Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1(CCOC2C=CC(NC(N)=O)=CC=2)CCCC1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[CH3:30])=[C:20]=[S:21]>>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([NH:19][C:20]([NH2:1])=[S:21])=[C:23]([CH3:30])[CH:24]=1
Reactant: COc1ccc(N=C=S)c(C)c1
Reactant: NC(=O)Nc1ccc(OCCN2CCCC2)cc1
Product: COc1ccc(NC(N)=S)c(C)c1

Procedure:
The title compound is prepared as described in Example 1 for [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-urea but using 1-isothiocyanato-4-methoxy-2-methyl-benzene. Title compound: ES-MS: 196.9 [M+H]+; single peak at tR=2.46 min (System 2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[Na].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:22]([O:19][C:18](=[O:20])[CH2:17][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[C:2]=1[NH2:1])[CH3:23]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Br)cc1
Reactant: CCI
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A slurry of 35.6 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)benzeneacetic acid, sodium salt in 500 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and stirred at ambient temperature for 24 hr. The mixture was filtered and the filtrate was poured into 3.5 liters of water. The solid which precipitated was collected by filtration, washed with water and recrystallized from absolute ethanol to yield 26.8 g (74%) of the titled compound as tiny gold needles, m.p. 107°-109° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:16]1([CH:4]([NH:3][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (0.67 g, 2.01 mmol) in DCM (25 ml), were sequentially added triethylamine (0.84 ml, 6.04 mmol) and benzenesulfonyl chloride (0.31 ml, 2.42 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc, and washed with water and brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-(phenylsulfonamido)acetate (370 mg; 46% yield).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](=[O:27])[NH:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[NH:18][C:17]([CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(F)cccc1F)C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (460 mg, 1.23 mmol, Eq: 1.00) in CH2Cl2 (6 mL) was added TFA (2 mL) dropwise. The reaction was stirred at RT for 1 h. The solvent was evaporated to afford 2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide trifluoroacetate which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]([Cl:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH:7]=1.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1.O>C1COCC1>[Cl:20][C:5]1[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:7][C:2]2[NH:1][C:27](=[O:28])[O:21][C:3]=2[CH:4]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(N)c(O)cc2Cl)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)oc3cc2Cl)c1=O
Reaction time: 1 h
Yield: 62.6 %

Procedure:
0.6 g (1.9 mmol) of 3-(5-amino-2-chloro-4-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.35 g (2.2 mmol) of CDI were dissolved in 5 ml of THF, followed by stirring for 1 hour under heating and refluxing. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.41 g (yield: 63%) of the desired product. Melting point: 263-265° C. 1H-NMR (400 MHz, CDCl3) δ value: 3.78(3H,s), 6.84(1H,s), 6.85(1H,d), 7.28(1H,s), 7.46(1H,d)ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][NH:24]C(OC(C)(C)C)=O)=[O:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][NH2:24])=[O:22])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(COc2ccc(CCNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc(COc2ccc(CCNC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of tert-butyl 2-{[2-(4-{[2-(acetylamino)-1,3-thiazol-4-yl]methoxy}phenyl)ethyl]carbamoyl}hydrazinecarboxylate (305.0 mg, 0.667 mmol) in anhydrous dichloromethane (20 ml) was added trifluoroacetic acid (2.48 ml, 33.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr,and concentrated under reduced pressure. Dichloromethane (20 ml) was added to the residue and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove trifluoroacetic acid azeotropically. Ethyl acetate (30 ml) was added to the residue and the mixture was stirred. The precipitate was collected by filtration, washed 5 times with ethyl acetate and 5 times with diethyl ether, and dried under reduced pressure to give the title compound (253.4 mg, 0.547 mmol, yield 81.9%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:8][CH2:7]1)C.CO.[OH-].[Na+].Cl>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:7][CH2:8]1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ccccc2NC(=O)c2cccc(Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCN(c2ccccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 60 °C
