Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:15][O:16][C:17]1[C:25]([CH3:26])=[C:24]2[C:20]([C:21](=[O:27])[O:22][CH2:23]2)=[C:19]([O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:18]=1[CH2:35]/[CH:36]=[C:37](\[CH3:40])/[CH2:38]Br>CN(C=O)C>[CH3:34][O:33][CH2:32][CH2:31][O:30][CH2:29][O:28][C:19]1[C:18]([CH2:35]/[CH:36]=[C:37](\[CH3:40])/[CH2:38][CH:7]([P:3]([O:5][CH3:6])([O:2][CH3:1])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:17]([O:16][CH3:15])[C:25]([CH3:26])=[C:24]2[C:20]=1[C:21](=[O:27])[O:22][CH2:23]2
Reactant: CCOC(=O)CP(=O)(OC)OC
Reactant: COCCOCOc1c(C/C=C(\C)CBr)c(OC)c(C)c2c1C(=O)OC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2)P(=O)(OC)OC
Reaction time: 0.17 h

Procedure:
To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° was added 50% NaH/oil (33 mg), and the mixture stirred for 10 minutes. (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy7-methyl -3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (600 mg) was added at the same temperature and allowed to reach room temperature in 30 minutes. The reaction was poured onto water and extracted with EtOAc. The organic layers were washed with water, dried over sodium sulfate, and evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by EtOAc) to obtain ethyl (E)-6-(4-methoxyethoxymethoxy -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(dimethylphosphono) -4-methyl-4-hexenoate as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(C)C)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCN2CCOCC2)ccc1N
Reaction time: 24 h

Procedure:
4-amino-3-methoxybenzoic acid (Aldrich; 5 g, 29.9 mmol) was stirred and dissolved in DMF (100 mL) at ambient temperature. 4-(2-aminoethyl)morpholine (Aldrich; 4.7 mL, 35.8 mmol) was added followed by DIPEA (15.6 mL, 89.7 mmol) and HATU (13.7 g, 36.0 mmol) causing a slight exotherm. The brown solution was stirred for 24 h and the solvent evaporated to a brown gum.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[NH:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:21])=[C:16]([F:29])[CH:15]=1>C(Cl)Cl>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:21])=[C:16]([F:29])[CH:15]=1
Reactant: COc1ccc(CNc2ccc(S(=O)(=O)Nc3nccs3)c(F)c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)c(F)c1
Reaction time: 1 h
Yield: 55 %

Procedure:
Trifluoroacetic acid (8 mL, 0.1 mol) was added to the mixture of the [A] 4-(2,4-dimethoxy-benzylamino)-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (2.59 g, 0.00612 mol) in methylene chloride (33 mL). The reaction mixture was stirred for one hour (turned into a purple solution) then concentrated to give the crude product, which was purified using Gilson preparative HPLC (reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8) to give the product as a yellow solid (0.92 g, 55%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][C:9]=1[OH:20].[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36]Br)[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]>O1CCCC1.CN(C)C=O>[CH2:21]([O:23][C:24]([C:26]1[C:27]2[S:35][CH:34]=[C:33]([CH2:36][O:20][C:9]3[CH:10]=[C:11]([C:14]4[N:15]=[N:16][N:17]([CH3:19])[CH:18]=4)[CH:12]=[CH:13][C:8]=3[CH3:7])[C:28]=2[C:29]([Cl:32])=[N:30][CH:31]=1)=[O:25])[CH3:22]
Reactant: Cc1ccc(-c2cn(C)nn2)cc1O
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(C)nn4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.56 g, 1.73 mmol) (Aldrich), 2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenol (0.24 g, 1.27 mmol) (from Example 21 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.40 g, 1.15 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in dichloromethane to give 4-chloro-3-[2-methyl-5-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenoxy-methyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.25 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]#[N:14])=[CH:10][C:9]=2[S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:4][CH:3]=1.[Br:22]Br.O>O1CCOCC1>[Br:22][C:10]1[C:9]([S:15]([C:18]([F:19])([F:21])[F:20])(=[O:16])=[O:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:12][C:11]=1[C:13]#[N:14]
Reactant: N#Cc1cc(S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Reactant: BrBr
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2)c(S(=O)(=O)C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
A solution of 5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole-2-carbonitrile (0.87 g, 0.0026 mol) in dioxane is cooled, treated with bromine (0.46 g, 0.00286 mol), stirred at room temperature for two hours, treated with additional bromine (0.21 g, 0.0013 mol), stirred overnight at room temperature, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water, saturated sodium meta-bisulfite solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as a tan solid (0.27 g, mp 170°-185° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]#[N:9].[OH2:17].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]([NH2:9])=[O:17]
Reactant: N#CC(N)c1ccc(F)cc1
Reactant: O
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(F)cc1
Reaction time: 3 h
Yield: 38 %

