Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[NH:15]1C2C(=CC=CC=2)C=C1C(OC)=O.CO.C(Cl)Cl>N(C)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: CNC
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
Stir ethyl indole-2-carboxylate 1 (X═H, 4.67 mmol) or methyl indole-2-carboxylate 2 (X═H, 4.67 mmol) in Me2NH/H2O (50 mL, 40%). Stir the reaction mixture at rt for 16 h monitoring by tlc (10% MeOH/CH2Cl2). Concentrate the mixture to minimum volume, dilute with H2O and collect the solid by filtration. Wash the filter cake with H2O and dry under vacuum at 60° C. to provide dimethyl amide 4 (X═H, R2═R3=Me), tlc Rf=0.65 (silica gel, 10% MeOH/CH2Cl2).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[NH:20][N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:20]2[N:19]=[CH:18][C:17]3[C:22](=[C:23]([F:25])[CH:24]=[C:15]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:16]=3)[C:21]2=[O:26])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: O=Cc1c(Br)cccc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Br)c3C=O)ncc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
1518 mg (5.75 mmol) of 2,6-dibromobenzaldehyde, 506 mg (2.30 mmol) of 6-tert-butyl-8-fluoro-2H-phthalazin-1-one, 1499 mg (4.60 mmol) of cesium carbonate, 42 mg (0.22 mmol) of copper(I) iodide, and 115 mg (0.479 mmol) of 4,7-dimethoxy-1,10-phenanthroline were weighed into a 20 mL reaction vial fitted with a stir bar and septum cap. Added 8 mL of anhydrous dioxane. Purged the reaction mixture with nitrogen for 15 min. Stirred at 100° C. for 16 h. Partitioned the reaction mixture between 25 ml, of 10% MeOH/CH2Cl2 and 25 mL of water. Separated phases and extracted the aqueous phase with 25 mL of 10% MeOH/CH2Cl2. Filtered to break the stable emulsion. The combined organic extracts were washed with 75 mL of brine, dried over MgSO4, and the solvent was removed on rotavap. Purified by silica gel flash chromatography using gradient elution with 0→40% EtOAc/hexane to obtain 406 mg of the title compound as a yellow solid. MS (ESI) doublet 403, 405 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:15][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine. LCMS (MH+): m/z=451.1, tR (minutes, Method G)=2.50
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([NH:10]C(=O)C)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]>Cl.CCO>[NH2:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:14]
Reactant: CC(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: Cl
Solvent: CCO
Product: Cc1c(N)ccc(C#N)c1Cl
Yield: 59.5 %

Procedure:
A solution of N-(3-chloro-4-cyano-2-methylphenyl)acetamide (25 g, 0.119 mol) in 250 mL of concentrated HCl/EtOH (1:1) was refluxed 2 hrs. The EtOH was concentrated and ethyl acetate was added to the residue and the aqueous layer was neutralized with addition of saturated NaHCO3 solution. The organic layer was separated and dried over Na2SO4 and concentrated to give the crude aniline which was further purified by column chromatography using DCM as a solvent to yield the title compound (11.8 g, 60%).
Reaction SMILES: OC[C@@H](N[C:11](=[O:25])[C@@:12]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:27]>O1CCOCC1>[CH3:24][C@@:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:25])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)CC[C@](C)(C(=O)O)c1ccccc1
Yield: 73 %

Procedure:
To a solution of Example 40A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.02 g, 73%). 1H NMR (300 MHz, CDCl3): δ ppm 0.88 m, 6 H) 1.09 m, 2 H) 1.52 m, 4 H) 1.99 m, 2 H) 7.35 m, 5 H).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].CO[CH2:22][CH:23]([CH3:34])[CH2:24][C@@H:25]([C:27]([O:29][P:30]([NH2:33])(=[O:32])[O-:31])=[O:28])[NH2:26]>CN.CO>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].[CH3:4][NH:1][CH2:22][CH:23]([CH3:34])[CH2:24][C@@H:25]([C:27]([O:29][P:30]([NH2:33])(=[O:32])[O-:31])=[O:28])[NH2:26]
Reactant: COCC(C)C[C@H](N)C(=O)OP(N)(=O)[O-]
Agent: CN
Agent: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CO
Product: CNCC(C)C[C@H](N)C(=O)OP(N)(=O)[O-]
Reaction time: 1200 h

