Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.C(=O)=O>CC(C)=O>[N:5]([C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[N:7]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Agent: O=C=O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(N2CCC(N=C=S)=N2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Thiophosgene (11.5 g) was added slowly to a solution of 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (23 g) (prepared according to Reference Example 1 of European patent specification No. 22-578) in acetone (250 ml) at 0° in an atmosphere of carbon dioxide. The addition was completed in about 20 minutes and was then allowed to warm to room temperature for 1 hour. The resulting insoluble solid, the hydrochloride of the starting base, was filtered off and washed with fresh acetone. The combined filtrate and washings were evaporated in vacuo to give crude 3-isothiocyanato-1-(3-trifluoromethylphenyl)-2-pyrazoline as a gum (13 g) which subsequently crystallised. This compound was used directly without purification but the presence of the isothiocyanate group was confirmed by infra red spectroscopy which exhibited a broad band in the region of 2005 cm-1. This gum (3.8 g) was suspended in toluene (40 ml) and stirred during the addition of butylamine (1.5 g). When the gum changed into a colourless solid. After 2 hours, the mixture was warmed to about 35° for 10 minutes and then cooled back to room temperature. The resulting solid was collected, washed with a little fresh toluene and recrystallised from propanol in long prisms, m.p. 197°-198° of 3-(3-butylthioureido)-1-(3-trifluoromethylphenyl)-2-pyrazoline.
Reaction SMILES: [C:1]([N:5]1[C:9]([Cl:10])=[C:8]([CH2:11]O)[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:18].O>C(OCC)C>[Br:18][CH2:11][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=1[Cl:10]
Reactant: CC(C)(C)n1nc(C(F)(F)F)c(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)n1nc(C(F)(F)F)c(CBr)c1Cl
Temperature: -10 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 9.2 g (35.7 mmoles) of (1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 100 ml of diethyl ether was cooled to −10° C. Thereto was added 11.6 g (42.9 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature overnight to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 10.0 g (yield: 87.3%) of 4-bromomethyl-1-tert-butyl-5-chloro-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH3:30])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:29][CH3:30])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1oc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)o3)C[C@H]2OC)nc1Cl
Yield: 89.9 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-oxazole-5-carboxylate obtained in Example (107c) (0.12 g, 0.27 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (5 mL) and THF (3 mL), to obtain 0.10 g of the title compound as a colorless solid (89%).
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13]([CH3:15])=C)[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:3])[CH3:2].[O:28]=[O+][O-]>CO>[C:1]([S:4][CH:5]1[N:8]([CH:9]([C:13](=[O:28])[CH3:15])[C:10]([OH:12])=[O:11])[C:7](=[O:16])[CH:6]1[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])(=[O:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(N2C(=O)c3ccccc3C2=O)C1SC(C)=O
Solvent: CO
Product: CC(=O)SC1C(N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(C)=O)C(=O)O
Yield: 63 %

Procedure:
To a solution of α-[4-acetylthio-3-phthalimido-2-oxo-azetidin-1-yl]-α-isopropenyl acetic acid (100 mg) in methanol (10 ml) at 0° C. is introduced excess ozone. After the gas at the outlet makes a potassium iodide starch paper coloured, the reaction mixture is bubbled with sulfur dioxide gas. The reaction mixture is concentrated, and the obtained residue is dissolved in aqueous solution of sodium hydrogen carbonate, washed with ether, neutralized with hydrochloric acid, and extracted with methylene chloride. The extract solution is washed with water, dried, and evaporated to give α-[4-acetylthio-3-phthalimido-2-oxoazetidin-1-yl]-α-acetyl-acetic acid (64 mg). Yield: 63%. Foam.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([CH3:23])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:25])[CH:20]=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2cnn(CC(C)NC(=O)OCc3ccccc3)c2c1
Reaction time: 3 h
Yield: 58.2 %

