Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:18])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].O.[N+]([O-])([O-])=[O:21].[NH4+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[O:21])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(CCC(=O)OC)c1C
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)OC)c1C
Yield: 59.8 %

Procedure:
3,5-Dimethyl-4-(2-methoxycarbonylethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (127 g) was dissolved in acetic acid (1900 mL), water (1900 mL) and tetrahydrofuran (1900 mL) and cooled to −30° C. Cerric ammonium nitrate (1097 g) was added in portions with stirring to give a reddish-orange suspension. The suspension was stirred at 0° C. for 2 hours, neutralized to pH 7 with sodium bicarbonate and extracted with ethyl acetate (2000 mL). The ethyl acetate layer was separated, washed with brine (200 mL) and dried over anhydrous sodium sulfate (20 g). The solvent was removed to give 80.2 g (60%) of 5-formyl-4-(2-methoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>C(Cl)Cl.CN(C=O)C>[CH2:16]([O:5][C:4](=[O:6])[C:3]1[C:2]([Cl:1])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:11])[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)cncc1Cl
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 3,5-dichloroisonicotinic acid (52 mmol) in 250 mL DCM and 5 mL DMF were added 11.4 mL thionylchloride. The mixture was heated to 40° C. for 2.5 h, cooled to RT before 100 mL EtOH were added. The solution was stirred at RT for 10 min and then concentrated in vacuo. The crude mixture was taken up in EtOAc and quenched with sat. aq. NaHCO3 solution under ice cooling. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (95/5 to 85/15) gives the desired product as colorless oil;
Reaction SMILES: Cl[C:2]1C2OCCCC=2C(C)=C(C2C(C3SC=CC=3)=NN(C)C=2C=O)C=1.[Cl:26][C:27]1[C:36]2[O:35][CH2:34][CH2:33][CH2:32][C:31]=2[C:30]([CH3:37])=[C:29]([C:38]2[C:39]([C:49]3[S:50][CH:51]=[CH:52][CH:53]=3)=[N:40][N:41]([CH3:48])[C:42]=2[CH:43]([OH:47])[C:44]([O-:46])=[O:45])[CH:28]=1>C1CCCCC1.C(OCC)(=O)C>[Cl:26][C:27]1[C:36]2[O:35][CH2:34][CH2:33][CH2:32][C:31]=2[C:30]([CH3:37])=[C:29]([C:38]2[C:39]([C:49]3[S:50][CH:51]=[CH:52][CH:53]=3)=[N:40][N:41]([CH3:48])[C:42]=2[CH:43]([OH:47])[C:44]([O:46][CH3:2])=[O:45])[CH:28]=1
Reactant: Cc1c(-c2c(-c3cccs3)nn(C)c2C(O)C(=O)[O-])cc(Cl)c2c1CCCO2
Reactant: Cc1c(-c2c(-c3cccs3)nn(C)c2C=O)cc(Cl)c2c1CCCO2
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)C(O)c1c(-c2cc(Cl)c3c(c2C)CCCO3)c(-c2cccs2)nn1C

Procedure:
Using the procedure described in example 1, step 5, 4-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazole-5-carbaldehyde (35a) (180 mg, 0.48 mmol) is converted, after purification by preparative TLC (dichloromethane/ethyl acetate 70/30) into 2-[4-(8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl]-2-hydroxyacetate (35b) (69 mg, 0.16 mmol, 33%).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16](=O)[NH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:23][CH3:24])[CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:33])=O>C1(C)C=CC=CC=1>[Cl:33][C:16]1[C:15]2[C:20](=[CH:21][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:25])(=[O:1])[CH2:3][CH2:4]3)=[C:13]([O:23][CH3:24])[CH:14]=2)[N:19]=[CH:18][N:17]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCS(=O)(=O)CC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Yield: 52 %

