled to 0° C. and concentrated aqueous hydrochloric acid (10 ml) was added slowly. The reaction mixture was stirred at 80° C. for 0.5 hours. One third of the total volume of isopropanol was evaporated. Water (100 ml) was added to the concentrated mixture and aqueous sodium hydroxide (4N) was added to adjust the pH to 7 to 8. The aqueous phase was extracted three times with ethyl acetate (3×200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1 to 1:1) to give 3-amino-N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-methoxy benzamide (2.3 g, 48% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: N#Cc1ccc(N(Cc2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-Cyanophenyl)amino]pyrimidine and 4-nitrobenzyl bromide
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([CH2:18][CH3:19])[C:11]=1[N:20]=[C:21]=[S:22])[CH3:9].Cl>>[CH2:8]([C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([CH2:18][CH3:19])[C:11]=1[NH:20][C:21]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[S:22])[CH3:9]
Reactant: CCc1cc(CC)c(N=C=S)c(CC)c1
Reactant: NC1CCCCC1
Agent: Cl
Product: CCc1cc(CC)c(NC(=S)NC2CCCCC2)c(CC)c1
Reaction time: 12 h

Procedure:
20.0 g of cyclohexylamine are taken and 15.0 g of 2,4,6-triethyl-phenyl isothiocyanate are introduced whilst stirring. The reaction takes place with slight evolution of heat. The mixture is left to stand for 12 hours and is then stirred with dilute hydrochloric acid and filtered. The crystalline reaction product is triturated with dilute methanol filtered off, washed and dried; yield 22.0 g; melting point 97°-99° C. The elementary analysis and NMR- and IR-spectrum agree with the assumed structure.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[CH:9]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:8][CH2:7][C:6]=2[CH:22]=1.BrBr>CO>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(Br)c(OC)cc21
Agent: BrBr
Solvent: CO
Product: CCN1C(=O)C(C(=O)OC)CCc2cc(Br)c(OC)cc21

Procedure:
When 7-bromo-3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one was treated with bromine in MeOH at ambient temperature, bromination occurred at 3-position of the 1-benzazepine-2-one ring system. In addition, a transesterification due to the presence of methanol was observed which resulted in a formation of 7-bromo-3(R,S)-methoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[CH:12]([C:13](O)=[O:14])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[C:25]=1[NH2:26])[CH3:23]>>[CH2:22]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH3:32])[C:25]=1[NH:26][C:13]([CH:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]1=2)=[O:14])[CH3:23]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(C)c1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2ccc(C(C)C)cc21
Yield: 50.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 2.34 g of Compound C in place of Compound A and 0.90 g of 2,6-diethylaniline in place of aniline to obtain 1.26 g of Compound 13.
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3](=[O:22])[C:4]([NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][CH:11]=1)([CH2:6][CH3:7])[CH3:5].C(O)C.C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pd]>[Cl:1][CH2:2][C:3](=[O:22])[C:4]([NH:8][C:9](=[O:21])[C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][CH:15]=1)([CH2:6][CH3:7])[CH3:5]
Reactant: CCN(CC)c1ccc(C(=O)NC(C)(CC)C(=O)C(Cl)Cl)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(C(=O)NC(C)(CC)C(=O)CCl)cc1
Reaction time: 3 h
Yield: 76.6 %

Procedure:
The N-(3,3-dichloro-1-ethyl-1-methyl-2-oxopropyl)-4-diethylaminobenzamide (390 mg) prepared in the previous step, 50 mL of ethanol and 75 mg of 5% palladium over charcoal were placed in a hydrogenation bottle and hydrogenated in a Parr apparatus (50 psia, room temperature) for 3 hours. The reaction mixture was filtered through celite and the solvent eliminated under reduced pressure, to yield a crude product. The crude product was dissolved in ethyl acetate and then shaken with saturated aqueous sodium bicarbonate. The phases were separated and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then eliminated using a rotary evaporator, yielding 270 mg N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-diethylamino-benzamide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[CH:6]=[C:7]([NH2:9])[CH:8]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:9][C:7]1[CH:6]=[C:5]([NH:10][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Cl:13])[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=1
Reactant: O=C(O)CCCCl
Reactant: Nc1cc(N)cc(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(NC(=O)CCCCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
Mix 5-(trifluoromethyl)benzene-1,3-diamine (300 mg, 1.70 mmol), 4-chlorobutanoic acid (230 mg, 1.87 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 650 mg, 3.40 mmol), 1-hydroxybenzotriazole (HOBt, 230 mg, 1.70 mmol) and diisopropylethylamine (450 mg, 3.40 mmol) in dichloromethane (10 mL), stir overnight at room temperature. Concentrate the reaction mixture under reduced pressure to obtain the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=1:10) to yield the product (250 mg, 52%). MS: (M+1): 281.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:51][CH2:50]3)=[CH:45][N:44]=2)[C:28]1=[O:59].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([N:49]5[CH2:54][CH2:53][N:52]([CH:55]6[CH2:56][O:57][CH2:58]6)[CH2:51][CH2:50]5)=[CH:45][N:44]=4)[C:28](=[O:59])[N:27]([CH3:26])[CH:32]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 70 °C
Yield: 80.6 %

Procedure:
A mixture of 103b (100 mg, 0.28 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (131 mg, 0.28 mmol), PdCl2(dppf) (25 mg, 0.03 mmol), and K3PO4.3H2O (149 mg, 0.56 mmol) was suspended in THF (10 mL)/H2O (5 mL). After three cycles of vacuum/argon flash, the mixture was heated at 70° C. for 6 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 103c as a yellow solid (150 mg, 60%). LCMS: [M+H]+ 665
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[CH:12]([O-])([O-])OCC.C1(C)C(C)=CC=CC=1>C(O)C>[N:1]1[N:2]=[CH:12][N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[S:4][C:3]=12
Reactant: CCOC([O-])[O-]
Reactant: NNc1nc2ccccc2s1
Solvent: CCO
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)sc1nncn12
Temperature: 105 °C

Procedure:
2-Hydrazinobenzothiazole (125 grams; 0.76 mole), ethyl orthoformate (112.4 grams, 0.76 mole), and 2 liters of xylene were heated together with stirring in a three-necked 5-liter flask. An 8-inch column with a condenser was placed in one neck. The reaction was heated to 105° C. and soon all the solid had gone into solution and the solution turned red. Ethanol began to distill from the reaction and about 125 milliliters of it was collected before the reaction was stopped and allowed to cool to room temperature. The yellow precipitate was collected and triturated with diethyl ether. The s-triazolo(3,4-b)benzothiazole product thus obtained was recrystallized from chloroform, m.p. 174.5°-7° C.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[CH2:3][CH:4]=O.C[O:11][C:12]([CH:14](P(OC)(OC)=O)[NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:13]>>[CH2:19]([O:18][C:16]([NH:15][CH:14]([CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH:6]([CH3:8])[CH3:7])[C:12]([OH:13])=[O:11])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(C)(C)CC=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Product: CC(C)C(C)(C)CCC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
This aldehyde may be converted to the title compound by reaction with N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester, followed by catalytic reduction and hydrolysis by the procedures described in Example 4.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(F)cc1
Product: COC(=O)C(=O)Nc1ccc(F)cc1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-fluoroaniline and methyl chlorooxoacetate.