Procedure:
To a solution of the product from Step A (0.95 g, 3.19 mmol) in DMF (10 mL) was added cesium carbonate (1.26 g, 3.70 mmol) followed by iodomethane (0.23 mL, 3.70 mmol) at room temperature. After stirring for 3 h, saturated aqueous ammonium chloride (30 mL) was added and the mixture extracted with ethyl acetate (3×65 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% ethyl acetate in hexane to 30% ethyl acetate in hexane) to give a syrup (0.63 g, 92%): MS (ES) m/z 340(M+).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=O)[N:23]=[C:13]2[C:12]1=[O:26])[CH3:10]>O.C(O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=[N:2][OH:3])[N:23]=[C:13]2[C:12]1=[O:26])[CH3:10]
Reactant: CCn1c(=O)c2nc(C=O)cn2c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c2nc(C=NO)cn2c2ccccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of 0.2 g of hydroxylamine hydrochloride and 0.25 g of sodium acetate in 2 ml of water was added to a suspension of 0.5 g of the product of Example 22 in 10 ml of ethanol and the mixture was stirred at 90° C. for 4 hours and was then filtered. The recovered product was washed with water and dried in vacuo to obtain 0.435 g of pure 4,5-dihydro-5-ethyl-4-oxo-imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime melting at 286°-288° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10].[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:9])[C:3]=1[CH2:2][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1cncc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91.2 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine (15 g, 62.2 mmol), 4-hydroxybenzaldehyde (7.97 g, 65.4 mmol) and caesium carbonate (22.3 g, 68.5 mmol) in DMF (150 ml) was stirred for 4.5 h at room temperature. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with sodium carbonate solution (×2) and brine, dried (MgSO4) and evaporated in vacuo to give the title compound as a brown solid (16 g). δH (DMSO-d6), 9.91 (1H, s), 8.74 (2H, s), 7.91 (2H, d, J 8.6 Hz), 7.27 (2H, d, J 8.6 Hz), 5.37 (2H, s); m/z (ESI) 282 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccc(Cl)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccc(Cl)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 211.5 %

Procedure:
To a solution of 7-(5-chloro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) and aminoguanidine hydrochloride (0.46 g) in ethanol (30 ml) were added concentrated hydrochloric acid (0.9 ml) and water (0.9 ml), and the mixture was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solution was concentrated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid (10 ml), and the mixture was concentrated. Precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 164) (1.4 g) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[N-:30]=[N+:31]=[N-:32].[Na+].CC(C)=O>O>[N:30]([C:3]1([CH3:2])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:5]2[S:4][CH2:29]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(N=[N+]=[N-])CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2,2-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:25][C:26]1[CH:27]=[C:28]([CH3:51])[C:29]2[O:33][C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[N:31][C:30]=2[CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32]4[O:33][C:29]5[C:28]([CH3:51])=[CH:27][C:26]([CH3:25])=[CH:50][C:30]=5[N:31]=4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CCCN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
The mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.6 g, 0.00135 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.59 g, 0.00162 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) and sodium carbonate (0.36 g, 0.00338 mol) in ethylene glycol dimethyl ether (50 mL) and water (10 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. After cooled the mixture to the room temperature, more N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.24 g, 0.00066 mol), tetrakis(triphenylphosphine)palladium (0.078 g, 0.000068 mol) were added, and the mixture was stirred at 80° C. for 5 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish oil which was purified by flash column chromatography on silica using 5%-25% isopropanol/dichloromethane as a mobile phase, and the product was triturated with N,N-dimethylformamide to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.28 g, 0.00051 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.9 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl[CH2:16][C:17]([NH2:19])=[O:18]>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH:10]3[CH2:16][C:17]([NH2:19])=[O:18])=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: NC(=O)CCl
Reactant: CC1=C2CCNCC2c2ccccc21
Product: CC1=C2CCNC(CC(N)=O)C2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and chloroacetamide are reacted in accordance with the process described in Example 1. Reaction period four hours at 60°. M.P. of the title compound 167°-168° from acetone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:23][CH2:24][CH2:25][CH3:26])[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC1(C(O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCC1(C(=O)c2ccc(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-butyl-2-[(3,4-dichloro-phenyl)-hydroxy-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.520 g, 1.29 mmol) in DCM (20 mL) at 0° C. under nitrogen was added DMP (0.658 g, 1.55 mmol) in a single portion. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes, then diluted with DCM, washed with 1 N NaOH and brine, then dried (MgSO4), filtered and concentrated in vacuo to a yellow oil (0.62 g). Purification by chromatography (silica, 10-20% EtOAc in hexanes) gave 2-butyl-2-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.441 g, 1.10 mmol, 85%) as a clear colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].[Na]>S(=O)(=O)(O)O>[C:9]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CC(=O)Oc1cccc(Cl)c1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
3-Chlorophenol (100 g, 0.78 mol) was dissolved in acetic anhydride (75 mL, 0.8 mol). Upon addition of 1 drop of concentrated sulfuric acid, the temperature raised to 120° C. After 45 minutes, the mixture was cooled and poured into a solution of sodium hydrogenocarbonate (8 g in 1 L of water) and extracted with diethylether. The organic layer was washed with a saturated sodium hydrogenocarbonate solution, dried over magnesium sulfate and evaporated under reduced pressure. The resulting oil was used directly in the next step (84%). IR (KBr): υ: 3072 (C—H aromatic), 2939 (C—H aliphatic), 1773 (C═O), 1196 (C—O) cm−1.
Reaction SMILES: O[CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:40]([CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]1[CH:19]=[CH:18][C:6]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[N+:41]=[N-:42]
Reactant: COC(=O)c1ccc(COc2ccc(C(O)c3ccccc3)cc2)o1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2ccc(C(N=[N+]=[N-])c3ccccc3)cc2)o1
Temperature: 100 °C
Yield: 84 %

