Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][C@H:25]1[CH2:30][NH:29][C@H:28]([CH3:31])[CH2:27][NH:26]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:26]2[CH2:27][C@@H:28]([CH3:31])[NH:29][CH2:30][C@@H:25]2[CH3:24])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(Cl)c2ccc(Br)cc2)c1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Yield: 62 %

Procedure:
The crude benzhydryl chloride (approx. 135 mmol) was combined with 46.3 g (405 mmol) of trans-2,5-dimethylpiperazine (purified by recrystallization from toluene to mp=115°-119° C.) and 30 mL of toluene and heated at reflux overnight under nitrogen. The toluene was removed under vacuum, and the residue was redissolved in 2000 mL of diethyl ether and washed with 500 mL of 1.0M sodium hydroxide and 1000 mL of water. The ether solution was dried over sodium sulfate and the solvent removed to give a dark oil. The product was purified by chromatography on silica gel with 1-10% ethanol in dichloromethane to give 41.0 g (62%) of (±)-trans-1-(4-bromo-α-(3-(tert-butyldimethylsilyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a 1:1 mixture of diastereomers. NMR (300 MHz, CDCl3); δ0.15 (s, 6H); 0.9 (m,12H); 1.2 (d,J=6 Hz,3H); 1.4-1.6 (m,2H); 2.2-3.0 (m,5H); 5.2 and 5.3 (s,1H); 6.6-7.5 (m,8H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[C:4]([CH3:9])=[N:3]1.[C:10]([O-])(=[O:12])[CH3:11].[K+].C(OC(=O)C)(=O)C>CCOC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:10](=[O:12])[CH3:11])[C:4]([CH3:9])=[N:3]1
Reactant: Cc1nn(C)c(C)c1N
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A suspension of 1,3,5-trimethylpyrazol-4-amine (1 g, 7.99 mmol), potassium acetate (0.862 g, 8.79 mmol) and acetic anhydride (0.889 mL, 7.99 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(1,3,5-trimethylpyrazol-4-yl)acetamide (1.390 g, 104%) as a off-white solid. Mass spectrum: MH+ 168
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1
Reactant: CN1CCN(c2ncccc2C(=O)O)C(c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ncccc2CO)C(c2ccccc2)C1
Yield: 88.5 %

Procedure:
In 150 mL of THF was dissolved 10.2 g of 2-(4-methyl-2-phenylpiperazin-1-yl) pyridine-3-carboxylic acid under nitrogen atmosphere. To 300 mL of THF was added 10.2 g of lithium aluminum hydride, and the above THF solution was added in a thin stream to the mixture over 50 minutes under reflux. After refluxing the mixture for 4 hours, the mixture was cooled to 0° to 5° C., and 40.5 mL of water was gradually added in a thin stream thereto. Aluminum hydroxide was separated therefrom by filtration, and the filtrate was concentrated with an evaporator. The residue was allowed to recrystallize from an ether, to give 8.6 g of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol. Its yield was 98%.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CN(C)C=O.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>C(OCC)(=O)C.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>[CH2:17]([C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH:16]=[CH2:15]
Reactant: Nc1ccc(F)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(F)ccc1N
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A round-bottom flask was fitted with a condenser, stirbar and septa and flushed with nitrogen. 2-bromo-4-fluoro aniline (9.70 g, 40.9 mmol), N,N-dimethylformamide (100 mL), allyltributyltin (15.0 mL, 48.9 mmol) and Pd(PPh3)4 (1.50 g, 1.30 mmol) were added, giving a mixture that was warmed to 80° C. After 17 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (300 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×150 mL). The aqueous washes were combined and extracted with ethyl acetate (50 mL). The organic extracts were then combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 35% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([OH:19])[CH:14]([N+:16]([O-])=O)[CH3:15])[CH:10]=[CH:9][N:8]=1>[Pd].C1COCC1.CO>[NH2:16][CH:14]([CH3:15])[CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][CH3:5])[CH:12]=1)[OH:19]
Reactant: COc1cc(C(O)C(C)[N+](=O)[O-])ccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)N)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium formate (1.13 g, 18 mmol) and palladium on charcoal (10%, 175 mg) is added to a solution of 1-(2-methoxypyridin-4-yl)-2-nitro-propan-1-ol (760 mg, 3.6 mmol) in 17.5 ml THF and 17.5 ml methanol. The reaction mixture is stirred overnight at room temperature, filtered through a path of cellites and concentrated. Yield 620 mg of a racemic mixture of two diastereomers, 95%.
Reaction SMILES: CC([NH:4]P([O:9][C:10]1[CH:15]=CC(Cl)=CC=1Cl)(OC)=S)C.CC([N:33]=[C:34]=[O:35])(C1C=CC=C(C([N:30]=[C:31]=[O:32])(C)C)C=1)C.[OH-].[Na+].CCN(C(C1C=CC=C(C)C=1)=O)CC>O.CC(=O)OCC>[NH2:30][C:31]([O:9][CH2:10][CH3:15])=[O:32].[NH2:4][C:34]([NH2:33])=[O:35]
Reactant: CC(C)(N=C=O)c1cccc(C(C)(C)N=C=O)c1
Reactant: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(N)=O
Product: NC(N)=O
Reaction time: 0.08 h

