Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)cn1
Temperature: 60 °C
Yield: 32.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was mixed with 3-5 ml of dry dimethylformamide and 3-fluorophenol (0.244 ml, 2.7 mmol) was added to the stirred suspension. When the gas evolution was ceased the reaction mixture was heated at stirring at 60° C. and 5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reaction mixture in one portion. The reaction-mixture was stirred at 60° C. for about 12 hours. The reaction mixture was then mixed with 50 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting mixture was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 190 mg (33% yield) of desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1.[OH-].[K+]>[Cu]>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([O:15][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(O)cc1
Reactant: Clc1ccc(Br)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
4-Bromochlorobenzene (3.8 g), hydroquinone monomethyl ether (3.1 g) and potassium hydroxide (1.5 g) and copper powder (0.1 g) were mixed and the reaction was carried out at 160° C. to 200° C. for 3 hours. After cooling to room temperature, the reaction mixture was extracted with benzene (100 ml) and washed with 1 N sodium hydroxide, water, and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and the residue was purified by medium pressure column chromatography using silica gel, to obtain 4-(4-chlorophenoxy)phenol methyl ether (2.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].CCOCC>CN(C)C=O>[CH2:16]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH3:17]
Reactant: CCI
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCSc1ccccc1Br
Temperature: 57.5 °C
Reaction time: 12 h

Procedure:
To a suspension of 1.00 g (5.3 mmol) of 2-bromo-benzenethiol and 1.47 g (10.6 mmol) of potassium carbonate in 15 ml of N,N-dimethylformamide was added 1.65 g (10.6 mmol) of iodoethane at 0° C. The reaction mixture was stirred at 55-60° C. for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml×3), dried over MgSO4 and concentrated to afford 1-ethylmercapto-2-bromobenzene as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@@H:23]1[O:25][CH2:24]1)(=O)=O>>[CH2:22]([O:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:3]=1[C:1]#[N:2])[C@@H:23]1[O:25][CH2:24]1
Reactant: CCOC(=O)CCCc1cccc(O)c1C#N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Product: CCOC(=O)CCCc1cccc(OC[C@H]2CO2)c1C#N
Yield: 80.2 %

Procedure:
Using the method of example 1(a), supra, ethyl 4-(2-cyano3-hydroxyphenyl)butanoate (1.9 g, 7.33 mmol) and (R)-glycidyl nosylate (1.78 g, 7.6 mmol) were used to prepare 1.70 g (80%) of the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[I:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[O:29])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(c1ccc(I)cc1)c1ccc(OC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 2 (25 mg, 0.05 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. The resulting solid was filtered out and dried under vacuo to yield the title product (16 mg, 80%); LCMS; 100% ESI+ Calcd: 407.3, found m/z: 408.5 (M+1); 1H NMR (500 MHz, DMSO-d6); δ 1.71-1.80 (m, 1H), 1.82-2.06 (m, 2H), 2.10-2.20 (m, 1H), 3.16-3.30 (m, 2H), 3.90-4.00 (m, 1H), 4.23-4.27 (m, 1H), 4.38 (dd, J1=10.0 Hz, J2=2.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.95 (d, J=8.0 Hz, 2H):
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]([S:23][CH2:24][CH:25]([CH3:29])[C:26](Cl)=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CC(N(C)C)=O>[C:15]([S:23][CH2:24][CH:25]([CH3:29])[C:26]([N:10]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:27])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Reactant: O=C(O)CNC1Cc2ccccc2C1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(CSC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
N-(2-Indanyl)glycine (1.0 g) is suspended in 10 ml of dimethylacetamide, then 2.0 g of 3-benzoylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 100 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. After ethyl acetate is distilled off under reduced pressure, the residue is subjected to silica gel column chromatography and eluted with acetone-benzene (1:9). The oil obtained is crystallized from an ethyl ether-petroleum ether mixture, to give 1.4 g of N-(3-benzoylthio-2-methylpropionyl)-N-(2-indanyl)glycine, colorless needles showing a melting point of 113°-115° C.
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]([F:15])([F:1])[C:11]([F:13])([F:12])[F:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(CC(F)(F)C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(F)(F)Cc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of 4-(2,2,3,3,3-pentafluoropropyl)toluene (9.97 g, 39.4 mmol) in carbon tetrachloride (300 ml) were added 2,2′-azobisisobutyronitrile (0.33 g, 197 mmol) and N-bromosuccinimide (8.50 g, 47.3 mmol) and the mixture was heated under reflux overnight. After cooling to room temperature, insoluble material was filtered off, and the filtrated was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 50:1, 20:1) to give 1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene (3.66 g, 31% (yield by two steps)) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH3:12][C:13]([CH3:15])=O.C([BH3-])#N.[Na+].CC(O)=O>CCO>[CH:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11])([CH3:15])[CH3:12]
Reactant: CC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1O

