Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 62.7 %

Procedure:
To stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (126 g, 0.59 mol) in DMF (1.0 L) was added sodium carbonate (249 g, 2.34 mol) and methyl iodide (145 mL, 2.34 mol). The reaction mixture was heated at 60° C. for 4 h. On completion, the reaction mixture was filtered and the residue washed with DCM. The aqueous phase was separated and extracted with DCM. The combined organic layers were dried, concentrated under reduced pressure and purified by column chromatography over silica eluting with ethyl acetate:hexane to afford the title compound (85 g, 63%). 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (d, 1H), 8.05 (s, 1H), 3.9 (s, 1H), 2.4 (s, 1H).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(OCC1C=CC=CC=1)=O.C([Li])CCC.[C:24]([O:29][CH2:30][C@@H:31]1[O:33]C1)(=[O:28])CCC>O1CCCC1>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:1][C@H:30]([CH2:31][OH:33])[O:29][C:24]2=[O:28])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reaction time: 8 h

Procedure:
A mixture of N-(carbobenzyloxy)-3-fluoroaniline (1.000 g, 4.08 mmol) in dry tetrahydrofuran (10 ml) is cooled with a dry ice/acetone bath to about -78° and then n-butyllithium (1.87 ml of a 1.6M mixture in hexanes, 2.91 mmol) is added. (R)-glycidyl butyrate (0.420 g or 0.413 ml, 2.91 mmol) is then added via syringe and the cooling bath allowed to dissipate overnight, with the reaction mixture reaching 20°-25°. The reaction mixture is quenched by the careful addition of saturated aqueous ammonium chloride, the entire mixture transferred to a separatory funnel with dichloromethane washings, and the mixture extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a concentrate which is purified by chromatography over silica gel, eluting with acetonitrile/chloroform (10/90) containing 1% methanol, to give the title compound.
Reaction SMILES: [C:1]([Li])(C)(C)C.[F:6][C:7]([F:23])([F:22])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=1.IC.O>CCCCC.O1CCCC1>[CH3:1][C:12]1[CH:13]=[C:8]([C:7]([F:22])([F:23])[F:6])[CH:9]=[CH:10][C:11]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 4 h

Procedure:
tert-Butyl 2-methyl-4-trifluoromethylphenylcarbamate is prepared in the following manner: 154 ml of a 1.5 M solution of tert-butyllithium in pentane are added dropwise over 1 hour to a solution, kept at −70° C. under an argon atmosphere, of 30 g of tert-butyl 4-trifluoromethylphenylcarbamate in 390 ml of anhydrous tetrahydrofuran. The mixture is stirred for 4 hours at −20° C., cooled to about −70° C., supplemented with 16.4 g of iodomethane and then stirred for 16 hours at a temperature close to 20° C. After hydrolysis with 300 ml of distilled water, the mixture is extracted with twice 160 ml of ethyl acetate in total. The combined organic extracts are dried over magnesium sulphate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in petroleum ether, separated by filtration, washed with the same solvent and dried under reduced pressure (2 kPa). 20.5 g of tert-butyl 2-methyl-4-trifluoromethylphenylcarbamate are thus obtained in the form of a beige solid melting at 101° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[O:34]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2=[O:34])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: O=C1CCCCC1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC1CCCCC1=O
Reaction time: 96 h