Procedure:
190.8 g of Rucoflex XS-5570-55, 102.9 g of Rucoflex S-1011-55 and 6.7 g of DMPA are reacted with 73.2 g of TMXDI in the presence of the T-12 at 85° C. for 4 hours to prepare a prepolymer. 3.4 g of sodium hydroxide and 1.83 g of EA are dissolved in 660 g of water, and then the prepolymer is dispersed by adding the aqueous solution containing NaOH and EA. After 5 minutes, a solution of 4.08 g of DETA in 51 g of water is added and stirring is continued for 15 minutes to form the aqueous poly(urethane/urea) dispersion. A finely divided dispersion having a solids content of 34.9% and a pH of 7.95 is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OCCCC)=O)[CH2:8][CH2:7]1.[CH:25]([O-:27])=[O:26].[NH4+].[C:29]1([CH3:35])[CH:34]=CC=C[CH:30]=1.O>[Fe]>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([O:5][CH:6]2[CH2:7][CH2:8][N:9]([C:25]([O:27][C:29]([CH3:35])([CH3:34])[CH3:30])=[O:26])[CH2:10][CH2:11]2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C[O-]
Reactant: CCCCOC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Reactant: Cc1ccccc1
Agent: [Fe]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)c(Cl)c2)CC1
Yield: 79 %

Procedure:
tert-Butyl 4-(4-amino-3-chlorophenoxy)piperidine-1-carboxylate was prepared in the same manner as tert-Butyl 4-(3-(4-amino-5-chloro-2 methylphenoxy)propyl)piperazine-1-carboxylate. Reaction of N-Boc-4-hydroxypiperidine with sodium hydride in anhydrous THF, followed by 2-chloro-4-fluoro-1-nitrobenzene (commercially available from Acros) gave tert-butyl 4-(3-chloro-4-nitrophenoxy)piperidine-1-carboxylate. Reduction of the tent-butyl 4-(3-chloro-4-nitrophenoxy)piperidine-1-carboxylate using ammonium formate and iron dust in refluxing toluene-water mixture gave tert-butyl 4-(4-amino-3-chlorophenoxy)piperidine-1-carboxylate in 79% yield. 1H-NMR (400 MHz, CDCl3): δ 6.88 (m, 1H), 6.70 (m, 2H), 4.26 (m, 1H), 3.79 (s, br, 2H), 3.68 (m, 2H), 3.30 (m, 2H), 1.86 (m, 2H), 1.71 (m, 2H), 1.56 (s, 9H). MS (EI): 227 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[CH:8][C:7]([OH:21])=[CH:6][CH:5]=2.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])([CH3:28])[CH3:27])[CH:8]=2)[NH:3][C:2]=1[CH3:1])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Yield: 49 %