Procedure:
7-(3-(1,1-Dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (4.2 g, 11.4 mmol) was suspended in thionyl chloride (45 ml) and DMF (0.1 ml) then heated at reflux for 2.5 hours. The residue was diluted with toluene, the thionyl chloride was evaporated under vacuum, the residue was then azeotroped with toluene three times. The residue was taken up in water and basified (pH8) with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with dichloromethane (×4), the organic layer was washed with water and brine then filtered through phase separating paper. The organic layer was concentrated under vacuum to give an orange solid. The solid was flash chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ether then filtered and dried to give 4-chloro-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (2.27 g, 52%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][CH2:36][OH:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:33]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCCCNCc1ccccn1
Product: Cc1ccc(N(CC(=O)N(CCCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-[(pyridin-2-ylmethyl)-amino]-propan-1-ol
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1N
Product: CC(=O)Nc1c(C)cccc1C

Procedure:
reacting 2,6-dimethylaniline with acetic anhydride to form N-(2,6-dimethylphenyl) acetamide,
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15](O)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][N:7]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>C(COC)OC.O>[NH:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:25]=[C:15]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1
Reactant: Nc1ncc(-c2cccc(F)c2)nc1C(=O)O
Reactant: Nc1ccccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(-c2cccc(F)c2)nc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
3-amino-6-(3-fluorophenyl)pyrazine-2 carboxylic acid (0.096 g, 0.41 mmol), ortho-phenylenediamine (0.049 g, 0.45 mmol), diethyl cyanophosphonate (0.07 g, 0.45 mmol), and triethylamine (0.083 g, 0.82 mmol) were combined in 5 mL of dimethoxyethane. The mixture was heated to 200° C. for 10 min in the SmithSynthesizer microwave. The cooled mixture was poured into 30 mL of H2O and the mixture was filtered to collect 3-(1H-benzimidazol-2-yl)-5-(3-fluorophenyl)pyrazin-2-amine (23 mg) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:38][S:39][CH2:40][CH2:41][C@H:42]([NH2:52])[C:43](=[O:51])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.ON1C2N=CC=CC=2N=N1>CN(C=O)C>[N:1]1([CH2:6]/[CH:7]=[CH:8]\[C:9]2[CH:10]=[CH:11][C:12]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:13]([CH:28]=2)[C:14]([NH:52][C@@H:42]([CH2:41][CH2:40][S:39][CH3:38])[C:43](=[O:51])[CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:15])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CSCC[C@H](N)C(=O)Cc1ccccc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(/C=C\Cn2ccnc2)ccc1CCc1ccc(F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)c1cc(/C=C\Cn2ccnc2)ccc1CCc1ccc(F)cc1)C(=O)Cc1ccccc1

Procedure:
A solution of pentafluorophenyl 5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (0.25 g, 0.5 mmol), (3S)-5-methylsulfanyl-2-oxo-1-phenylpentan-3amine (0.16 g, 0.6 mmol), 1-hydroxy-7-azabenzotriazole (0.075 g, 0.55 mmol) in DMF (2 ml) was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was taken up in ethyl acetate, washed with 5% sodium hydrogen carbonate and saturated sodium chloride and evaporated to dryness. The residue was then purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give the title compound which was isolated as the hydrochloride salt by treatment with HCl/ether. Yield: 70%
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C([Li])CCC.[C:29](O)(=O)[C:30](O)=[O:31]>CCCCCC.C(N=CC)(C)(C)C.ClP(=O)(OCC)OCC.O1CCCC1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:29][CH:30]=[O:31])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reactant: O=C(O)C(=O)O
Agent: CC=NC(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C(=CC=O)c2ccc(C)cc2)cc1
Reaction time: 30 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 30 hours. The following reagents were used: 4,4'-dimethylbenzophenone (21 g), diisopropylamine (32.2 mL), 1.55M n-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (17.6 mL) and tetrahydrofuran (200 ml). The work up, varied only in that the oxalic acid catalyzed hydrolysis was done overnight at room temperature, furnished 23 g of crude product which was crystallized from hexane to give 18.1 g of 3,3-bis(4-methylphenyl)-2-propenal, mp 92°-93.5° C. Anal Calcd for C17H16O: C, 86.40; H, 6.82 Found: C, 86.48; H, 6.75.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.[CH3:12][NH2:13]>C1COCC1.CO>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:13][CH3:12])=[O:10])[CH:4]=1
Reactant: CN
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 4 h