Procedure:
To a stirred solution of methyl 5-((4-(hydroxy(phenyl)methyl)phenoxy)methyl)-furan-2-carboxylate (325 mg, 0.96 mmol) in toluene (4.5 mL) under nitrogen was added diphenylphosphoryl azide (0.25 mL, 1.15 mmol) followed by DBU (0.17 mL, 1.15 mmol). The reaction was heated at 100° C. for 3 h. The reaction was quenched by the addition of saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified via silica gel chromatography, eluting with 0-25% EtOAc in isohexane, to give the title compound as a colourless oil (293 mg, 84%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29])=[CH:11][CH:10]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Triethylamine 0.7 ml (5.0 mmol) was added to a solution of 500 mg (2.5 mmol) of 2-(4-bromophenyl)ethanamine in tetrahydrofuran (5 ml). 2-Nitrobenzenesulfonyl chloride (664.6 mg, 3.0 mmol) was then added thereto, and the mixture was stirred at room temperature for one hr. Thereafter, a saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give 915 mg (yield 95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:38])=[C:17]([NH:19][C:20](=[O:37])[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH:18]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:27]([NH:26][C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([NH:19][C:17]2[CH:18]=[C:13]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:14]=[CH:15][C:16]=2[CH3:38])=[O:37])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]
Reactant: COc1ccccc1B(O)O
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Product: COc1ccccc1-c1ccc(C)c(NC(=O)COCC(=O)Nc2ccc(Cl)cc2C(=O)O)c1

Procedure:
Using the same method as in Example 19-(ii), 2-methoxybenzene boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester to give 5-chloro-2-[((2-[(2′-methoxy-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:67][CH2:68][CH2:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][NH2:79]>O1CCCC1>[NH2:79][CH2:78][CH2:77][O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][NH:67][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCOCCOCCOCCN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 200 mg, 324 μmol) and HATU (136 mg, 357 μmol) combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min at room temperature. The reaction mixture was slowly added dropwise to a solution of 1,11-diamino-3,6,9-trioxaundecane (312 mg, 304 μL, 1.62 mmol) in dry tetrahydrofuran (1.5 mL) at 0° C. The reaction was done after stirring at room temperature for 20 min. It was filtered and injected into Gilson reverse-phase high-performance liquid chromatography for purification. The desired fractions was converted to free base and lyophilized to afford (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide as a white solid (169 mg, 66% yield). LCMS (ES+) m/z calcd. for C39H47Cl2F2N5O6 [(M+H)+]: 790. found: 790.