Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:21]=[N:22][N:23]([CH3:37])[C:24]=4[NH:25][C:26]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:30])=[O:27])=[C:16]([F:38])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].O1CCCC1.[Li+].[OH-]>CO>[F:38][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)[CH:19]=[CH:18][C:17]=1[C:20]1[N:21]=[N:22][N:23]([CH3:37])[C:24]=1[NH:25][C:26]([O:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nnn(C)c4NC(=O)O[C@H](C)c4ccccc4)c(F)c3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2F)nnn1C)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.8 %

Procedure:
In a 250 ml, round-bottomed flask, 1-{3′-fluoro-4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazole-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (95 mg, 185 μmol) was combined with tetrahydrofuran (5 mL) and methanol (1.5 mL) to give a light yellow solution. 1M LiOH (1.85 mL, 1.85 mmol, Eq: 10) was added and the reaction was stirred at 25° C. for 22 h. The crude reaction mixture was concentrated in vacuo, acidified with 1M HCl and extracted with dichloromethane. The aqueous layer was back-extracted with dichloromethane (1×15 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 10% methanol in dichloromethane) to afford 85 mg (92%) of the desired product as a white powder. (M+H)′=501.1 (m/e). 1H NMR (DMSO-d6) δ ppm 12.39 (br. s., 1H), 9.92 (br. s., 1H), 7.64-7.78 (m, 3H), 7.59 (d, J=7.8 Hz, 2H), 7.37-7.50 (m, 5H), 7.02-7.37 (m, 2H), 5.74 (br. s., 1H), 3.89 (s, 3H), 1.41-1.60 (m, 4H), 1.09-1.32 (m, 3H).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].C(N(CC)CC)C.[CH3:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[C:23]=1[CH2:32][O:33][CH3:34])(=[O:21])=[O:20]>C(Cl)Cl>[O:9]=[C:4]1[CH:5]2[CH2:8][CH:1]([CH2:7][CH2:6]2)[C:2]([O:10][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:23]([CH2:32][O:33][CH3:34])[C:24]=2[CH3:31])=[CH:3]1
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)Cl)c1C
Reactant: O=C1CC(=O)C2CCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC2=CC(=O)C3CCC2C3)c1C
Temperature: 0 °C
Yield: 101.6 %

Procedure:
0.8 g (5.8 mmols) of bicyclo[3.2.1]octan-2,4-dione (the preparation thereof is described for example in U.S. Pat. No. 5,608,101 and in the references cited therein) are dissolved in 15 ml of methylene chloride at 20° C. The solution is mixed with 0.97 ml of triethylamine and cooled to a temperature of 0° C. Then, a solution of 1.6 g (5.8 mmols) of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid chloride in 10 ml of methylene chloride is added dropwise. The reaction mixture is stirred for half an hour at a temperature of 0° C. and is subsequently diluted with methylene chloride. After washing and drying, the organic phase is concentrated by evaporation. 2.23 g of 4-methylsulphonyl-3-methoxymethyl-2-methylbenzoic acid-4-oxo-bicyclo[3.2.1]oct-2-en-2-yl-ester is obtained in amorphous form. This can be used for the next step without purification.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:20]1([S:26]([O:8][N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)c1ccccc1
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A dichloromethane (50 ml) solution of triethylamine (3.1 g, 0.0306 mole) was slowly added to a stirred dichloromethane (50 ml) suspension of N-hydroxyphthalimide (5.0 g, 0.0306 mole) and benzenesulfonyl chloride (5.4 g, 0.0306 mole) at ice-bath temperature. The stirred reaction mixture was kept at ambient temperature for about 24 hours. The product was partitioned between dichloromethane and distilled water and the dichloromethane extract was dried with magnesium sulfate. Solvent was removed under reduced pressure and the residue was crystallized with ethyl acetate-n-pentane (2:1 v/v) to give 8.0 g (87%) of colorless crystals; mp 186°; mass spectrum M+ 303 (calcd. M+ 303).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[N:9]=[C:8]([S:15][CH2:16][CH3:17])[N:7]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)C>[CH2:16]([S:15][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[CH:11]=[C:10]([S:12][CH2:13][CH3:14])[N:9]=1)[CH3:17]
Reactant: CCSc1cc(COC(C)=O)nc(SCC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCSc1cc(CO)nc(SCC)n1

