Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]([NH:14][NH:15][C:16](=[O:18])[CH3:17])=O)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCCl>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:18][C:16]([CH3:17])=[N:15][N:14]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(C(=O)NNC(C)=O)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1cccc2oc(-c3nnc(C)o3)cc12
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a solution (400 ml) of N′-(4-methoxybenzo(b)furan-2-ylcarbonyl)acetohydrazide (15.6 g) in 1,2-dichloroethane were added triethylamine (21 ml) and triphenylphosphine (19.8 g) and the reaction temperature was set to 5° C. To this reaction mixture was added dropwise diethyl azodicarboxylate (40% toluene solution) (33 ml) over 15 min. The reaction temperature was set to room temperature and the mixture was stirred for 1.5 hr and washed with saturated aqueous solution of ammonium chloride. After partitioning, the obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/ethyl acetate) to give the title compound (4.6 g) as pale-yellow crystals.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:36]#[CH:37])[CH:33]=[CH:34][CH:35]=1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:37]#[C:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1cccc(OC)c1
Product: COc1cccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)c1

Procedure:
2-isoquinolin-3-yl-7-(3-methoxyphenyl)ethynyl-chromen-4-one oxime was prepared in 22% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-methoxyphenylacetylene. The title compound was isolated as an orange solid and as a 93/7 mixture of Z/E oxime isomers.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31]C=CC=4C)=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[C:38]([CH3:37])[CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:3]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)c1

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 3-methylbenzylamine, m.p. 130-132° C. MS [(+)ESI, m/z]: 538 [M+H]+ Anal. Calcd for C36H33N3O2: C, 80.12; H, 6.16; N, 7.79. Found: C, 80.01; H, 6.33; N, 7.61.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13]([OH:23])(=[O:22])[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O.B(F)(F)F.CCOCC>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[O:23][C:13](=[O:22])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:7]1
Reactant: O=CCOc1ccc(Cl)cc1Cl
Reactant: O=C(O)C(O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1OC(COc2ccc(Cl)cc2Cl)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution containing 5.1g (0.025 mole) of 2,4-dichlorophenoxyacetaldehyde, 4.25g (0.028 mole) of mandelic acid, and 10.0g (0.07 mole) of boron trifluoride etherate in 250 ml of ether was allowed to stir for 2 hours at ambient temperature, washed with aqueous sodium carbonate and water, dried and concentrated. The residual solid was purified by silica chromatography to give 2.7g of 2-(2,4-dichloro-phenoxymethyl)-5-phenyl-1,3-dioxolan-4-one, trans isomer, having a melting point of 68°-71°.
Reaction SMILES: C(=O)=[N:2][S:3](Cl)(=[O:5])=[O:4].[C:8]([Si:12]([CH3:28])([CH3:27])[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=1)([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[S:3](=[O:4])(=[O:5])([O:23][C:17]1[C:16]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:14]([O:13][Si:12]([C:8]([CH3:9])([CH3:11])[CH3:10])([CH3:27])[CH3:28])=[CH:19][C:18]=1[CH:20]([CH3:22])[CH3:21])[NH2:2]
Reactant: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(C)C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(C)C)c1OS(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
N-Chlorosulfonyl isocyanate (3.43 mL, 39.4 mmol) was added to a warm solution of 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropylphenol (11.59 g, 37.6 mmol) in 400 mL toluene. The resulting solution was heated to reflux for 6 hours and then cooled to room temperature and stirred overnight. The reaction was concentrated in vacuo, and the residue was quenched with ice water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give an orange oil. Chromatography on silica gel gave 6.06 g of 4-(tert-butyl-dimethyl-silanyloxy)-2,6-diisopropylphenyl sulfamate as an orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>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].CN(C)C=O>[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([F:25])([F:26])[C:21]([F:22])([F:23])[F:24])[CH2:9]2)[CH:3]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1cccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccccc2Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 1 of Preparation 6, 2-acetylphenylboronic acid (9.0 mg, 0.06 mmol), Pd(dppf)Cl2 (2.0 mg, cat.) and a 2N sodium carbonate solution (0.5 mL) were added to N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at 80° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: COCCNCCOC
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Product: COCCN(CCOC)c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1
Yield: 84 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and bis(2-methoxyethyl)amine (Aldrich), the title compound was obtained as a white solid in 84% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[Br:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18].CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[C:7]([O:8][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][Br:13])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: O=C(O)CCCBr
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCCBr)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a mixture of pentafluorophenol (3.3 g, 17.96 mmol), 4-bromobutanoic acid (3.0 g, 17.96 mmol) and DMAP (0.440 g, 3.59 mmol) in CH2Cl2 (30 ml), cooled to 0° C., EDAC.HCl (5.2 g, 26.94 mmol) was added in portion. The mixture was then stirred at 0° C. for 30 minutes. Then it was gradually warmed to room temperature and stirred for 480 minutes. Then the mixture was diluted with NaH2PO4 aqueous (5%, 50 ml) and acidified with HCl 1N to pH 3-4. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2×50 ml). The organic phase washed with brine, dried over Na2SO4 and evaporated to give an oil that was purified by flash chromatography (n-Hexane/EtOAc 98:2) to yield 4-bromobutanoic acid pentafluorophenyl ester (5.2 g, 86%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[S:5]C=C[CH:8]=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([CH2:16][C:17]#[N:18])=[O:15].N1CCOCC1.[S]>CC(=O)CC>[NH2:18][C:17]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:16]=1[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:15]
Reactant: N#CCC(=O)c1cccs1
Reactant: CC(=O)c1cccs1
Agent: [S]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: Cc1sc(N)c(C(=O)c2cccs2)c1C
Yield: 44 %