Procedure:
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0° C. The resulting mixture was stored at 3° C. for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:28]>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:28])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccc(Cl)cc1
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1c(F)cccc1F

Procedure:
A mixture of yellow mercuric oxide. (0.75g, 0.0034mol), N-[3-(2-,6-difluorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (1.11 g, 0.003mol) and methanolic ammonia solution (40 ml) was stirred for 15 hours at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by recrystallisation from ethanol gave the desired product. Yield 0.54 g (51%),m.p. 136°-137 ° C.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])[CH:2]=[CH2:3].[OH-].[Na+].Br[CH2:17][CH2:18][CH2:19][Cl:20]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:20][CH2:19][CH2:18][CH2:17][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:13]
Reactant: C=CCn1c(=O)[nH]c2ccccc21
Reactant: ClCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CCn1c(=O)n(CCCCl)c2ccccc21
Reaction time: 5 h
Yield: 84 %

Procedure:
To a stirred and heated mixture of 17.5 parts of 1,3-dihydro-1-(2-propenyl)-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminium chloride and 150 parts of a sodium hydroxide solution 60% are added dropwise 20.5 parts of 1 -bromo-3-chloropropane at 60° C. Upon completion, stirring at 60° C is continued for 5 hours. The reaction mixture is cooled, water is added and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 21 parts (84%) of 1-(3-chloropropyl)-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:27]=[N:28][CH:29]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:25][CH2:24]2)=[CH:19][C:18]=1[F:26])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:27]=[N:28][CH:29]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:24][CH2:25]2)=[CH:19][C:18]=1[F:26])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 5-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (270 mg, 0.681 mmol) in methanol (10 mL) was added 1M hydrochloric acid (2 mL, 2 mmol.) and the mixture stirred at room temperature for 2 hours. Solvent was removed in vacuo, and then saturated aqueous NaHCO3 added and the mixture extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with TBME and the solid collected by filtration to give the title compound as an off-white solid (103 mg, 41%). LCMS (Method A): RT 5.68 [M+H]+371. 1H NMR (DMSO-d6, 400 MHz) 7.81 (1 H, s), 7.37-7.34 (1 H, m), 7.27 (1 H, d, J=9.37 Hz), 6.95 (1 H, d, J=9.34 Hz), 6.91 (1 H, dd, J=12.49, 1.92 Hz), 6.75 (1 H, dd, J=8.27, 1.96 Hz), 6.56-6.46 (1 H, m), 3.71-3.65 (2 H, m), 3.48-3.43 (2 H, m), 1.89-1.80 (1 H, m), 0.91-0.85 (2 H, m), 0.65-0.57 (2 H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12](B(O)O)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][C:25]=1Br)(=[O:22])[CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.COCCOC.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([NH:23][C:24]1[C:34]([C:12]2[C:13]([CH3:15])=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][C:11]=2[CH3:19])=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(Br)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(C)=O)c(-c2c(C)cc(OCc3ccccc3)cc2C)c1
Yield: 96 %