Procedure:
Then, 30 g of concentrated sulfuric acid was added to 1.45 g of water, to which 20 g of 2-amino-2-(4-fluorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 8.4 g (yield, 38%) of 2-amino-2-(4-fluorophenyl)acetamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:28][C@H:29]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C@H:30]([CH3:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(C(C)(C)C)(C)C>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.C1(C)C=CC=CC=1>[OH:28][C@H:29]([CH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C@H:30]([CH3:41])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:3]=2)=[CH:34][CH:33]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: NC(=O)Nc1cccc(Br)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: Cc1ccccc1
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccc(NC(N)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 120 °C
Yield: 61.5 %

Procedure:
Prepared according to the method described in Example 12b) from 3-bromophenylurea (0.215 g), ethanol (1 ml), toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.2 g, Example 11)), and tetrakis(triphenylphosphine)palladium (0) (0.02 g) with heating at 120° C. for 4 hours. After work-up, the residue was purified by normal-phase HPLC eluting a gradient of 0-25% ethanol in dichloromethane to give the title compound as a solid (0.116 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:28]([F:31])([F:30])[F:29])[CH2:17][C@H:16]2[CH3:32])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43](C)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([N:43]4[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:45][CH2:44]4)=[CH:3][CH:4]=3)(=[O:14])=[O:13])[C@H:16]([CH3:32])[CH2:17]2)=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(Br)c2ccccc12
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Yield: 66.9 %