Procedure:
The procedure of Example 1 was followed except that 2-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(thiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 44%; IR (KBr) cm−1: 3390, 3269, 1552, 1429, 1272, 852, 772; 1H NMR (CDCl3):δ1.86 (s, 3H), 2.17 (s, 3H), 5.78(bs, 2H), 7.07 (dd, 1H, J=3.8 and 4.8 Hz), 7.56 (dd, 1H, J=2.8 and 0.8 Hz), 7.58 (dd, 1H, J=5.0 and 0.8 Hz); orange solid, mp: 117-118° C. (petroleum ether).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([NH:3][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(SC)ncc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNc1nc(SC)ncc1C(=O)O
Yield: 92 %

Procedure:
A mixture containing 6.33 g (26.0 mmol) of ethyl 4-ethylamino-2-methylthio-5-pyrimidinecarboxylate, 65 mL (65.0 mmol) of 1N NaOH and 60 mL of ethanol is refluxed for 1 hour. The ethanol is evaporated off under reduced pressure and the residue is diluted in 100 mL of water. 65 mL of aqueous 1N HCl solution are added and the white precipitate formed is drained by suction. The solid is rinsed with water and dried under vacuum. 5.1 g of expected product are obtained in the form of a white solid. Melting point=188°C. Yield=92%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH3:22].C(I)C>O.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH2:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Temperature: 60 °C
Yield: 98 %

Procedure:
A 12-L, 4-necked flask equipped with a reflux condenser, nitrogen inlet, thermocouple, addition funnel, and mechanical stirrer was charged with 400 g 2-Acetamido-5-nitrophenol. The flask was charged with 790 g potassium carbonate and 2.0 L of dimethylformamide (DMF). The mixture was stirred and warmed to 60±2.50° C. 294 g of ethyl bromide or ethyl iodide was added over 10 minutes to one hour while maintaining a 60° C. internal temperature. The reaction mixture was stirred for at least one hour or until the mixture turned yellow and the concentration of 2-Acetamido-5-nitrophenol was less than 1%, if needed additional ethyl bromide or ethyl iodide was added to reduce the concentration of 2-Acetamido-5-nitrophenol present. The mixture was cooled to 20±5° C. 4 L of water was added and while maintaining a 25±5° C. internal temperature. The suspension was stirred for a minimum of 30 minutes and collected by vacuum filtration. The product was washed and the pH monitored for a pH of <8. If the pH was >8, the product was washed with 1.0 L portions of warm water until the pH was <8. The resultant product was washed with heptane and vacuum dried. Yield 98%, strength 98.6%, mp 164-165° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:6]=1[Cl:7]
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1ncn(Cc2ccc3ccccc3c2)c1Cl
Temperature: 85 °C
Yield: 89.6 %