Procedure:
A mixture of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (15 g, 47 mmoles) (from Preparation 1A), tetrabutylammonium bromide (15 g, 47 mmoles), anhydrous potassium carbonate (34.32 g, 0.234 mole), 2-chlorocyclohexanone (8.9 g, 67 mmoles) in DMF (60 ml) was stirred for 4 days. The reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate solution was washed with 0.4N NaOH, water and extracted with 1N HCl (50 ml). The acid extract was basified with saturated sodium carbonate solution and extracted with methylene chloride. The extract was dried and filtered through silica, the filtrate was concentrated and the concentrate diluted with pentane. The oiled-out material solidified on standing and was crystallized from toluene (30 ml) to yield the title compound, mp. 96°-99°.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.CO.N.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:18])([CH3:16])[CH3:17])[CH2:11][CH2:10]1
Reactant: CC(C)(O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)[C@H]1CC[C@H](N)CC1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 2-(trans-4-(dibenzylamino)cyclohexyl)propan-2-ol (120 g×8, 356 mmol) and Pd(OH)2 (15 g×8) in methanol (1000 mL) and MeOH/NH3 (100 mL) was stirred under H2 (50 psi) at 50° C. for 72 hrs, then the catalyst was removed and the filtrate was concentrated in vacuo and The crude product was chromatographed on silica gel (DCM/MeOH 20:1-DCM/MeOH/NH3 5:4:1) to give the 2-(trans-4-aminocyclohexyl)propan-2-ol as a pale yellow solid (210 g, 47.5% yield).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3OC3)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1)C1OC1.C(O)(=O)C=C>>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)([CH3:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: C=CC(=O)O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 80 °C

Procedure:
34.8 g of bisphenol A diglycidyl ether was heated to 70° C. under continuous stirring and then 14.4 g of acrylic acid was added slowly under nitrogen atmosphere. After maintaining the reaction at 70° C. for 2 hours, 19.6 g of maleic anhydirde was added and then the temperature was raised to 80° C. under mechanical stirring for 2-3 hours to complete the reaction.
Reaction SMILES: CS(O[CH:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([O:9][CH:10]([CH2:15][O:16][S:17]([CH3:20])(=[O:19])=[O:18])[O:11]2)[CH2:7]1)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>CN(C)C=O.O.CCOCC.C(Cl)Cl>[CH3:20][S:17]([O:16][CH2:15][CH:10]1[O:11][CH:12]2[CH2:14][CH:8]([CH2:7][CH:6]=[CH:13]2)[O:9]1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)OCC1OC2CC(CC(OS(C)(=O)=O)C2)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)OCC1OC2C=CCC(C2)O1

Procedure:
A solution of 660 mg of 7-methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane of the formula IIb and 1.4 g of tetrabutylammonium fluoride in 7.5 ml of dimethyl formamide is heated under nitrogen for 7 hours to 60°C. The cooled reaction mixture is treated with 20 ml of methylene chloride and 80 ml of ether and shaken successively with 80 ml of an 8% sodium bicarbonate solution, 100 ml of water and 50 ml of sodium chloride solution. The aqueous layers are extracted separately twice with 100 ml of the same solvent mixture on each occasion. The combined organic fractions are dried over sodium sulphate. The solvent is distilled off under reduced pressure to give an oily product whose spectrum properties correspond to those of the pure racemic 3-methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]non-6-ene of the formula IIIa. Preparative chromatography on basic aluminium oxide with benzene as eluant gives the crystalline product of melting point 53°-56°C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[C:22]=1[F:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:30](=[O:32])=[O:31]>C1COCC1>[CH2:13]([O:20][C:21]1[C:22]([F:29])=[C:23]([F:28])[C:24]([F:27])=[C:25]([CH:26]=1)[C:30]([OH:32])=[O:31])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C=O
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (white solid, 19.33 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 7.42 (m, 6H), 5.14 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:27])[C:15]([F:26])([F:25])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:27])[C:15]([F:25])([F:26])/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccc(F)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using (E)-1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-4-(4-fluoro-phenyl)-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
15.29 g (61 mmol) Z-Val-OH and 21.96 g (61 mmol) H-Val-MeVal-Pro-OMe were dissolved in 610 ml dichloromethane and cooled to 0° C. After addition of 8.16 ml (73.2 mmol) N-Methylmoropholine, 2.77 g (20.3 mmol) HOBt and 11.74 g (61 mmol) EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
15.29 g (61 mmol) of Z-Val-OH and 21.96 g (61 mmol) of H-Val-MeVal-Pro-OMe were dissolved in 610 ml of dichloromethane and cooled to 0° C. After addition of 8.16 mol(73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26].CC1C=CC(S(O)(=O)=O)=CC=1>CC1C=CC=CC=1>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Yield: 93 %