Procedure:
A solution of 1.6 g (0.0059 mol) of 4-acetoxymethyl-2,6-diethylthio-pyrimidine in 3 ml of ethanol is treated at 0° C. with a solution of 0.86 g (0.0065 mol) of sodium hydroxide in 2.5 ml of ethanol. After 5 minutes the mixture is diluted with 150 ml of diethyl ether and washed neutral with water. The organic phase is dried over anhydrous magnesium sulphate and evaporated. In this manner there is obtained as the residue 2,6-diethylthio-4-hydroxymethyl-pyrimidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=1)[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:3]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=1)[C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl 2-({[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethyl)phenyl]thio}methyl)benzoate (640 mg, 1.276 mmol) was dissolved in THF (20 ml). Lithium hydroxide (61 mg, 2.552 mmol) in water (10 ml) was added. The mixture was stirred at room temperature and the reaction was followed by LC-MS. After 24 hours, more lithium hydroxide (30 mg) and water (10 ml) were added. After in total 70 hour, LC-MS showed the reaction was complete. The mixture was evaporated to remove THF. The residue was washed with diethyl ether, then acidified with 10% HCl, pH=2, and extracted with EtOAc (×2). The extracts were combined and washed with brine, dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE SI, 5 g/25 ml), using DCM and then MeOH/DCM (0.5:99.5, then 1:99) as eluant, gave the title compound (510 mg), yield 82%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH2:26])[C:17]2=[O:27])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N:26]([S:36]([CH3:35])(=[O:38])=[O:37])[S:36]([CH3:35])(=[O:38])=[O:37])[C:17]2=[O:27])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)cc1OC
Temperature: 5 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of 2-[1-(3,4-dimethoxyphenyl)-3-oxobutyl]-4-aminoisoindoline-1,3-dione (1.02 g, 2.77 mmol) and triethylamine (1.40 g, 13.85 mmol) in methylene chloride (40 mL) was cooled to 5° C. Methanesulfonyl chloride (1.27 g, 11.08 mmol) was added at 5-8° C. and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with sat. Sodium bicarbonate (20 mL), 1N hydrogen chloride (20 mL), water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give 2-[1-(3,4-dimethoxyphenyl)-3-oxobutyl]-4-[bis(methylsulfonyl)amino]isoindoline-1,3-dione (1.18 g, 81%) as a white solid: mp 194-196° C.; 1H NMR (DMSO-d6) δ 8.02-7.93 (m, 3H), 6.99-6.90 (m, 3H), 5.65 (t, J=6.7 Hz, 1H), 3.75-3.65 (m, 1H), 3.71 (s, 6H), 3.56 (s, 6H), 3.53-3.46 (m, 1H), 2.11 (s, 3H); 13C NMR (DMSO-d6) δ 205.79, 166.58, 165.78, 148.64, 148.32, 138.48, 135.86, 132.68, 131.50, 129.85, 129.15, 125.06, 119.35, 111.58, 110.91, 55.49, 55.39, 49.27, 44.52, 43.53, 43.49, 29.92; Anal. Calcd. for C22H24N2O9S2: C, 50.37; H, 4.61; N, 5.34, S, 12.23. Found: C, 50.43, H, 4.77; N, 5.16; S, 12.22.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:27][CH3:28])[N:21]=[C:22]([CH:25]=[CH2:26])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1.C(O)C>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[C:24]2[C:19](=[C:20]([O:27][CH3:28])[N:21]=[C:22]([CH2:25][CH3:26])[CH:23]=2)[N:18]([CH3:29])[CH:17]=1
Reactant: C=Cc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Reaction time: 2 h
Yield: 104 %

Procedure:
The product from Example 92A (0.04 g, 0.083 mmol) and 10% Pd/C (0.022 g, 0.021 mmol) were combined in ethyl acetate (3 mL)/ethanol (3 mL), degassed under vacuum, placed under a balloon of hydrogen and stirred for 2 hours. The mixture was filtered through Celite and the Celite pad was washed repeatedly with ethyl acetate. The filtrate was concentrated to afford the title compound (0.042 g, 105%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O.Cl.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccccc1C(=O)c1ccccc1
Yield: 93 %

Procedure:
To a mechanically stirred solution of 1000 grams (7.12 moles) of benzoyl chloride in 6000 grams of toluene was added 1000 grams (7.50 moles) of anhydrous aluminum chloride over a 20- 30 minute period. The temperature of the reaction mixture rose to near the boiling point during the addition, and heating at reflux was maintained for three additional hours. After cooling, 1200 milliliters of water were added, slowly at first, followed by 1000 milliliters of concentrated hydrochloric acid. The organic layer was separated, washed twice with hot water and concentrated on a rotary evaporator. Vacuum distillation of the residual oil provided 1300 grams (93% yield) of white, semi-solid methyl benzophenone; (b.p. 180°-200° C., 10- 15 mm Hg; m.p. 50° C.) The infrared spectrum revealed a carbonyl band at 1665 cm -1.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)C1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(C(=O)C2CC2)c1

Procedure:
A Parr hydrogenation tube is charged with palladium on carbon (0.030 g). cyclopropyl-(3-nitrophenyl)methanone of Preparation 45 (0.250 g) and 10 mL of methanol. The tube is shaken at room temperature under 40 psi of hydrogen overnight. The reaction mixture is then filtered through Celite and concentrated to give 0.207 g of the title product which is used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C)C=O>O>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccccc3)n2)n[nH]1
Temperature: 180 °C
Yield: 34.5 %

