Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N:17]1([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:21]=[CH:20][N:19]=[CH:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([OH:28])[C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[CH:31][CH:30]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Cn2ccnc2)cc1
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(Cn3ccnc3)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-5-nitro-indolinone and 4-(imidazol-1-ylmethyl)benzoic acid in dry DMF in the presence of TBTU, HOBT and Hunig's base.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:11][CH3:12])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc(CC(C)C)c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(CC(C)C)ccc1C(C)=O

Procedure:
46 g of 3 -isobutyl anisole are added to 500 cc of absolute benzene, and 22 g of acetyl chloride are added. 73 g of tin(IV) chloride are subsequently added dropwise while stirring and cooling at 5°-10°. After stirring at 23° for 16 hours, the reaction mixture is poured on ice, washed once with 2 N hydrochloric acid, twice with a 2 N caustic soda solution and once with water, and the water phases are again extracted twice with benzene. The organic phases are dried over anhydrous sodium sulphate and concentrated. The desired product is obtained in amorphous, pure form from methanol with the careful addition of water. NMR spectrum (CDCl3) inter alia δ=0.9 d (J=6 Hz), 1.3-2.3 m, 2.45 s, 2.55 s, 3.9 s, 6.6-6.9 m, 7.65 d (J=8.6).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=1[C:19]([OH:21])=[O:20]>O1CCCC1>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]2[C:13]([O:21][C:19](=[O:20])[C:11]=12)=[O:15]
Reactant: COc1cccc(C(=O)O)c1C(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1cccc2c1C(=O)OC2=O
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Acetic anhydride (70 ml) was added to a mixture of 3-methoxyphthalic acid (51.0 g, 0.26 mol) in anhydrous tetrahydrofuran (250 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the solvent was removed in vacuo and the resulting solid material was dried in a vacuum oven at 50° C. overnight to afford 3-methoxyphthalic anhydride (45.9 g, 99%) as a colourless solid. 1H NMR (DMSO-d6) 7.97 (1H, dd), 7.63 (1H, d), 7.60 (1H, d), 4.02 (3H, s). MS: [M+H]+ 179.
Reaction SMILES: ClS(N=C=O)(=O)=O.N[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.NC1C=C(C=CC=1OC)C(NC1C=CC(F)=C(F)C=1)=O.C(N(CC)CC)C.[OH-].[Li+]>C(Cl)Cl.Cl.O.O1CCCC1>[C:13]([OH:15])(=[O:14])[C:12]1[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(N)cc1
Agent: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6.1 %

Procedure:
Chlorosulfonyl isocyanate (1.7 mL, 19.5 mmol) was dissolved in 20 mL of methylene chloride and cooled to 0° C. Methyl 4-aminobenzoate (2.5 g, 16.2 mmol) dissolved in 20 mL of methylene chloride was added dropwise to the chlorosulfonyl isocyanate solution. Upon stirring, a precipitate slowly formed. After 2 hours, the mixture was filtered, and the solid collected and dried; yield 4.21 g. A portion of this solid (1.0 g, 3.4 mmol) was placed in a flask containing 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.95 g, 3.4 mmol), triethylamine (1.2 mL, 8.5 mmol), and 50 mL of tetrahydrofuran. The mixture was stirred overnight. The tetrahydrofuran was evaporated under reduced pressure, and the resulting solid was dissolved in methylene chloride (50 mL). The methylene chloride was sequentially washed with 25 mL of 1N hydrochloric acid, water, and brine. A precipitate was formed, which was recovered by filtration and triturated with a mixture of methylene chloride and methanol. The solid was dried under vacuum; yield 0.67 g. A portion of this solid (0.30 g, 0.6 mmol) was suspended in a 9:1 mixture of tetrahydrofuran and water (10 mL). Lithium hydroxide (48.3 mg, 2.0 mmol) was added, and the resulting mixture was refluxed overnight. The mixture was diluted with 1N hydrochloric acid (50 mL) and extracted with diethyl ether (1×50 mL) and ethyl acetate (1×50 mL). The organics were combined, dried with magnesium sulfate, and filtered. The resulting filtrate was evaporated under reduced pressure to give a white foam. The foam was triturated with hot ethyl acetate and ether, then dried under vacuum to give 0.12 g of benzoic acid, 4-[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]amino]-. Microanalysis for C22H18F2N4O7S.0.25 H2O.0.1 C4H8O2; calculated C=50.40; H=3.64; N=10.50. found: C=50.29; H=3.71; N=10.14.
