Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][N:3]1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.S(Cl)(Cl)=O.[CH2:24](O)[CH3:25]>>[CH2:24]([O:8][C:7]([CH:6]1[CH2:5][CH2:4][N:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=2)[C:2]1=[O:1])=[O:9])[CH3:25]
Reactant: CCO
Reactant: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 57.5 °C
Yield: 65 %

Procedure:
A mixture of 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid obtained in step 1 (0.7 g, 2.56 mmol), thionyl chloride (0.36 g, 3.0 mmol), and ethanol (10 ml) were heated at 55-60° C. for 2 hours. The mixture was cooled and solvent was removed. The residue was dissolved in ethyl acetate (20 ml). The organic layer was washed with sat. NaHCO3 and saturated brine solution, dried over Na2SO4 and evaporated to obtain 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester as a yellow oil (0.5 g, 65%).
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:16]Br>C(#N)C>[C:1]1([S:7]([CH2:9][Br:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: CS(=O)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(CBr)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Methyl phenyl sulfoxide (21.644 g, 154.4 mmol) was dissolved in anhydrous pyridine (27.4 mL, 2.2 eq) and dry acetonitrile (100 mL). The solution was cooled to −40° C. under an argon atmosphere. A solution of bromine (49.4 g, 2eq) in dry acetonitrile (50 mL) was added slowly, maintaining the same temperature. The mixture was stirred at −40° C. for 1 h and then overnight at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. The organic layer was washed with Na2S2O3 20%, dried over anhydrous Na2SO4 and concentrated to dryness.
Reaction SMILES: [NH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O.C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC/C=C\CCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCC/C=C\CNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 29.5 %

Procedure:
A rapidly stirred solution of (Z)-7-aminohept-5-enoic acid (0.61 g), sodium hydroxide (0.51 g) in water (5 ml) was treated with 4-chlorobenzenesulphonyl chloride (0.9 g) in chloroform (2.5 ml). The solution was stirred for 24 hours then evaporated with chloroform (4×15 ml). The aqueous layer was treated with hydrochloric acid to pH=1 and extracted with chloroform (4×40 ml). These chloroform extracts were combined, dried over magnesium sulphate and evaporated to dryness. The residue was recrystallised from isopropanol to give the title compound (0.4 g). N.M.R; 250 MHz; δ(CDCl3) (ppm): 1.7 (m, 2H) 2.05 (m, 2H), 2.35 (m, 2H), 3.6 (t, 2H), 4.9 (t, 1H) 5.3 (m, 1H), 5.45 (m, 1H) 7.45 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([OH:28])[C:26]=1[OH:27])[CH:22]=[O:23]>>[CH2:2]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:28][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[C:26]=1[O:27][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH:22]=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1cc(O)c(O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCC

Procedure:
The title compound was prepared according to the method as described in Example 9 above from 1-bromohexadecane and 3,4,5-trihydroxy-benzaldehyde, except the reaction mixture was heated at reflux for 4 days. After cooling, the solid material was removed by filtration and the solid washed with dichloromethane. The combined organic extracts were evaporated under reduced pressure to yield the title compound which was recrystallised from dichloromethane-ethanol.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]2[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][N:6]2[CH:13]=1.S(Cl)([Cl:16])=O>ClC(Cl)Cl>[ClH:16].[Cl:1][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:13]=[C:3]([CH3:2])[N:4]=[C:5]2[CH:10]=1