Procedure:
A solution of 2-amino-5-nitrophenol (2.00 g, 13.0 mmol) in absolute EtOH (52 mL) and acetone (14.3 mL, 195 mmol, 15 equiv.) is treated with sodium cyanoborohydride (408 mg, 6.49 mmol), the pH is adjusted to 4.5–5.0 with glacial AcOH, and the mixture is stirred at ambient temperature for 4 days, during which time additional acetone (2×14.3 mL), sodium cyanoborohydride (3×408 mg) and glacial AcOH is added. The reaction mixture is then readjusted to pH 6, concentrated under reduced pressure, diluted with water (50 mL) and CH2Cl2 (75 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M 90 g silica gel cartridge with EtOAc/heptane (20/80). Pooling and concentration of those fractions with an Rf=0.59 by TLC (EtOAc/hexanes, 50/50) gives the title compound, mp 108–110° C.; MS (ESI+) for C9H12N2O3 m/z 197 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: COc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Yield: 7.8 %

Procedure:
The product from Example 4a (5.0 g, 175 mmol) was reacted with 4-methoxy-benzenethiol (2.45 g, 175 mmol) for 18 h following the procedure from Example 4b giving the product as a solid (3.76 g, 78%).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]([C:8](=[CH2:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCl>[CH2:12]([O:11][C:9]([CH:8]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:19][PH:1](=[O:2])[OH:3])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(CC(C)C)C(=O)OCc1ccccc1
Reactant: O=[PH2]O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(C[PH](=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A vigorously stirred mixture of 17.6 g (0.27 mol) of crystalline phosphinic acid and 43.6 g (0.2 mol) of benzyl 2-isobutylacrylate in 400 ml of dichloromethane was cooled to 0° C. and treated dropwise with 53.4 g (0.53 mol) of triethylamine while maintaining the temperature at below 5° C. After completion of the addition, a solution of 56.0 g (0.52 mol) of trimethylsilyl chloride in 100 ml of dichloromethane was added while stirring vigorously and maintaining the temperature at 10-12° C. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 24 hours. The mixture was then treated with 200 ml of water and 30 ml of 10% sulfuric acid. The organic phase was separated and washed with 200 ml of saturated sodium chloride solution. The combined aqueous extracts were re-extracted with 100 ml of dichloromethane and the organic phase was washed with 100 ml of sodium chloride solution and added to the previously obtained dichloromethane extracts. After drying over anhydrous sodium sulfate, the dichloromethane was removed by evaporation to give 59.2 g of [(RS)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid in the form of a colorless oil. (b) The compound prepared in the preceding paragraph was dissolved in 600 ml of ethyl acetate. Thereafter, 25.0 g of S(-)-α-methylbenzylamine were added and the solution was left to crystallize for 24 hours. The crystalline salt was collected by filtration and dried to give 34.0 g of a white solid which was recrystallized overnight from a mixture of 120 ml of ethanol and 48 ml of ethyl acetate. The solid was collected and dried to give 21.3 g of a crystalline salt which was recrystallized overnight from a mixture of 120 ml of ethanol and ethyl acetate. There were obtained 16.8 g of [(R or S)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid S(-)-α-methylbenzylamine salt in the form of white crystals of melting point 137-138° C. and [α]58920 =-8.9° (c=5% in ethanol).
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C(OC([N:35]1CCCC1COC1C=CN=CC=1)=O)(C)(C)C>>[N:35]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[C:20]3=[O:27])(=[O:15])=[O:16])=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccncc1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3ccncc3)cc2C1=O
Yield: 55 %

Procedure:
5-(2-(Pyridin-4-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (23) was prepared according to the same procedure for compound 10, except using compound 22, purified with ethyl acetate to afford 1.17 g (55%) of 23 as a yellow solid, mp 204.2-205.3° C. 1H NMR (300 MHz, CDCl3) δ 11.44 (s, 1H), 8.37 (d, J=5.7 Hz, 2H), 8.03 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.79 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.96 (d, J=6.0 Hz, 2H), 4.17-4.05 (m, 2H), 3.90 (m, 1H), 3.32 (m, 1H), 3.10 (m, 1H), 1.85 (m, 2H), 1.60 (m, 2H). LCMSm/e: 387.9 (M+H). Anal. Calcd for C18H17N3O5S.0.75H2O: C, 53.92, H, 4.65; N, 10.48. Found: C, 54.14, H, 4.39; N, 10.35.
Reaction SMILES: N1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:19])[N:7]=2)C=CN=C1.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([NH:25][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:19])[N:7]=1)([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)N
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Product: CCC(C)NC1=NS(=O)(=O)c2cc(C(=O)O)ccc2N1