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[C:5]([O-:8])([O-])=[O:6].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[F:19][C:20]([F:31])([C:27]([F:30])([F:29])[F:28])[C:21]([F:26])([F:25])C(Cl)=O>C(Cl)(F)(F)C(Cl)(Cl)F>[F:31][C:20]([F:19])([C:27]([F:28])([F:29])[F:30])[C:21]([F:25])([F:26])[C:1]([O:4][O:8][C:5](=[O:6])[C:21]([F:26])([F:25])[C:20]([F:31])([F:19])[C:27]([F:30])([F:29])[F:28])=[O:3]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: O=C(OOC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.3 h
Yield: 37 %

Procedure:
A round-bottom flask is charged with 50 ml of CFC-113 and 2.0 g of sodium percarbonate (13 mmoles or 19 mmoles of H2O2 equivalent). After chilling the contents of the flask to 0° C., 3.73 ml of heptafluorobutyryl chloride (25 mmoles) is added and the resulting slurry is stirred magnetically for 3.3 hours. The reaction mixture is filtered through a pad of Drierite® on glass wool, washing through with fresh CFC-113, an operation assumed to remove any unreacted percarbonate and any free H2O2. The filtrate, now measuring 45 ml in volume, is found to be 0.10 M in peroxide for a 37% yield based on starting heptafluorobutyryl chloride. In order to make sure that all of the sodium percarbonate and hydrogen peroxide has been removed by filtration through Drierite®, the peroxide solution is washed three times with 45–50 ml of water. On retitration, the solution is found to still be 0.10 M in peroxide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([Cl:33])[C:30]([O:34][CH3:35])=[CH:29][C:28]=1[O:36][CH3:37])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([Cl:19])=[N:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:23][C:24](=[O:25])[NH:26][C:27]2[CH:32]=[C:31]([Cl:33])[C:30]([O:34][CH3:35])=[CH:29][C:28]=2[O:36][CH3:37])[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccnc(Cl)c2c1=O
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3c(Cl)nccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vial is charged with (5-Chloro-2,4-dioxo-1,4-dihydro-2H-pyrido[4,3-d]pyrimidin-3-yl)-acetic acid tert-butyl ester (53.1 mg, 0.17 mmol), 2-Bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (58.1 mg, 0.187 mmol), and Cs2CO3 (124.3 mg, 0.34 mmol). The mixture is treated with DMF (3 ml) and the solution stirred at RT overnight. The reaction mixture is treated with water and the product extracted with EtOAc (3×10 ml). The organic extracts are combined and washed with water (2×10 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude material is purified using flash column chromatography with an eluent system of isohexane:EtOAc to give the title compound; [M+H]+ 539.
Reaction SMILES: [C:1]([S:26]([NH:29][CH2:30][CH3:31])(=[O:28])=[O:27])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>>[C:1]([S:26]([N:29]([CH2:34][CH2:33][C:32]([OH:36])=[O:35])[CH2:30][CH3:31])(=[O:27])=[O:28])([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:24])([F:25])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CC(=O)O
Product: CCN(CCC(=O)O)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Comparative Example C5 was prepared by the Michael addition of C8F17SO2N(C2H5)H to acrylic acid to produce C8F17SO2N(C2H5)CH2CH2CO2H. GLC analysis indicated about 20% unreacted starting material was present. The acid was then converted to the potassium salt.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][O:17][C:16]3[CH:19]=[C:20]4[C:24](=[CH:25][C:15]2=3)[CH2:23][CH2:22][O:21]4)[C:7]1=[O:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[I-].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[O:26]=[C:7]1[C:8]2([CH2:18][O:17][C:16]3[CH:19]=[C:20]4[C:24](=[CH:25][C:15]2=3)[CH2:23][CH2:22][O:21]4)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([CH:29]=[CH:28][CH:27]=1)[O:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CBr
Reactant: O=C1N(Cc2cccc(O)c2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a stirred solution of 1′-(3-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.46 g, 1.18 mmol) in N,N-dimethylformamide (4 mL) were added potassium carbonate (0.32 g, 2.36 mmol), ethyl bromoacetate (0.20 mL, 1.77 mmol), and potassium iodide (0.024 g, 0.14 mmol) at ambient temperature. The mixture was stirred at 40° C. for 16 h. Water (50 mL) and ethyl acetate (150 mL) were added to the mixture. The organic solution was separated and the aqueous layer was extracted with ethyl acetate (2×80 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate from 2:1 to 1:1) to afford ethyl {3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]phenoxy}acetate (0.52 g, 93%): mp 45-46° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.15 (m, 3H), 7.06-6.96 (m, 2H), 6.90 (br s, 1H), 6.84-6.76 (m, 2H), 6.50 (s, 1H), 6.43 (s, 1H), 5.07-4.96 (m, 2H), 4.87-4.78 (m, 1H), 4.75-4.68 (m, 1H), 4.60-4.50 (m, 4H), 4.22 (q, J=7.1 Hz, 2H), 3.11-2.91 (m, 2H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.9, 168.7, 161.8, 161.3, 158.2, 142.0, 137.6, 132.7, 130.0, 128.7, 123.8, 123.4, 120.7, 120.2, 119.9, 118.9, 114.0, 113.7, 109.2, 93.2, 80.6, 72.4, 65.4, 61.4, 57.7, 44.0, 29.0, 14.1; MS (ES+) m/z 471.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19](O)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH2:8][CH3:9])=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCN1CCCC1CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)Cc1ccc(Cl)c(Cl)c1