Reactant: Cc1cn2ccc(CO)cc2n1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1cn2ccc(CCl)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred mixture of 10.7 parts of 2-methylimidazo[1,2-a]pyridine-7-methanol monohydrochloride and 150 parts of trichloromethane were added dropwise 9.6 parts of thionyl chloride. The resulting solution was stirred for 15 minutes at room temperature. The reaction mixture was evaporated in vacuo and the residue was stirred in 80 parts of 2-propanone. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 11.8 parts (100%) of 7-(chloromethyl)-2-methylimidazo[1,2-a]pyridine monohydrochloride; mp. 178.5 (intermediate 16).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH3:13][C:14]1[N:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][CH:15]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: Cc1cccc(C=O)n1
Product: Cc1cccc(C=NNC(=S)NC2CC3C=CC2C3)n1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.545 mmol) and 6-methyl-2-pyridine carboxaldehyde (66 mg, 0.545 mmol) similar to Example 3 and isolated as a pale white solid (83 mg, 53%). 1H NMR (CDCl3): 10.46 (s, 1H), 8.00 (s, 1H), 7.68-7.61 (m, 3H), 7.15 (dd, J=2.1, 6.3 Hz, 1H), 6.22-6.13 (m, 2H), 4.28 (s, 1H), 3.07 (s, 1H), 2.94 (s, 1H), 1.91-1.83 (m, 1H), 2.57 (s, 3H), 1.64 (d, J=9.0 Hz, 1H), 1.53 (d, J=8.7 Hz, 1H), 1.49-1.43 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[Br:14]Br.O>C(Cl)(Cl)Cl.C(OCC)C>[Br:14][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: CC(=O)c1ccccc1C(F)(F)F
Reactant: BrBr
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CBr)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45° C. for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2′-(trifluoromethyl)acetophenone, yield 66%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10](Cl)(=[O:12])[CH3:11].O>CN(C)C1C=CC=CC=1>[C:10]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(Br)cnc1N
Reactant: CC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CC(=O)Nc1ncc(Br)cc1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
To a solution of 2-amino-5-bromo-3-methylpyridine (300 mg) in N,N-dimethylaniline (486 mg) was added acetyl chloride (138 mg), and the mixture was stirred for 3 hours at 70° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform) to give 2-acetamido-5-bromo-3-methylpyridine (120 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29](=O)[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:30])[CH2:28][C:27]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc([N+](=O)[O-])c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Yield: 49.5 %

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) (1.1 g, 4.0 mmol) and 2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) (1.23 g, 4.4 mmol) according to the general procedure K. Obtained as a light yellow solid (989 mg).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O.O1CCOCC1>[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:16])[C:1]=1[OH:4]
Reactant: O=C([O-])[O-]
Reactant: NCCCCCCCC(=O)O
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)NCCCCCCCC(=O)O)c1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A 50% (by weight) solution of potassium carbonate (24 mL, 36 g, 0.127 mol, 1.23 eq), 8-aminocaprylic acid (16.44 g, 0.103 mol, 1.00 eq), and water (20 mL) were added to a 250 mL round bottom flask equipped with a magnetic stir bar and an addition funnel. The white cloudy mixture was treated with a solution of oligo(3-methylsalicylate) (15.90 g, 0.114 mmol 1.11 eq) and dioxane (90 mL), added over five minutes. The addition funnel was replaced with a condenser, and the reaction mixture was heated to 90 degrees C. for 4 hours (at which time the reaction was determined to have finished, by HPLC). The clear orange reaction mixture was cooled to 40 degrees C. and acidified to pH=1 with 3% (by vol.) aqueous hydrochloric acid. All the dioxane and some of the water were stripped (60 degrees C., 50 mm). The water layer from the resulting two-phase mixture was decanted while still warm. The orange oil was crystallized from 65% ethanol-water to give a tan solid upon cooling to -10 degrees C. The solid was recrystallized from 50 mL of 65% ethanol-water. The off-white solid was washed with hot water (30 mL) to remove most of the remaining salicylic acid. The solid was recovered by filtration and was dried over 6 hours in a 50 degrees C. vacuum oven. The N-(3-methylsalicyloyl)-8-aminocaprylic acid was isolated as a light tan solid (12.32 g, 