Procedure:
A mixture of (2R)-1-[(4-bromo-1-naphthyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazine (250 mg, 0.47 mmol), 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (175.1 mg, 0.94 mmol), tris(dibenzylidineacetone)dipalladium (0) (4.3 mg, 0.0047 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (8.78 mg, 0.014 mmol) and sodium tert-butoxide (56.5 mg, 0.59 mmol) were charged to a microwave vial. Toluene (3.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 35 minutes. Reaction was complete as determined by TLC. Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine then dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography to yield tert-butyl 4-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-1-naphthyl]piperazine-1-carboxylate as yellow gum (200.1 mg, 66.9% yield).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([O-:25])=[O:24]
Reactant: COC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of methyl salicylate (15.2 g, 0.1 mol), 4-chloro-3-nitrobenzotrifluoride (22.6 g, 0.1 mol), and potassium carbonate (8.3 g, 0.06 mol) in dimethylformamide (100 mL) was stirred under argon and heated in an oil bath to 150° C. for 70 min. The reaction mixture was diluted with ethyl acetate (300 mL), filtered, and the residue washed with ethyl acetate. The combined filtrates were evaporated, and the crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a pale yellow solid; mp 69°-70° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[I-].ClC1C=CC=C[N+]=1C.[O:21]1[C@@H:25]2[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C@@H:24]2[NH:23][C:22]1=[O:33].CCCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:23]2[C@H:24]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:26][C@H:25]3[O:21][C:22]2=[O:33])=[O:10])[CH:2]=1
Reactant: O=C1N[C@H]2c3ccccc3C[C@H]2O1
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2C(=O)O[C@@H]3Cc4ccccc4[C@@H]32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of m-tolylacetic acid (8.57 g, 0.0571 mol), 2-chloro-1-methylpyridinium iodide (19.0 g, 0.0744 mol) and (3aS-cis)-(−)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one (10.0 g, 0.0571 mol) in CH2Cl2 (130 mL) were added TEA (18.0 mL, 0.129 mol) and 4-dimethylaminopyridine (DMAP, 1.39 g, 0.0114 mol) at 0° C. The reaction mixture was stirred at rt for 3 h then treated with hexane (130 mL). The resulting slurry was passed through a pad of silica gel, eluting with 3:2 EtOAc/hexane. The filtrate was concentrated to an oil and recrystallized in hot hexane to recover 13 g (74%) of the title compound as a white solid. HPLC: Rt=9.85 (Method E). MS (ES+): mass calculated for C19H17NO3, 307.36; m/z found 330.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.65 (d, J=7.6 Hz, 1H), 7.08-7.37 (m, 7H), 5.95 (d, J=6.8 Hz, 1H), 5.27-5.31 (m, 1H), 4.26 (dd, J=15.9, 39.1 Hz, 2H), 3.40 (d, J=3.5 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:20].[Na+:21]>O.O1CCOCC1>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:21]
Reactant: COc1ccccc1Oc1cccc2c1NC(=O)C2
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1Oc1cccc(CC(=O)[O-])c1N
Reaction time: 30 h
Yield: 49.6 %

Procedure:
A mixture of 2-oxo-7-(2-methoxyphenoxy)indoline (2.7 g) and sodium hydroxide (2.1 g) in water (30 ml) and dioxane (30 ml) was refluxed with stirring for 30 hrs. The reaction mixture was concentrated in vacuo, and the residue was dissolved in water and filtered. The filtrate was washed with diethyl ether, neutralized with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with saline, dried over magnesium sulfate and then evaporated in vacuo. The residue was treated with an aqueous solution of sodium bicarbonate, and the resultant oily substance (3.0 g) was crystallized by treating with ethyl acetate to give crystalline sodium 2-[2-amino-3-(2-methoxyphenoxy)phenyl]acetate (1.55 g). mp 101°-103° C. I.R. (NaCl, Nujol): 3500, 3400, 1615, 1600, 1580, 1500, 1470, 1390, 1310, 1265, 1200 cm-1.
Reaction SMILES: C(NS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)C.[CH2:20]([N:23]([CH2:40][CH3:41])[S:24]([C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])(=[O:26])=[O:25])[CH:21]=[CH2:22].[CH2:42]([O:44][P:45]([O-:49])[O:46][CH2:47][CH3:48])[CH3:43]>>[CH2:40]([N:23]([CH2:20][CH2:21][CH2:22][P:45]([O:46][CH2:47][CH3:48])(=[O:49])[O:44][CH2:42][CH3:43])[S:24]([C:27]([F:39])([F:38])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])(=[O:26])=[O:25])[CH3:41]
Reactant: C=CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOP([O-])OCC
Agent: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCOP(=O)(CCCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC

Procedure:
The procedure of Example 1 was repeated with the exception that N-ethylperfluorobutanesulfonamide was used in place of N-butyltrifluoromethanesulfonamide to make N-allyl-N-ethylperfluorobutanesulfonamide (b.p. 50°-55° C. at 0.12 to 0.10 torr). The latter was reacted with diethylphosphite to produce the desired compound, diethyl 3-(N-ethylperfluorobutanesulfonamido)propanephosphonate (b.p. 148°-152° C. at 0.4-0.5 torr). A solution of the phosphonate prepared in Example 3 (30.0 g, 0.062 mole) and bromotrimethylsilane (20.0 g, 0.130 mole) was stirred under a reflux condensor and calcium chloride drying tube for 24 hours, water (75 ml) was added, and then mixture stirred for 15 minutes. The resulting white precipitate was filtered and washed with water (50 ml) and diethylether (100 ml), then dried in an oven at 100° C. for 24 hours at 10-20 torr, to yield the desired compound, 3-(N-ethylperfluorobutanesulfonamido)propanephosphonic acid (m.p. 138.5°-140° C.).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([Mg]Br)=[CH2:10]>C1COCC1>[CH:9]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])=[CH2:10]
Reactant: O=Cc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1
Reaction time: 12 h