Procedure:
4,5-dichloroimidazole (40.0 mmol, 5.479 g) and KOH (44.0 mmol, 2.469 g) were placed in a round bottom flask with 100 mL acetonitrile. The mixture was brought to reflux (85° C.) and stirred 1 h until KOH was consumed. 2-Bromomethylnapthalene (40.00 mmol, 8.844 g) was added and the solution was stirred at reflux for 17 hours. KBr was removed by vacuum filtration and the filtrate was collected. The volatiles were removed by rotary evaporation to give 4,5-dichloro-1-(naphthalen-2-ylmethyl)-1H-imidazole as a light brown solid. 4,5-dichloro-1-(naphthalen-2-ylmethyl)-1H-imidazole (18 mmol) was dissolved in acetonitrile (40 mL) in a round bottom flask. The solution was brought to reflux and iodomethane (5 mL) was added. The reaction was stirred at reflux for 20 h after which time it was cooled. The resulting white precipitate was collected by filtration and analyzed. Yield: 89.6% 1H NMR (300 MHz, d6-DMSO): δ 3.86 (s), 5.68 (s), 7.53-7.59 (m), 7.93-8.03 (m), 9.51 (s) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2cccc(F)c2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 88.1 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(3-fluorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.60 g, 8 mmol) and potassium phthalimide (2.22 g, 12 mmol) in N,N-dimethylformamide (30 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[[6-benzyloxy-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.95 g, 88.2%) as crystals.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]3[CH2:38][O:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH:26]3[CH2:38][O:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2ccc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3COc3cccnc3)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(NC(=O)N3CCNCC3COc3cccnc3)cc2)cc1
Reaction time: 2 h

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4′-methoxybiphenyl-4-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (114.9 mg, 0.182 mmol) in MeOH (1 mL). After 2 h, the reaction mixture was concentrated under reduced pressure, and the material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired fractions were brought to pH 12 with 1 N NaOH in H2O and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 28.6 mg (38%) of the desired product as a white solid. LC-MS: RT=4.97 min, [M+H]+=419.2.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].ClCl>>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Cl:21]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: ClCl
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)c(Cl)c1
Yield: 60 %

Procedure:
65 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-toluene and 2 parts by weight of phosphorus pentachloride were treated with chlorine gas for half an hour at 200° C. Fractional distillation gave 43.2 parts by weight (60% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzyl chloride of boiling point 135°-145° C. and refractive index nD25 : 1.5427.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[C:33]([O:35][CH3:36])=[O:34]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:36][O:35][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([O:8][C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([CH:10]([CH3:25])[C:11]([OH:16])([C:17]3[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]=2[F:9])=[CH:28][C:27]=1[F:26]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1cc(F)c(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2cc(Cl)c(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)cc2F)cc1F

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-5-fluoro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=532.2 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:30]=[CH:29][C:15]3[N:16]([CH3:28])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH3:27])[CH:21]=4)=[N:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH2:31]([N:38]=[N+:39]=[N-:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:30]=[CH:29][C:15]3[N:16]([CH3:28])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5[N:40]=[N:39][N:38]([CH2:31][C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[CH:27]=5)[CH:21]=4)=[N:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCc1cccc(Nc2nc3cc(Oc4ccnc(C(=O)NC)c4)ccc3n2C)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2cccc(-c4cn(Cc5ccccc5)nn4)c2)n3C)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[2-(3-Ethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide (1 eq) (prepared using previously described example 2), benzyl azide (1 eq) in t-butanol (0.1M) was added sodium ascorbate (0.05 eq), and copper (II) sulfate pentahydrate (0.01 eq). The resulting mixture was allowed to stir for 1 hour at room temperature. The mixture was then diluted with water and the solid collect via suction filtration. MS: MH+ 531
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[CH2:10]([O:17][C:18](=[O:24])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:24])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCOC(=O)CCBr
Agent: Cl
Product: CCOC(=O)CCN1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 49.7 %

Procedure:
Using the same reactions described above, 7.23 g (0.03) of ethyl β-bromopropionate and 7.33 g (0.04 m) of proline benzyl ester hydrochloride gave N-(2-carbethoxy)ethyl-L-proline, benzyl ester (4.6 g, 50.2%). This compound (4.6 g, 0.015 m) was hydrogenated over palladium-on-carbon to give 2.96 g (78%) of N-(2-carbethoxy)ethyl-L-propline, hydrochloride, m.p. 169°-171°. This compound (2.42 g, 0.0096 m) was condensed with 2.25 g (0.0072 m) of L-alanyl-L-proline, benzyl ester hydrochloride in the dicyclohexylcarbodiimide procedure to give 0.8 g of N-(2-carbethoxy)ethyl-L-prolyl-L-alanyl-L-proline, benzyl ester. The pro-drug precursor was hydrolyzed with barium hydroxide in aqueous methanol to give 0.498 g (64%) of N-(2-carboxyethyl)-L-prolyl-L-alanyl-L-proline, m.p. 133°-136°.