Yield: 96.4 %

Procedure:
2-Aminomethyl-1-(ethyl)pyrrolidine (Aldrich) (3.2 g, 25 mmol) and 3,4-dichlorophenylacetic acid (7.7 g, 37.6 mmol, 1.5 eq) were coupled in CH2Cl2 in the presence of DCC (10.6 g, 51 mmol, 2 eq) as described in Example 7 to give the desired product (7.6 g, 97%) as a colorless oil: 1H-NMR (CDCl3) ∂7.41 (d, J=8.2 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.13 (dd, J=2.0, 8.2 Hz, 1H), 6.13 (br s, 1H), 3.51 (s, 2H), 3.37 (m, 1H), 3.07 (m, 2H), 2.65 (m, 1H), 2.53 (m, 1H), 2.04-2.21 (m, 2H, CH2CH3 ), 1.81 (m, 1H), 1.67 (m, 1H), 1.35-1.60 (complex m, 2H), 0.99 (t, J=7.2 Hz, 3H); CIMS (MH+ calcd for C15H20Cl2N2O): 315. Found (MH+): 315; Anal. (calcd for C15H20Cl2N2O): C,H,N.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19].O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:7]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C(c1ccc(O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(c1ccc(O)c([N+](=O)[O-])c1)C1CCCC1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
22.9 g (0.1 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclopentyl-acetate are dissolved in 50 ml of CH2Cl2 and added dropwise at 5° C. to a solution of 50 ml of conc. HNO3 /50 ml of H2O. The mixture is stirred for 15 min, then 100 ml of H2O are added and the organic phase is separated off. The aqueous phase is extracted three times with 50 ml of CH2Cl2, and the organic phases are washed 5 times with water, dried, concentrated to a small volume and filtered through silica gel. After concentration, the product is obtained in 71% yield (20 g). The product is further processed in crude form.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Br)(Cl)Cl.O>CCCCCC.O1CCCC1>[Br:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nccc1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a mixture of 17.6 g of N,N-dimethyl-1H-pyrazole-1-sulfonamide and 200 ml of tetrahydrofuran was added dropwise 80 ml of a 1.3M solution of n-butyl lithium in hexane at −78° C., and the resulting mixture was stirred at −78° C. for 15 minutes. To the mixture, a solution of 35.8 g of 1,2-dibromo-1,1,2,2-tetrachloroethane in 60 ml of tetrahydrofuran was added dropwise, and the resulting mixture was stirred at −78° C. for 15 minutes. The reaction mixture was returned to room temperature, and stirred for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 21.3 g of 5-bromo-N,N-dimethyl-1H-pyrazole-1-sulfonamide of the formula:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:30]1COCO[CH2:31]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@@H:15]([CH2:31][OH:30])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1OCOCO1
Reactant: CC(C)CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Intermediate (2a) (14.5 g, 46.3 mmol) was dissolved in DCM (151 mL, 2.4 mol) and stirred at 0° C. under nitrogen. 1 M titanium tetrachloride in DCM (48.6 mL) was added and stirred for 15 minutes. DIPEA (8.9 mL, 51.0 mmol) was added dropwise at 0° C. and the mixture was stirred for 75 minutes. 1,3,5-Trioxane (4.6 g, 51.0 mmol) in DCM (30 mL) was then added. After 10 minutes a second equivalent of 1 M titanium tetrachloride in DCM (48.6 mL) was added and the mixture stirred at 0° C. for 5 hours. The reaction was then quenched with 250 mL of saturated ammonium chloride. Water and DCM were added, and the aqueous phase was extracted twice more with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to provide intermediate (2b) (13.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([NH:10][C:11]2[CH:26]=[C:25]([F:27])[C:14]([C:15]([O:17]CC3C=CC=CC=3)=[O:16])=[C:13]([F:28])[CH:12]=2)=[O:9])=[CH:6][C:5]=1[C:31]([F:34])([F:33])[F:32])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([F:28])[C:14]([C:15]([OH:17])=[O:16])=[C:25]([F:27])[CH:26]=2)=[O:9])=[CH:6][C:5]=1[C:31]([F:33])([F:34])[F:32])[CH3:2]
Reactant: CCOc1ccc(C(=O)Nc2cc(F)c(C(=O)OCc3ccccc3)c(F)c2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(C(=O)Nc2cc(F)c(C(=O)O)c(F)c2)cc1C(F)(F)F
Yield: 98.8 %

Procedure:
Benzyl 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoate (4) (25 mg, 52 μmol) was dissolved in methanol (10 mL) and was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (10 bar). The solvent was removed in vacuo to afford 4-(4-ethoxy-3-(trifluoromethyl)benzamido)-2,6-difluorobenzoic acid (XXX-02) (20 mg, 97%) as a white solid: m/z 388.1 (M−H)− (ES−). 1H NMR (400 MHz, MeOD) δ: 8.23 (1H, d), 8.19 (1H, dd), 7.53 (2H, dt), 7.30 (1H, d), 4.26 (2H, q), 1.46 (3H, t).