Procedure:
Benzaldehyde (342 mg) was mixed with THF (4 ml) and further mixed with vinylmagnesium bromide (1 N solution) (4 mL), followed by stirring for 12 hours to obtain the title compound (320 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:22])[CH2:23][N:31]3[CH2:32][CH2:33][C:28]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:29][CH2:30]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC2CO2)C1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC3(CC2)OCCO3)C1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a stirred solution of 3.20 g (9.64 mmol) of 1-[3-(4-chloro-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone and 2.07 g (14.5 mmol) of 1,4-dioxa-8-azaspiro[4.5]decane in CH2Cl2 (65 mL) was added 1.79 g (2.89 mmol) of Yb(OTf)3.H2O. The reaction was stirred overnight and was then directly purified by flash chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 3.70 g (81%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.35. MS (electrospray), m/z calculated for C24H31ClN4O4 [M++H], 475.20, observed 475.1.
Reaction SMILES: [CH3:1][N:2]1[C@:6]([CH2:13][OH:14])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5](=[O:15])[N:4]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:3]1=[O:28].CN(C1C=CC=CN=1)C.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH2:40][CH2:39]1>N1C=CC=CC=1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:4]2[C:5](=[O:15])[C:6]([CH2:13][O:14][C@@H:40]([CH2:39][CH:38]=[O:44])[C:41]([OH:43])=[O:42])([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:2]([CH3:1])[C:3]2=[O:28])=[CH:17][C:18]=1[C:24]([F:25])([F:27])[F:26])#[N:21]
Reactant: O=C1CCC(=O)O1
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)[C@@]1(CO)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO[C@@H](CC=O)C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 7 h

Procedure:
To a solution of 0.60 g of (S)-4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 24 mL of pyridine was added 19 mg of dimethylaminopyridine and 1.54 g of succinic anhydride. The mixture is stirred at 110° C. for 7 hours then evaporated to dryness. The crude product is washed with water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 50/50 heptane/ethyl acetate to give the desired compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([Cl:16])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2c(c1)OCCO2

Procedure:
A mixture of 1,4-benzodioxane-6-carboxylic acid (0.5 g), benzene (20 ml) and thionyl chloride (5 ml) is heated for one hour under reflux. The reaction mixture is evaporated to dryness under reduced pressure. To the residue is added benzene (50 ml), then the solvent is again distilled off to leave 1,4-benzodioxane-6-carbonyl chloride. This compound dissolved in benzene (20 ml) is added dropwise, while stirring, to a mixture of 1-(3,4,5trimethoxybenzyl)piperazine dihydrochloride (1 g), triethylamine (1.5 g) and N,N-dimethylacetamide (20 ml), followed by stirring at room temperature for 30 minutes. To the reaction mixture are added water (100 ml), ethyl acetate (200 ml) and hexane (50 ml), then extraction is conducted. The extract is washed with water, dried, and concentrated under reduced pressure. The residue as purified by means of a silica gel column chromatography (hexane:acetone=1:1-2:3) to afford an oily product, which is dissolved in ethyl acetate. To the solution is added 1N hydrogen chloride - acetic acid solution (5 ml), and the mixture is left standing. The supernatant is removed by decantation, and the precipitates are recrystallized from ethyl acetate to give 1-(1,4-benzodioxan-6-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.7 g) as colorless prisms, m.p. 180°-185° C.