41%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C@@H:20]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH2:21][OH:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH2:34][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C@@H:20]([O:23][Si:24]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:32])[CH3:33])[CH:21]=[O:22])=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@@H](C=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Freshly distilled dimethyl sulfoxide (0.85 g, 10.8 mmol) was added by syringe to a -78° C. solution of oxalyl chloride (0.69 g, 5.41 mmol) in anhydrous THF (22.6 mL). After 10 minutes, the alcohol of Step 3 (2 g, 4.51 mmol) in anhydrous THF (2.3 mL) was added over a period of 1.2 minutes to the -78° C. solution. The solution was stirred for 20 min. and then triethylamine (2.28 g, 22.6 mmol) was added dropwise. The 78° C. bath was removed and the reaction solution was allowed to warm to room temperature. After 1 hour at room temperature, the white, opaque mixture was poured into H2O (25 mL). The solution was extracted with ether (2×5 mL). The combined organic layers were washed with 1N HCl (25 mL), 5% NaHCO3 (25 mL) and brine (25 mL), and then dried with MgSO4. The filtrate was concentrated at 30° C. in vacuo to give the title compound as a clear, pale yellow liquid (2.08 g, 104% crude yield, TLC, 10% ethyl acetate in hexane, Rf 0.32). 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:47]=[C:48]2[N:52]([CH3:53])[C:51](=[O:54])[NH:50][C:49]2=[O:55])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CO.C(O)(=O)C>O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8](/[CH:47]=[C:48]2\[C:49](=[O:55])[NH:50][C:51](=[O:54])[N:52]\2[CH3:53])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=C2C(=O)NC(=O)N2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
To a mixture of the E and Z-isomers of 5-[[2-butyl-3-[[2'-(N-triphenylmethyl-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-3H-imidazol-4-yl]methylene]-1-methyl-2,4-imidazolidinedione (0.400 g, 0.552 mmol ) was added methanol (50 mL) and glacial acetic acid (0.2 mL). This white heterogeneous mixture was refluxed for 3 hour in which time a solution formed. The solution was cooled to room temperature and diluted with water (5 mL) and hexanes (50 mL). The aqueous methanol fraction was evaporated in vacuo and then triturated with ethyl acetate. The insoluble residue was collected and determined to be the E-isomer. HPLC eluant 45%(0.1%TFA in H2O) 55% MeCN, RT 1.9[95%] MS (CI) 483 (M+1)
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:23][CH2:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Fc1c(F)c(F)c(-c2c(F)c(F)c(CBr)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixed solution of a mixture comprising the 4-methylperfluorobiphenyl mentioned above, an N-bromo succinic imide (NBS) (26.7 g, 150 mmol), AIBN (0.99 g, 6 mmol) andacarbon tetrachloride (100 mL) was subjected to heating under reflux for 1 week. During this process, the progress of the reaction was confirmed by TLC, and NBS and AIBN were added on a timely basis. Ultimately, 285 mmol NBS and 15 mmol AIBN were added to the solution. After the reaction was completed, the solution was cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=100:1), and the 4-(bromomethyl)perfluorobiphenyl (7.36 g, 18 mmol, total yield from methyl lithium 60%) was isolated.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[CH:14]=[O:15].[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].Cl.[CH2:25]1COCC1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:16][C:17]([F:19])([F:18])[CH:14]([C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:25])[CH:13]=1)[OH:15]
Reactant: C1CCOC1
Reactant: Cc1cccc(-c2ccccc2)c1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alternatively, tetrabutylammoniumfluoride (TBAF 1.0 N in THF 13 uL, 3.3 mg, 0.013 mmol) was added to a mixture of 3-methyl-biphenyl-2-carboxaldehyde (0.25g, 1.27 mmol) and trifluoromethytrimethyl silane (0.25 g, 1.53 mmol), in THF (1.5 ml) at 0° C. The reaction was warmed to room temperature and stirred for 4 hours. HCl (3.0 N, 2.0 ml) was added, and the mixture was stirred for 3 hours. The mixture was concentrated, dissolved in methylene chloride, filtered through silica gel, and concentrated to give 0.15 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:13].[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)#N.Cl.[OH-:23].[Na+]>ClC=C(Cl)Cl.O.C(Cl)Cl>[NH2:12][C:9]1[CH:8]=[C:7]([F:13])[C:6]([F:5])=[CH:11][C:10]=1[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:23]