Procedure:
To a flask was added 140 g of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid, obtained according to the Example 3, 100 g of ethanol, 2.5 g of 4-methylbenzenesulfonic acid and 600 g of methyl benzene. The mixture was refluxed for 15 hours to remove water. The excess ethanol was recovered by distillation. At room temperature the mixture was washed with 200 g of water, with 200 g of a 4% (wt/wt) aqueous solution of sodium hydroxide and finally with water. The solvent was completely removed under reduced pressure to give carfentrazone-ethyl as a faint yellow transparent and viscous liquid in a yield of 93% with a purity of 98.6%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=4)=[O:36])=[C:30]([F:45])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:55]1N=N[C:57]2C=CC=N[C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C1COCC1.Cl>CN(C=O)C.O>[CH2:56]([NH:55][C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=4)=[O:36])=[C:30]([F:45])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:46])[CH3:57]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O)c[nH]4)c3)cc2F)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2S)-5-tert-butoxy-2-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid (80 mg, 0.13 mmol), HATU (57 mg, 0.15 mmol) and N,N-diisopropylethylamine (49 mg, 0.38 mmol) in anhydrous DMF (8 ml) was stirred at room temperature for 10 minutes, followed by addition of 2-Methylamine in THF solution (0.1 ml, 0.2 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 4˜5% MeOH/CHCl3 to give tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate as white solid. Yield: 40 mg, 48%.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:42]=[CH:41][CH:40]=[C:39]([C@H:43]([OH:54])[C@@H:44]3[N:49]4[CH2:50][C@H:51]([CH:52]=[CH2:53])[CH:46]([CH2:47][CH2:48]4)[CH2:45]3)[C:37]=2[CH:38]=1.CO.ClCCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:42]=[CH:41][CH:40]=[C:39]([C@H:43]([OH:54])[C@@H:44]3[N:49]4[CH2:50][C@H:51]([CH:52]=[CH2:53])[CH:46]([CH2:47][CH2:48]4)[CH2:45]3)[C:37]=2[CH:38]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)[C@H](N)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boc-Val-OH (2.00 g.,9.26 mmol) and DCC (1.90 g, 9.26 mmol) were dissolved in dry DMF (20 ml) under a nitrogen atmosphere. The mixture was stirred continuously for one hour at 0° C. A solution of quinidine (1.50 g, 4.63 mmol) and DMAP (0.06 g, -0.65 mmol) in DMF (100 ml) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred and allowed to warm to room temperature. After 24 hours, the reaction was checked by TLC (1:13 methanol/dichloromethane mixture) and LC-MS analysis, and was found to be complete. The urea derivative was removed by filtration and washed with ethyl acetate. Solvents from the combined filtrate and washing were totally removed under reduced pressure.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 142.7 %

Procedure:
To a solution of trimethyl((3-(trifluoromethyl)phenyl)ethynyl)silane (0.500 g, 2.06 mmol) in ethanol (10 mL) was added potassium carbonate (0.253 g, 1.8 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction mass was quenched in water, neutralized with dil. HCl and extracted with hexane and concentrated to afford 0.200 g of the crude product which was further purified by column chromatography using silica (60-120 mesh) eluting with pet. ether to afford 0.500 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 4.41 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.77-7.81 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:24][O:25][C@@H:26]1[CH2:30][N:29]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.3 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (375 mg, 1.19 mmol), methyl 4-[(2S,4S)4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3 N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-4-methoxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxybenzoate (650 mg, 98%) as a pale brown amorphous solid 1H-NMR (CDCl3) δ 2.03 (m, 1H), 2.31 (s, 3H), 2.32 (m, 1H), 3.29 (d, J=1.0 Hz, 3H), 3.57–3.68 (m, 5H), 3.88 (d, J=1.0 Hz, 3H), 3.99–4.06 (m, 2H), 4.46 (m, 1H), 6.19 (m, 1H), 6.80 (s, 1H), 6.81 (d, J=9.0 Hz, 1H), 6.96–7.19 (m, 4H), 7.29 (m, 2H), 7.50 (d, J=6.7 Hz, 1H), 7.95–8.10 (m, 3H); MS (ESI) m/z 562 (M++1).