Procedure:
[4-(Benzyloxy)-2,6-dimethylphenyl]boronic acid (333 mg, 1.30 mmol) and ethyl 4-(acetylamino)-3-bromobenzoate (286 mg, 1.00 mmol) were dissolved in a mixture of 2 M aqueous sodium carbonate solution (1.30 mL), toluene (10 mL) and 1,2-dimethoxyethane (1 mL), the air was substituted with argon gas, and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (65.7 mg, 0.16 mmol) and tris(dibenzylideneacetone)dipalladium(0) (36.6 mg, 0.04 mmol) were added. The reaction mixture was heated under reflux under an argon atmosphere for one day. After cooling the reaction mixture, brine was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=13/7) to give the title compound (401 mg, yield 96%) as a colorless amorphous powder.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.C([O:15][C:16](=[O:44])[C:17]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[F:43])([CH3:35])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][NH:31][C:30](=[O:33])[N:29]2[CH3:34])=[CH:21][CH:20]=1)C.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[F:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[O:36][C:17]([CH3:35])([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH:28]2[CH2:32][N:31]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[C:30](=[O:33])[N:29]2[CH3:34])=[CH:23][CH:24]=1)[C:16]([OH:44])=[O:15]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Trifluoromethylbenzyl bromide (0.03 mL, 0.169 mmol, d=1.546) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.050 g, 0.112 mmol) and sodium hydride (0.011 g, 0.281 mmol, 60% suspension on mineral oil), and pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, and washed with 1N HCl, water, and brine. The organic layer is dried, concentrated, and purified by LCMS. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H, J=7.8 Hz), 7.35 (d, 1H, J=7.8 Hz), 7.25-7-21 (m, 3H), 7.16 (d, 1H, J=7.8 Hz), 7.08-6.95 (m, 4H), 6.73 (d, 2H, J=7.8 Hz), 4.45, 4.37 (ABq, 2H, L=15.0 Hz), 3.95 (t, 2H, J=5.9 Hz), 3.68-3.60 (m, 1H), 3.38 (t, 1H, J=8.5 Hz), 3.29, 3.15 (ABq, 2H, J=13.7 Hz), 3.02-2.97 (m, 1H), 2.84 (s, 3H), 2.25-2.19 (m, 1H), 1.92-1.83 (m, 1H), 1.39 (s, 3H). MS [ES+] m/z exact mass calcd for C30H31N2O5F4 575.2169, found 575.2172.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:28])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:30](Cl)(OC1C=CC=CC=1)([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:28])[C@@H:14]([PH:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)OC(C)C
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@H](C(=O)OCCOC(=O)OC(C)C)[PH](=O)Oc1ccccc1
Yield: 97.2 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (methylethoxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (40) (0.88 g, 2.0 mmol) dissolved in 10 mL of anhydrous dichloromethane (DCM) was reacted with 0.58 mL (1.6 g, 6.0 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.12 g, 1.0 mmol) and triethylamine (TEA) (0.84 mL, 0.61 g, 6.0 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 1.1 g (81% yield) of the title compound (52a) as a colorless oil. Rf=0.45 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.08-1.09 (2s, 3H), 1.12-1.13 (2s, 3H), 1.25-1.32 (m, 6H), 1.44-1.50 (2d, J=5.6, 5.6 Hz, 3H), 1.85 (s, 3H), 1.99-2.06 (m, 2H), 3.13-3.18 (m, 2H), 3.28-3.32 (m, 2H), 3.98-4.05 (m, 2H), 4.82-4.91 (m, 2H), 6.38-6.42 (br. m, 1H), 6.79-6.85 (m, 1H), 7.15-7.23 (m, 6H), 7.30-7.38 (m, 4H) ppm. MS (ESI) m/z 674.19 (M+H)+, 696.09 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:34])[C:12]([CH3:33])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=3[F:31])[O:20][CH2:21][C:22]([O:24]C(C)C)=[O:23])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH3:34])[C:12]([CH3:33])=[C:13]([CH2:15][NH:16][C:17]3[C:18]([F:32])=[C:19]([CH:28]=[CH:29][C:30]=3[F:31])[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of isopropyl 2-[3-[[5-(3,5-difluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-difluoro-phenoxy]acetate (23 mg, 0.048 mmol, 1.0 eq) in THF (3 mL) at 0° C. was added LiOH (2M aqueous solution, 1 mL, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The THF was removed under reduced pressure and the remaining aqueous solution was adjusted to pH 3 by addition of 3M HCl. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (20 mg, 95%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:37])=[C:34]([CH3:49])[NH:33][C:32]=1[CH:50]=O>N1CCCCC1.C(O)C>[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][C@@H:39]2[CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:37])=[C:34]([CH3:49])[NH:33][C:32]=1/[CH:50]=[C:23]1\[C:24](=[O:29])[NH:25][C:26]2[C:22]\1=[CH:21][C:20]([S:17]([CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])=[CH:28][CH:27]=2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CCC[C@@H]1CN1CCCC1
Yield: 51.3 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (41 mg, 0.1 mmol) was condensed with 3,5-dimethyl-4-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (35 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solid was collected by vacuum filtration and purified on a silica gel column to give 36 mg (35%) of the titled compound.