Reaction SMILES: [Li]CCCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C@:32]1([OH:38])[C:33]2[N:34]([CH:35]=[N:36][CH:37]=2)[C@@H:30]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[F:21])[CH2:31]1
Reactant: c1ccc2scnc2c1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2C[C@](O)(c3nc4ccccc4s3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a 1.6 M solution of n-BuLi in hexane (0.29 mL, 0.46 mmol) cooled to −78° C. was added a solution of benzo[d]thiazole (56 mg, 0.42 mmol) in THF (1 mL). The crude was stirred at −78° C. for 1 hr. This solution was then cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) cooled at −78° C. After stirring at −78° C. for 2 hrs, the crude was warmed to room temperature. The crude was stirred at room temperature for 1 hr. The crude was quenched with sat. NH4Cl. The crude was diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 18 mg of the entitled product as the major diastereomer. MS 377.0 (M+H); LCMS condition A, retention time 1.23 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.09 (dd, 1H), 3.84 (dd, 1H), 5.96 (d, 1H), 7.02 (s, 1H), 7.24-7.53 (m, 6H), 7.85 (d, 1H), 7.93 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[O:14][N:13]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]([C:12]2[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[O:14][N:13]=2)=[C:10]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)OC)c2Cl)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
1.23 g (3.4 mmol) of methyl 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoate are dissolved in 30 ml of tetrahydrofuran/20 ml of water and treated with 0.15 g (3.8 mmol) of sodium hydroxide. After stirring at room temperature for 18 hours, the reaction mixture is concentrated, adjusted to pH 2 using 2N hydrochloric acid and extracted with dichloromethane. 1.05 g (94.8% of theory) of 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoic acid are obtained as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[N+:11]([O-])=O.[Cl-].[NH4+].CO>[Zn].O>[NH2:11][C:3]1[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH:8]=[CH2:9])[C:2]=1[Cl:1]
Reactant: C=CCn1nc(C)c([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: C=CCn1nc(C)c(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A mixture of 0.5 g (0.00248 mole) of 5-chloro-3-methyl-4-nitro-1-(2-propenyl)-1H-pyrazole (XX), 1.6 g (0.0198 mole) of ammonium chloride, 1.6 g of zinc powder, 20 mL of methanol and 20 mL of water was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with ethyl acetate-hexane (1:1) gave 0.10 g of 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), which was identical to the material prepared in Example 88 (method 1) above.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.Cl[Sn:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH3:22][Sn:21]([CH3:24])([CH3:23])[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccsc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1[Sn](C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl (2-bromo-3-thienyl)carbamate (4.81 g, 17.3 mmol) in THF (42 mL) was added 2.5 M n-butyllithium in hexanes (15.2 mL, 38.0 mmol) dropwise at −78° C. After stirring for 45 min, 1.0 M chlorotrimethylstannane in THF (19.0 mL, 19.0 mmol) was added. The resulting mixture was allowed to warm to room temperature. The reaction was quenched with brine (70 mL) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product. 1H NMR (300 MHz, CDCl3) δ 7.49 (1H, d, J=4.8 Hz), 7.13 (1H, d, J=4.8 Hz), 6.39 (1H, brs), 1.50 (9H, s), 0.36 (9H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:22])[C:10]([C:13]2([C:17]([O:19]CC)=[O:18])[CH2:16][CH2:15][CH2:14]2)=[N:11][N:12]=1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:22])[C:10]([C:13]2([C:17]([OH:19])=[O:18])[CH2:14][CH2:15][CH2:16]2)=[N:11][N:12]=1
Reactant: CCOC(=O)C1(c2nnc(-c3ccccc3Cl)n2C)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(-c2ccccc2Cl)nnc1C1(C(=O)O)CCC1

Procedure:
Ethyl 1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclobutanecarboxylate was reacted with potassium hydroxide in hydrous ethanol at room temperature to obtain 1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclobutanecarboxylic acid.