Procedure:
Compound 21 (38 mg) was dissolved in 2 mL of 10 M methyl amine in methanol and stirred in a sealed vial for 50 d. The reaction mixture was then concentrated under reduced pressure. Flash chromatography (SiO2, 5:2:0.25 CHCl3/MeOH/H2O containing 0.5% conc. NH4OH) gave the desired product (25 mg) was awhite solid. 1H NMR (D2O, 300 MHz) 7.588 (d, J=1.1 Hz, 1H), 6.081 (t, J=6.8 Hz, 1H), 4.275 (m, 1H), 3.995 (m, 1H), 3.896-3.746 (m, 2H), 3.403 (m, 1H), 2.570 (s, 3H), 2.320 (m, 2H), 1.753 (d, J=1.1 Hz, 3H), 1.504 (m, 1H), 1.352-1.225 (m, 2H), 0.693 (d, J=6.6 Hz, 6H); 31P NMR (D2O, 121 MHz) 6.359.
Reaction SMILES: [CH2:1]([C:6]1[CH:22]=[CH:21][C:9]([C:10](=[O:20])[CH2:11][C:12]2[CH:13]=C([CH:17]=[CH:18][CH:19]=2)C#N)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:23]([OH:26])(=[O:25])[CH3:24]>S(=O)(=O)(O)O.O>[CH2:1]([C:6]1[CH:22]=[CH:21][C:9]([C:10](=[O:20])[CH2:11][C:12]2[CH:13]=[C:24]([CH:17]=[CH:18][CH:19]=2)[C:23]([OH:26])=[O:25])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCc1ccc(C(=O)Cc2cccc(C(=O)O)c2)cc1

Procedure:
First, 3-cyanophenylacetic acid (3 g, 0.019 mol) is heated under reflux in thionyl chloride (50 ml) for 90 minutes. The excess thionyl chloride is then removed by distillation and the residual acid chloride added in one portion to a solution. 1-phenylpentane (2.76 g, 0,019 moles) in methylene chloride (10 ml). Anhydrous aluminum chloride (2.98 g) is added in small portions over 10 minutes. The reaction mixture is then heated under reflux for 1 hour, cooled and poured into a mixture of ice water (250 ml) and concentrated hydrochloric acid (50 ml). The mixture is extracted with ether (2×100 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica (hexane: ethyl acetate at 90:10 ) to yield 3-(4-pentylphenacyl) benzonitrile (1.13 g, m.p. 73° C.). This nitrile is heated under reflux in a mixture of 75% sulfuric acid (8 g) and acetic acid (8 g) for 90 minutes. The reaction mixture is then diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane to provide 3-(4-pentylphenacyl)benzoic acid (0.97 g), m.p. 109°-111° C., which was identified by IR and NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O>[CH3:22][C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:28])=[CH:30][CH:31]=1)([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 16.8 g. (0.1 mol) 4-methoxy-2-nitroaniline in 150 ml. anhydrous pyridine are added dropwise, while cooling with ice, 19.7 g. (0.1 mol) 4-tert.-butylbenzoic acid chloride. The reaction mixture is stirred for 1 hour at ambient temperature, poured into 1 liter of cold water and the precipitate obtained is filtered off with suction. There are obtained 32.3 g. (98% of theory) of the title compound in the form of yellow crystals; m.p. 103°-107° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+].O>CO>[C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:14])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)c2ccccc2-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCC(=O)c2ccccc2-c2ccccc2)cc1
Yield: 66.4 %

Procedure:
A solution of 4-[-2-[[1,1'-biphenyl]-2-yl]-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.563 g) in warm methanol (5 mL) was treated with 1N sodium hydroxide (3.3 mL). Within 5 minutes water (30 mL) was added, then after the methanol was removed in vacuo, the mixture was acidified with 1N hydrochloric acid (4.1 mL) and extracted with dichloromethane (1×60 mL, 2×10 mL). The combined organic layers were washed with water, then dried (MgSO4) and evaporated. The resulting yellow foam was taken up in diethyl ether, and after the the mixture was filtered to remove some insoluble material, the fillrate was evaporated and the residue was lyophilized from benzene to furnish 0.36 g of 4-[2-[[1,1'-biphenyl]-2-yl]-2-oxoethoxy]-alpha-oxobenzeneacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10](=[O:23])(=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10](=[O:23])(=[O:22])[C:11]=3[CH:16]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCBr)cc21
Product: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCN3CCC3)cc21