Yield: 91.5 %

Procedure:
To a suspension of 0.34 g (0.85 mmol) of {1-[2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid ethyl ester in a 1:1 mixture of water:methanol (10 mL) is added 0.64 mL (1.6 mmol) of sodium hydroxide as a 10% aqueous solution. The mixture is heated to 60° C. for 3 hours then cooled to room temperature, diluted with water, and the pH of the mixture is adjusted to approximately pH 5 by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.29 g (92%) of {1-[2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]([CH2:39][CH3:40])=[N:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=O)[CH2:42][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:64]1([S:67]([NH2:70])(=[O:69])=[O:68])[CH2:66][CH2:65]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:64]1([S:67]([NH:70][C:43]([C@@:18]23[CH2:42][C@H:17]2[CH2:16][C:15]([F:47])([F:46])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]4[C:38]([CH2:39][CH3:40])=[N:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19]3)=[O:45])(=[O:69])=[O:68])[CH2:66][CH2:65]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CCc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCc1nc2ccccc2nc1O[C@@H]1C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To (2R,6S ,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 7k, 26.2 mg, 0.040 mmol) was added sieves (4 A) and dichloroethane (397 μl). To this mixture was added carbonyldiimidazole (13.5 mg, 0.083 mmol), and the reaction mixture was stirred at 40° C. for 2 hr. The reaction mixture was then cooled to room temperature and cyclopropanesulfonamide (12.4 mg, 0.103 mmol) was added followed by DBU (15 μl, 0.100 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with dichloromethane and cooled to 0° C. This mixture was neutralized with HCl (4 N in dioxane, 67 μl), and the mixture was filtered to remove sieves. The eluant was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (CH3CN/H2O (0.1% TFA) gradient =45/55-85/15) to provide tert-butyl (2R,6S ,13aS,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-2-(3-ethylquinoxalin-2-yloxy)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (25.8 mg, 85% yield) as a light yellow solid. MS (ESI): m/z=763.0 [M+H], 761.3 [M−H]. Example 7 provided an IC50 of between 0.5 and 1.0 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; a HLM stability value of >100 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of between 1.0 and 2.0 nM in a replicon cell line assay in a 1b-con1 background.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]1[O:17][CH:14]1[CH2:15][CH3:16].[OH-].[Na+]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(OCC(O)CC)cc1
Yield: 82.4 %

Procedure:
In a closed vessel 16.7g of ethyl p-hydroxybenzoate, 7.2 g of 1,2-butylene oxide and 0.8 ml of a 50% aqueous solution of sodium hydroxide were heated at 150° C for 4 hours in the same manner as in Example 1. The reaction mixture obtained was treated in the same way as in Example 1 to afford 19.6g of 1-(p-ethoxycarbonylphenoxy)-butan-2-ol (compound No. 48) in an 82% yield, which had a melting point of 52° to 52.5° C when recrystallized from ethyl acetate and n-hexane.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:28])[CH:5]=[C:6]3[C@:25]([CH3:26])([C@@H:2]12)[C@@H:24]1[C@H:9]([C@H:10]2[C@:21]([CH3:27])([CH2:22][CH2:23]1)[C@@H:13]([CH:14]([CH3:20])[CH:15]([O:18][CH3:19])[O:16][CH3:17])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3.C([BH-](CC)CC)C.[Na+]>O1CCCC1>[O:1]1[C@H:3]2[C@@H:4]([OH:28])[CH:5]=[C:6]3[C@:25]([CH3:26])([C@@H:2]12)[C@@H:24]1[C@H:9]([C@H:10]2[C@:21]([CH3:27])([CH2:22][CH2:23]1)[C@@H:13]([CH:14]([CH3:20])[CH:15]([O:18][CH3:19])[O:16][CH3:17])[CH2:12][CH2:11]2)[CH:8]=[CH:7]3
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC[BH-](CC)CC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 86.3 %

Procedure:
In 200 ml of tetrahydrofuran was dissolved 11.8 g of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one, followed by addition of 36 ml of a 1.0M solution of sodium triethylborohydride in tetrahydrofuran under ice-cooling. The mixture was stirred under ice-cooling for 15 minutes, after which it was worked up in the same manner as Example 68 to give 10.24 g of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3α-ol (yield: 85%) showing the following physical properties.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O.O>O1CCOCC1.C(OCC)(=O)C>[Cl:5][C:6]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Br:2]