Procedure:
2-Methyl-3-benzyloxycarbonyl-5-hydroxyindole (10.0 g, 35.54 mmol, 1.0 eq) was dissolved in acetonitrile (250 mL), followed by ethyl-2-bromo-isobutyrate (7.63 g, 39.10 mmol, 2.0 eq). Potassium carbonate (9.82 g, 71.08 mmol, 8.7 eq) was also added followed by potassium iodide (catalytic amount). The reaction mixture was refluxed for 24 hours. The reaction mixture was washed with brine and extracted with ethyl acetate (3×100 mL) and dried over sodium sulfate. The product was chromatographed in a hexane to hexane/ethyl acetate 7:3. 6.88 g of the product was obtained, 48% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(CC(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
0.75 mole (175 g) of 4'-chloro-4-hydroxy-benzophenone, 1.5 l of methylisobutylketone, 0.975 mole (134 g) of K2CO3 and 0.8 mole (145 g) of ethyl 2-bromopropionate are placed in a 2-liter flask. The mixture is heated at reflux for 8 hours with vigorous agitation whereupon the reaction mixture is cooled and filtered on a Buchner funnel. The solvent is then evaporated under vacuum and the residue distilled; the desired ester is recovered at 198° to 201° C. under 0.1 mm of mercury. Yield 190 g (76%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3C=[CH:19][C:18](OC)=[CH:17][C:16]=3[CH3:23])=[CH:10][C:11]=2[CH3:13])[C:6](=[O:24])[CH:5]([C:25]([O:27]C)=[O:26])[C:4]1=[O:29])[CH3:2].[OH-].[Na+].C(#[N:34])C>O1CCOCC1.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([NH:14][C:15]3[C:16]([CH3:23])=[CH:17][CH:18]=[CH:19][N:34]=3)=[CH:10][C:11]=2[CH3:13])[C:6](=[O:24])[CH:5]([C:25]([OH:27])=[O:26])[C:4]1=[O:29])[CH3:2]
Reactant: CCN1C(=O)C(C(=O)OC)C(=O)c2cc(Nc3ccc(OC)cc3C)cc(C)c21
Reactant: CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)C(C(=O)O)C(=O)c2cc(Nc3ncccc3C)cc(C)c21
Temperature: 60 °C

Procedure:
Methyl 1-ethyl-6-(4-methoxy-2-methylphenylamino)-8-methyl-4-oxo-1,4-dihydroquinolone-3-carboxylate (30 mg) was dissolved in 5 ml of dioxane, 2.5 equivalents of a 1 N NaOH solution were added, and the mixture was heated at 60° C. for 4 h. Removal of the solvent in vacuo was followed by chromatography on an HPLC system to purify the product. The pure product was isolated from the reaction solution by chromatography on an HPLC system. This entailed use of a Merck Purospher-RP18 column and an acetonitrile:water mixture as eluent; the initial acetonitrile content was 15% and rose to 95% over the course of 20 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([OH:9])=[C:4]([Br:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([Br:10])[C:5]=1[O:9][CH3:11])[NH2:1]
Reactant: Nc1cc(Br)c(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Br)cc(N)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-bromo-3-methylbenzoic acid (8.6 g, 40.0 mmol) in CH2Cl2 was added DMF (0.4 mL), followed by oxalyl chloride (3.7 mL, 42 mmol) slowly over 10 minutes by syringe. The reaction was stirred for 1 hour at room temperature, and then concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])S(Cl)(=O)=O.[CH2:9]([O:11][C:12]([C:14]1[NH:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:13])[CH3:10].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O>[CH3:19][C:17]1[CH:18]=[C:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[NH:15][C:16]=1[C:2]([F:8])([F:7])[F:1]
Reactant: CCOC(=O)c1cc(C)c[nH]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(C)c(C(F)(F)F)[nH]1
Temperature: 25 °C
Reaction time: 144 h
Yield: 44.4 %

Procedure:
Trifluoromethanesulfonyl chloride (40.7 mL, 381.67 mmol) was added to the argon degassed solution of ethyl-4-methyl-1H-pyrrole-2-carboxylate (40 g, 254.45 mmol), K2HPO4 (132.9 g, 763.35 mmol), dichlorotris(1,10-phenanthroline) ruthenium (II) hydrate (3.6 g, 5.08 mmol) in acetonitrile. The reaction mixture was stirred for 6 d at room temperature adjacent to a fluorescent light bulb (23 W). The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×700 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 20% ethyl acetate/hexane; Rff-value 0.7) to afford title compound (25 g, 71.13% yield, white color solid).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:11][CH2:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[C:1]1([C:7]2[C:13]3[N:12]([CH:16]=[CH:15][N:14]=3)[CH2:10][CH2:11][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1CC1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: C1=C(c2ccccc2)c2nccn2CC1