Procedure:
According to the method in example 9, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxide and azetidine were converted to yield 6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxide as yellow solid, MS: 435 (MH+, 1Br).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH:38]4[CH2:40][CH2:39]4)=[N:19][C:20]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)=[CH:21][C:22]=3[C:23]([F:26])([F:25])[F:24])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH:38]1([C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:41])=[O:3])=[CH:10][CH:11]=3)=[C:22]([C:23]([F:24])([F:25])[F:26])[CH:21]=[C:20]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[N:19]=2)[CH2:40][CH2:39]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3C3CC3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3C3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 g], {6-[2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as pink solid.
Reaction SMILES: CC([O:5][C:6](=[O:42])[C@H:7]([NH:25][C@H:26]([C:31](N(C1CCS(=O)(=O)C1)C)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])(C)C.[NH:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[O:24]=[C:11]1[C:12]2[CH:13]=[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]3=[CH:16][C:17]=2[C:18](=[O:19])[N:10]1[CH2:9][CH2:8][C@@H:7]([NH:25][C@H:26]([C:31]([N:43]1[CH2:47][CH2:46][CH2:45][C@@H:44]1[C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:6]([OH:42])=[O:5]
Reactant: c1cncc(C2CCCN2)c1
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)N(C)C1CCS(=O)(=O)C1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)N1CCC[C@@H]1c1cccnc1

Procedure:
Prepared as described in Example 1, Part (a) using 3-pyrrolidin-2-yl-pyridine as HNR2R3 to afford the title compound as a dark solid; 145 mg.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].CI.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:32][N:5]([C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1)S(C)(=O)=O

Procedure:
Prepared analogously to Example 36 from (Z)-3-[1-(3-methylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone, methyliodide and potassium carbonate in acetone.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]([NH:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:30]=1[C:31]([F:34])([F:33])[F:32])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-].FC1C=CC(N2C(C(F)(F)F)=C(C(NC(CC3C=CC(C4C=CC(C(F)(F)F)=CC=4)=CC=3)C(O)=O)=O)C=N2)=CC=1>C1COCC1>[F:41][C:38]1[CH:39]=[CH:40][C:35]([N:29]2[C:30]([C:31]([F:34])([F:33])[F:32])=[C:26]([C:24]([NH:23][CH:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:14][CH:13]=4)=[CH:8][CH:7]=3)[C:3]([OH:42])=[O:2])=[O:25])[CH:27]=[N:28]2)=[CH:36][CH:37]=1
Reactant: COC(=O)C(Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)NC(=O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Agent: O=C(NC(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O)c1cnn(-c2ccc(F)cc2)c1C(F)(F)F
Yield: 91.5 %