Reactant: OCc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Clc1ccc(Oc2ccccc2CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
Phosphorus(III) tribromide (0.41 ml, 4.37 mmol) was added to a solution of 1-[2-(2,4-dichlorophenoxy)phenyl]methanol (420 mg, 1.56 mmol) in dioxane (10 ml). The reaction mixture was stirred for 1 hour at room temperature. Another portion of phosphorus(III) tribromide (0.41 ml, 4.37 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was cooled to 0° C. Water (5 ml) was added dropwise. The reaction mixture was warmed to room temperature and diluted with ethyl acetate (400 ml). It was washed with a 10% aqueous solution of sodium hydrogensulphate. The aqueous phase was extracted with ethyl acetate (50 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane 1:3 as eluent, to give 297 mg of 2-(2,4-dichlorophenoxy)benzyl bromide.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][N:5]2[C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:37][CH2:38][C:39]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].C(N(CC)CC)C>CN(C=O)C>[F:49][C:46]1[CH:47]=[CH:48][C:39]([CH2:38][NH:37][C:19]([C:3]2[C:2]([OH:1])=[C:6]3[C:7](=[O:18])[N:8]([CH3:17])[CH2:9][C@H:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:5]3[N:4]=2)=[O:21])=[C:40]([CH:45]=1)[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)c1cc(F)ccc1CN
Reactant: CN1C[C@H](c2ccccc2)n2nc(C(=O)O)c(O)c2C1=O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1cc(F)ccc1CNC(=O)c1nn2c(c1O)C(=O)N(C)C[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (7S)-3-hydroxy-5-methyl-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (246 mg, 0.856 mmol) in DMF (3 mL) were added HOAT (175 mg, 1.28 mmol), and EDC (246 mg, 1.28 mmol). The reaction mixture was stirred at ambient temperature 15 minutes then methyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (226 mg, 1.03 mmol) and triethylamine (0.13 g, 1.28 mmol) were added. The reaction was stirred at ambient temperature overnight. The solvent was removed in vacuo, and the resulting residue was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the product as a light pink solid. 1H NMR (400 MHz, d6-DMSO) δ 9.60 (bs, 1H), 8.60 (t, J=6.2 Hz, 1H), 7.61 (dd, J=9.5, 2.3 Hz, 1H), 7.45 (m, 2H), 7.36 (m, 3H), 7.04 (d, J=7.1 Hz, 2H), 5.75 (t, J=4.0 Hz, 1H), 4.68 (ABX, J=15.8, 6.2 Hz, 2H), 4.18 (dd, J=13.4, 4.5 Hz, 1H), 3.86 (s, 3H), 3.81 (dd, J=13.4, 4.0 Hz, 1H), 2.88 (s, 3H); ES MS (M+1)-453.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][C:25]=1[Cl:26]>>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][C:25]=1[Cl:26])[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: COC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Product: COC(=O)C(CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.42 g, 39%) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 4,5-dichlorophthalic anhydride (0.80 g, 3.64 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](OCC)=[O:20].C(O)(=O)C>CCCCCC.O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](=[O:20])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCOC(=O)COc1cccc(Cl)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
A solution of n-butyl lithium (16.0 g) in hexane (160 ml) was added to a stirred solution of dimethyl methylphosphonate (26.9 g) in anhydrous tetrahydrofuran (150 ml) at -60° C. in an atmosphere of nitrogen during 20 minutes. The solution was maintained at -60° C. for a further period of 10 minutes and was then treated with a solution of ethyl 3-chlorophenoxyacetate (23.4 g) in anhydrous tetrahydrofuran (50 ml) at -60° C. during a further period of 10 minutes. This solution was stirred at -60° C. for 90 minutes and then stirred at ambient temperature for 2 hours. The solution was treated with acetic acid (21 ml) and the solvents were evaporated under reduced pressure. Water (60 ml) was added to the residue and the mixture was extracted with diethyl ether. The ethereal solution was washed with water, with aqueous sodium bicarbonate solution (10% w/v) and with water, dried over magnesium sulphate, and evaporated. The resulting residue was left to stand at ambient temperature overnight. The resulting colourless crystals were filtered off, washed with a small volume of diethyl ether, and recrystallised from a mixture of petroleum ether (b.p. 40°-60° C.) and toluene, to give dimethyl 3-(3-chlorophenoxy)-2-oxopropylphosphonate (18.6 g) in the form of colourless needles, m.p. 78°-79° C. [elemental analysis: C, 44.9; H, 5.1; P, 10.7%. C11H14ClO5P requires C, 45.1; H, 4.8; P, 10.6%. νmax 825, 865, 1030, 1160, 1270, 1335, 1600 and 1735 cm-1 ].