Reactant: N#Cc1ccncc1
Reactant: Nc1ccc(F)c(F)c1
Reactant: [OH-]
Agent: Cl
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: ClC=C(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Nc1cc(F)c(F)cc1C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
BCl3 (6.2 ml, 1M in DCM) was added drop wise to 1,2-difluoro-4aminobenzene (0.5 g, 0.004 mol) in trichloroethylene (6.5 ml) at 0° C. and this mixture stirred for 15 min. 4-Cyanopyridine (0.48 g, 0.005 mol) was added and the solution was warmed to RT and stirred for 30 min. The solution was then heated at 80-90° C. for 1 h. The resulting solution was refluxed at 160° C. for 4 hr and stirred at RT over night. 3N HCl was added to the reaction mixture and refluxed at 110° C. for 1.5 h. The reaction mixture was cooled to RT and made basic (pH=12) with 6N NaOH. The reaction mixture was diluted with water and DCM. The resulting two layers were separated and the aqueous layer was extracted with DCM, dried over sodium sulphate and concentrated. The compound was purified by column chromatography using silica gel to yield title compound (0.25 g, 27%).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH:39][CH:40]2[CH2:42][CH2:41]2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[CH:40]1([NH:39][S:36]([C:32]2[CH:31]=[C:30]([NH:29][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:28])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:35]=[CH:34][CH:33]=2)(=[O:38])=[O:37])[CH2:42][CH2:41]1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 594.1 [(M−H)−]; mp 213° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[NH:10][N:9]=[CH:8]2.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CCOC(C)=O.CCO>[F:1][C:2]1[CH:23]=[C:22]([CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[NH:10][N:9]=[CH:8]2)[NH2:24]
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2-c2ccncc2)c(F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc3cn[nH]c3cc2-c2ccncc2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A mixture of 5-(2-fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1H-indazole (1.95 g, 4.5 mmol) and SnCl2.2H2O (10.2 g, 45.3 mmol) in EtOAc/EtOH (200 mL/10 mL) is stirred at 80° C. for 2 hours. Then aqueous NaHCO3 and EtOAc are added. The organic phase is dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (2:1) to give the desired product (1.10 g, 61.0% yield). MS (m/z): 321.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:15][CH:14]=2)=[C:6](CC#N)[CH:7]=1.[CH2:33]([OH:35])[CH3:34].[OH-:36].[K+].Cl>O>[OH:35][C:33]1[CH:7]=[CH:6][C:5]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])=[CH:17][CH:18]=2)=[C:4]([CH2:3][C:2]([OH:1])=[O:36])[CH:34]=1
Reactant: CCO
Reactant: [OH-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(O)cc2CC#N)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(O)cc2CC(=O)O)cc1
Yield: 16 %

Procedure:
To a mixture of 2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetonitrile (0.30 g) and ethanol (3 mL) was added a 4N aqueous potassium hydroxide solution (1 mL) and the mixture was stirred with heating under reflux for 24 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.05 g, 16%) of 2-[5-hydroxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from tetrahydrofuran-hexane gave pale-brown prism crystals. melting point: 194-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:19]([C:20]#[C:21][Si](C)(C)C)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[NH2:1][C:2]1[C:19]([C:20]#[CH:21])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Yield: 77.7 %

Procedure:
To a solution of (S)-6-amino-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (308 mg, 0.83 mmol) in 20 mL THF/methanol (1:1 ratio) at 0° C. was added K2CO3 (344 mg, 2.5 mmol) added. After 7 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (193 mg, 78%).