Procedure:
A solution of above acid in DMF (3.0 mL) was reacted with (2S)-amino-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester Hydrochloride (0.300 g, 0.797 mmol), HBTU (0.300 g, 0.797 mmol), and DIEA (0.425 mL, 2.40 mmol) as described in general procedure A. The crude compound was purified by flash column chromatography on silica gel using CHCl3 as the mobile phase to give 0.290 g (61%) of 2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.140 g, 0.235 mmol) in THF (4.0 mL) was treated with LiOH (0.035 g) by general procedure I to afford (0.125 g, 92%) of the title compound 2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-(4′-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 582 (M+1)+. 1H NMR (DMSO-d6) 8.94 [d, 1H], 8.07 [s, 1H], 7.76 [m, 2H], 7.57 [m, 4H], 7.42 [m, 6H], 4.64 [m, 1H], 3.22 [m, 1H], 3.05 [m, 1H].
Reaction SMILES: C(=O)(O)[O-].[Na+].[C@H:6]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10][C@H:9]([C:12]([O-:14])=[O:13])[CH2:8][CH2:7]1.[K+].O.[CH:27](Cl)(Cl)[Cl:28]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C@H:6]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:7][CH2:8][C@H:9]([C:12]([O:14][CH2:27][Cl:28])=[O:13])[CH2:10][CH2:11]1
Reactant: ClC(Cl)Cl
Reactant: O=C([O-])[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Product: O=C(OCCl)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3.06 g (0.036 mole) sodium bicarbonate, 5.46 g (0.018 mole) potassium benzyl trans-1,4-cyclohexanedicarboxylate, 50 ml water and 500 ml chloroform is added 6.17 g (0.018 mole) tetrabutylammonium hydrogen sulfate and the mixture is stirred at room temperature overnight. The layers are separated. The aqueous layer is extracted twice with chloroform and the combined chloroform layers are dried and evaporated to dryness. The resulting tetrabutylammonium salt is taken up in methylene chloride (20 ml) and the solution added dropwise to 20 ml of bromochloromethane at 0° C. The resulting mixture is stirred at ambient temperature for 70 hours, the solvent evaporated and ethyl acetate added to the residue. The precipitated tetrabutylammonium bromide is removed by filtration, the filtrate dried (Na2SO4) and evaporated in vacuo to obtain 5 g (91%) of crude product. Purification by silica gel chromatography, eluting with 1:3 ethyl ether/hexane gave 1.9 g (35%) of the desired product as an oil. 1H-NMR (CDCl3) ppm (delta): 1.0-2.4 (m, 10H), 5.1 (s, 2H), 5.7 (s, 2H), 7.3 (s, 5H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])=[CH:11][CH:10]=1)[CH3:7].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][C:22]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CCCCCC.O1CCCC1.ClCCl>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][CH2:17][CH2:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=2)([CH3:18])[CH3:19])=[CH:23][C:22]=1[O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C#CC(C)(C)c1ccc(OCC)cc1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
0.01 mol of a solution of butyllithium in hexane is added at -30° C. with stirring to 1.9 g (0.01 mol) of 3-[p-ethoxyphenyl]-3-methyl-1-butine in 10 ml of absolute tetrahydrofuran. After stirring for 3 hours, a solution of 2.2 g (0.01 mol) of 4-fluoro-3-phenoxy-benzaldehyde in 10 ml of tetrahydrofuran is added to the reaction mixture. The reaction mixture is warmed to room temperature and, after stirring at this temperature for 5 hours, water and dichloromethane (100 ml each) are added. The organic phase is separated off and concentrated in vacuo. 3.6 g of crude product are obtained, which contains 85% of 1-[4-fluoro-3-phenoxy-phenyl]-4-[p-ethoxyphenyl]-4-methyl-pent-1-in-1-ol (in addition to 7% of the corresponding ketone) according to GC-MS analysis. The crude product is catalytically hydrogenated under the conditions described in Example 8 δ). 3 g of 1-[4-fluoro-3-phenoxy-phenyl]-4-[p-ethoxyphenyl]-4-methyl-pentane (89% pure according to GC-MS analysis=2.7 g=69% of theory) are obtained. The compound is obtained pure by chromatography on silica gel (nD20 : 1.5580).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: O=C(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.2 %

Procedure:
The product from Step B (52 mmol) was treated with tetrabutylammonium tribromide (25.5 g, 52.9 mmol) in methanol/methylene chloride (1/3, 240 ml) under nitrogen. After stirring 3 days at room temperature, the solvents were removed in vacuo, and the residue dissolved in diethyl ether (200 ml), washed with water (4×50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography on silica gel (120 g) eluting with hexanes/ethyl acetate (30/1) afforded the desired □-bromoacetophenone (6.23 g) as a crystalline solid: 1H NMR (300 MHz, CDCl3) δ 7.70–7.81 (m, 2H), 7.55 (t, J=7.7 Hz, 1H), 4.39 (s, 2H); CI MS m/z=251 [C8H5BrClFO+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:5]=[CH:4]1.[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:22]([O:28][CH2:29][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:5]=[CH:4]1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(OCc1ccccc1)c1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2cccc(C(=O)OCc3ccccc3)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.1 %

Procedure:
To a suspension of sodium hydride (174 mg) in tetrahydrofuran (8.0 ml) was added dropwise a solution of benzyl indole-7-carboxylate (700 mg) in tetrahydrofuran (7.0 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. Chloromethyl pivalate (461 mg) was added to the mixture and the solution was stirred at ambient temperature for 3 hours. The reaction was quenched with 1N hydrochloric acid and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded benzyl 1-pivaloyloxymethylindole-7-carboxylate (1.08 g) as a yellow oil.