Reaction SMILES: IC.[Br:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([F:17])[C:7]([OH:18])=[C:6]([CH:19]=[O:20])[CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([F:17])[C:7]([O:18][CH3:21])=[C:6]([CH:19]=[O:20])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Yield: 97.6 %

Procedure:
Iodomethane (1.35 g) was added at room temperature to a mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (1.99 g), potassium carbonate (1.76 g), and DMF (40 mL), and the resultant mixture was stirred at 60° C. for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.03 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:45])[NH:31][CH:32]([C:34](=[O:44])[NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([NH2:43])[N:37]=1)[CH3:33])([CH3:28])([CH3:27])[CH3:26].[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52](O)=[O:53].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:25]([O:29][C:30](=[O:45])[NH:31][CH:32]([C:34](=[O:44])[NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([NH:43][C:52]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][N:46]=2)=[O:53])[N:37]=1)[CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: O=C(O)c1ccccn1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(NC(=O)c2ccccn2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (180 mg, 0.47 mmol) is added to a mixture of tert-butyl-N-{1-[(6-amino-4-chloropyridin-2-yl)carbamoyl]ethyl}carbamate J8 (100 mg, 0.32 mmol), pyridine-2-carboxylic acid (60 mg, 0.49 mmol) and DIPEA in NMP (1.5 ml) and the mixture is stirred at RT for 2 h and stirring continued at 50° C. for 17 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 27 mg (20%). HPLC-MS: M+H=420 (Method—2).
Reaction SMILES: C(Br)C1C=CC=CC=1.I[CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:10]([N:27]1[CH2:28][CH2:29][N:25]([C:17]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:14])[N:16]=2)[C:26]1=[O:30])[CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: CCCCI
Agent: BrCc1ccccc1
Product: CCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 73 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 73% yield: NMR (300 MHZ, CDCl3) δ 4.08 (q, J=7.2 Hz, 2H), 3.99-3.85 (m, 2H), 3.47-3.33 (m, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.41-1.22 (m, 7H), 0.74 (t, J=7.2 Hz, 3H); MS (ES+) m/z 312.3 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:4].C([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]2[C:48]3[C:43](=[CH:44][C:45]([C:49](O)=[O:50])=[CH:46][CH:47]=3)[C:42]([CH3:52])=[C:41]2[CH3:53])=[CH:35][CH:34]=1)=[O:26])(C)(C)C>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C@@H:3]([NH:2][C:49]([C:45]1[CH:44]=[C:43]2[C:48](=[CH:47][CH:46]=1)[N:40]([CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:28]3[C:27]([C:25]([OH:26])=[O:24])=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:38][CH:37]=1)[C:41]([CH3:53])=[C:42]2[CH3:52])=[O:50])[CH3:4])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](N)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)[C@@H]3CCCN3C(=O)OCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-benzyl 2-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 630 [M+H]+.