Procedure:
3-(Imidazol-1-yl)-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide was treated with sec-butylamine according to the general procedure Method A to give the title compound; m.p. >310° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[NH2:18].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:12]([N:8]1[C:9]2[C:4](=[C:3]([O:16][C:23]3[CH:24]=[CH:25][C:20]([C:17]([NH2:18])=[O:19])=[CH:21][CH:22]=3)[C:2]([Br:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: NC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.6 %

Procedure:
A 100-mL, round-bottom flask equipped with a balloon filled with air was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.300 g, 1.06 mmol), 4-carbamoylphenylboronic acid (0.437 g, 2.65 mmol), pyridine (1 mL), dichloromethane (40 mL), copper (II) acetate (0.580 g, 3.20 mmol) and 4 Å molecular sieves (4.0 g). The resulting mixture stirred for 3 days at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 3:1, ethyl acetate/petroleum ether) to afford (S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide (0.148 g, 35%) as yellow oil. MS (ESI, pos. ion) m/z 403, 405 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:15][CH2:16][C:17](=[O:19])[CH3:18])([CH:13]=[CH2:14])[C:8]2=O)=[CH:4][C:3]=1[O:20][CH2:21][C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO.O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH:13]=[CH2:14])([CH2:6]2)[CH2:15][CH2:16][C:17](=[O:19])[CH:18]=1
Reactant: C=CC1(CCC(C)=O)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reaction time: 48 h

Procedure:
Methyl {[6,7-dichloro-1-oxo-2-(3-oxobutyl)-2-vinyl-2,3-dihydro-1H-inden-5-yl]oxy}acetate (7.3 gm., 0.02 mole) is dissolved in a solution of methanol (100 ml) and water (50 ml.) containing sodium hydroxide (9.43 gm., 0.236 mole), taking care to keep the temperature below 25° C. The solution is kept at ambient temperature for 48 hours. The solution is concentrated in vacuo to 100 ml. in a rotary evaporator at room temperature and poured into water (250 ml.) containing concentrated hydrochloric acid (26 ml.) with cooling. The product is separated by filtration, washed with water, dried and recrystallized from a mixture of acetic acid and water to obtain [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=1)#[CH:34]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Reactant: C#Cc1ccc(CO)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 270 mg (83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:27])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 634.0 [(M−H−]; mp 251° C.
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([O:52]C)=O)=[CH:31][CH:30]=1.N>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[CH:48][N:47]=[C:46]2[C:50]([NH2:2])=[O:52])=[CH:31][CH:30]=1
Reactant: COC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: N
Product: NC(=O)c1nccn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-imidazole-2-carboxylate and ammonia. 1H-NMR (CDCl3, 400 MHz, δ) 8.59 (d, J=4.4 Hz, 1H), 8.23 (d, J=9.2 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.36 (dd, J=4.4, 9.2 Hz, 1H), 6.87 (s, 1H), 6.21 (s, 2H) ppm; m/e 353 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.Cl.[F:50][C:51]1[CH:56]=[CH:55][C:54]([C@H:57]([NH2:59])[CH3:58])=[CH:53][CH:52]=1>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:59][C@@H:57]([C:54]2[CH:55]=[CH:56][C:51]([F:50])=[CH:52][CH:53]=2)[CH3:58])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:37])=[O:38])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H](NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (R)-1-(4-fluorophenyl)ethylamine hydrochloride (EXAMPLE 7, Step C) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C23H18BrFN4O3S, 528.0; m/z found, 527/529 [M−H]−. HPLC (reverse phase): RT=10.03 min. 1H NMR (500 MHz, CDCl3): 11.34 (s, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.57 (dd, J=7.4, 1.4 Hz, 1H), 8.32 (dd, J=7.4, 1.4 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.87 (dd, J=8.4, 7.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 7.10-7.00 (m, 2H), 6.91 (dd, J=8.4, 2.0 Hz, 1H), 6.13 (br d, J=6.5 Hz, 1H), 5.25-5.15 (m, 1H), 1.53 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([Cl:12])[CH:5]=[CH:4][C:3]=1[OH:13].CCN=C=NCCCN(C)C.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N1C=CC=CC=1>O>[Cl:12][C:6]1[C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[C:3]([OH:13])=[CH:4][CH:5]=1
Reactant: Nc1c(O)ccc(Cl)c1C(F)(F)F
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(O)ccc(Cl)c1C(F)(F)F)c1ccncc1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 0.75 g of 2-amino-4-chloro-3-trifluoromethylphenol, 0.84 g of WSC, 0.42 g of isonicotinic acid and 5 ml of pyridine was stirred while heating at 80° C. for three hours. To the reaction mixture, 0.1 g of isonicotinic acid was added, and the reaction mixture was stirred while heating for further three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.54 g of N-[3-chloro-6-hydroxy-2-trifluoromethylphenyl]isonicotinamide.