Procedure:
Combine 25 g (0.17 mol) of cyclopropyl phenyl ketone with 50 g (0.73 mol) of imidazole, and heat to 200° C. for 18 hr. Isolation from 200 g of silica gel using methylene chloride, followed by crystallization from ether provides the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:41])[C@@H:35]([NH2:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:40][C@@H:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]([OH:33])=[O:41])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@H](C(=O)O)C(C)(C)C)nc(CC4CCCC4)c3c2)cc1
Yield: 87.6 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3,3-dimethyl-butyric acid methyl ester HCl (24.5 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed by sonication at rt for 3 h and then usual work up as described in general procedure C afforded 54.3 mg of the title compound as a white solid.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[C:20][CH3:21].C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:15]=[CH:16][C:9]=1[O:8][CH3:7])[C:19]#[C:20][CH3:21]
Reactant: CC#CCOc1cc(C=O)ccc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC#CCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 69.3 %

Procedure:
Piperidine (0.35 mL, 3.5 mmol) was added to a suspension of 4-methoxy-3-(but-2-ynyl)oxybenzaldehyde (0.72 g, 3.5 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.72 g, 3.2 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-{[3-(3-(But-2-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (0.81 g, 69%) was obtained as a yellow crystalline solid; mp 170-171° C.; δH (400 MHz, DMSO-d6) 1.82 (t, J=2.0 Hz, 3H, CH3), 3.80 (s, 3H, OCH3), 4.80 (d, J=2.0 Hz, 2H, OCH2), 6.74 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, 8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.27 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz DMSO-d6) 3.2, 55.6, 56.5, 74.7, 83.7, 111.9, 112.3, 116.6, 120.0, 120.3, 122.7, 123.2, 127.1, 131.2, 134.1, 141.1, 141.6, 146.9, 151.0, 164.1, 169.5; HRMS (ESI) calculated for C21H19NO5 [M+Na]+ 388.1155. found 388.12158; vmax 749, 1261, 1512, 1584, 1659, 2917, 3239, 3520 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[C:17]1([C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:31]2[CH2:30][CH2:29][CH:28]([C:26]3[O:27][C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:24][N:25]=3)[CH2:33][CH2:32]2)=[O:16])[O:4][N:3]=1
Reactant: c1ccc(-c2nnc(C3CCNCC3)o2)cc1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCC(c3nnc(-c4ccccc4)o3)CC2)c1C
Yield: 37.9 %

Procedure:
A solution of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (293 mg, 1.02 mmol), 4-(5-phenyl-1,3,4-oxadiazol-2-yl)piperidine (234 mg, 1.02 mmol), diisopropylethylamine (0.387 ml, 2.05 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 142 mg (37.9%) of the desired product as a solid.
Reaction SMILES: [C:1]1(=[O:34])[N:5]([CH2:6][C:7]([N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2OC(F)(F)F)=[O:8])[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]12.[CH2:35]([O:37][C:38](C1C=CC=CC=1NC(=O)CN1C(=O)C2=CC=CC=C2C1=O)=[O:39])[CH3:36].[H-].[Na+].BrCC(OC(C)(C)C)=O>>[CH2:35]([O:37][C:38]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:7](=[O:8])[CH2:6][N:5]1[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]2[C:1]1=[O:34])=[O:39])[CH3:36]
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1ccccc1NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
tert-Butyl 2-[N-(2-ethoxycarbonylphenyl)-2-phthalimidoacetamido] acetate may be prepared in a manner similar to that described in Example 4 for the preparation of tert-butyl 2-[2-phthalimido-N-(2-trifluoromethoxyphenyl)acetamido]acetate, but starting with N-(2-ethoxycarbonylphenyl)-2-phthalimidoacetamide (7.7 g), an oily suspension (50% by weight) (1.26 g) of sodium hydride and tert-butyl bromoacetate (4.3 g). After recrystallisation in diisopropyl ether, tert-butyl 2-[N-(2-ethoxycarbonylphenyl)-2-phthalimidoacetamido]acetate (6.1 g), m.p. 127° C., is thereby obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]C(O)=O)([O-:20])=[O:19].N1CCCCC1.CCCCCC>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=Cc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (8.09 g, 34.5 mmol) and 2-nitrophenylacetic acid (9.40 g, 51.9 mmol) in xylene (60 ml) was added piperidine (0.3 ml) and the mixture was heated under reflux for 26 hrs while removing water producing with the progress of reaction. After allowing to stand overnight, hexane was added to afford as crystals 2,6-di-tert-butyl-4-(2-nitrostyryl)phenol (7.67 g, 62.9%).