Procedure:
The mixture of (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg), phenylboronic acid (84 mg), Na2CO3 (145 mg), Tetrakis(triphenyl-phosphine)palladium(0) (40 mg), N,N-dimethylformamide (DMF) (1 ml) and water (1 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the reaction mixture was purified by preparative LC-MS to give (5-methyl-1H-pyrazol-3-yl)-(1-phenyl-isoquinolin-3-yl)-amine (40 mg). LC-MS m/e 301(MH+).+.) 1H NMR(CDCl3): δ 2.23(s, 3H), δ 5.86(s, 1H), δ 7.22(m, 1H), δ 7.40(m, 1H), δ 7.55(m, 5H), δ 7.70(m,4H), δ 7.90(d, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.CS(O[CH:20]([CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH3:21])(=O)=O.C(O)(=O)C>CN(C)C(=O)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:20]([CH3:21])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC(C)COc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
To a suspension of 8.0 g of sodium hydride (60% dispersion in oil) (washed with hexane) in 190 ml of N,N-dimethylacetamide is added dropwise 35.2 g of methyl p-hydroxyphenylacetate in 60 ml of N,N-dimethylacetamide. The mixture is stirred at room temperature for one hour and at 50° C. for 20 minutes. To the mixture is added dropwise 53 g of 3-(p-chlorophenoxy)propan-2-ol O-methanesulfonate in 100 ml of N,N-dimethylacetamide. The mixture is stirred and heated at 100° C. for 18 hours. After pouring into 2 liters of ice-water containing 6 ml of acetic acid and chilling in an ice bath for 2 hours, the mixture is filtered and the solid washed with water. The damp waxy product is dissolved in dichloromethane and the solution dried (MgSO4). The solvent is removed under reduced pressure to give 52.6 g of product as an oil. The oil is crystallized from hexane and recrystallized from methanol to give the product as white crystals, mp 84°- 85° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]4[CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 1.57 g) in THF (dry) (60 ml) was added 2-chloroethanesulfonyl chloride (1.652 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-methylphenoxy)phenyl)pyridin-2-amine (2.17 g) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, and dried in vacuo. The precipitates were crystallized from DMSO (15 mL)/EtOH (200 ml) at 80° C. to room temperature to give the title compound (1.91 g) as colorless crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[C:31](=[O:33])[NH2:32])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:16]=1[C:31]([NH2:32])=[O:33]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
In analogy to GP 4, 163 mg of {3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamic acid tert-butyl ester (0.28 mmol) were suspended in dichloromethane, 0.29 ml of TFA (3.78 mmol, 13 eq.) were added and the mixture was stirred at rt for 4 h. The reaction mixture was concentrated, redissolved in dichloromethane and sodium hydroxide solution (1M, aq.) was added. After phase separation the organic phase was concentrated to afford 129 mg (96%, 0.27 mmol) of the desired product, which required no further purification.
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:25][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:7]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:6]=3[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:16]=2)[CH:21]=1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Yield: 93.6 %

Procedure:
Following the procedure described in Method B, Step 5 of Example 1, the title compound was prepared from 6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-ol (0.33 g, 1 mmol), cesium carbonate (0.75 g, 2.3 mmol), ethyl bromoacetate (0.16 mL, 1.4 mmol) in acetone (20 mL). Crystallization from hexane furnished the title compound as a white solid (0.39 g), mp 84-86° C. Mass spectrum (+APCl, [M+H]+) m/z 417. 1HNMR (300 MHz, DMSO-d6): δ8.25 (s, 1H), 8.00 (d, 1H, J=9.1 Hz), 7.94-7.84 (m, 2H), 7.69-7.66 (m, 1H), 7.60 (d, 1H, J=7.5 Hz), 7.35-7.25 (m, 4H), 4.93 (s, 2H), 4.20 (q, 2H, J=7.1 Hz), 2.98 (t, 2H, J=7.3 Hz), 1.72 (p, 2H, J=7.3 Hz), 1.43-1.28 (m, 4H), 1.23 (t, 3H, J=7.2 Hz), and 0.83 ppm (t, 3H, J=7.1 Hz). Elemental Analysis for C27H28O4.0.5H2O: Calculated: C, 76.21; H, 6.87; N, 0.00. Found: C, 76.48; H, 6.69; N, 0.12.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[O:2].[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:68](O)[CH2:69][OH:70]>C(OCC)(OCC)OCC.C(OCC)(=O)C.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[O:2]1[CH2:68][CH2:69][O:70][CH:1]1[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: COC(=O)Cc1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-formylphenyl)acetate (1.72 g, 9.66 mmol) was dissolved in ethylene glycol (2.3 mL) and triethyl orthoformate (1.8 mL). Tetrabutylammonium tribromide (0.048 g) added and the reaction stirred at RT for 1 hour. Further tetrabutylammonium tribromide (0.434 g) added and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-15% ethyl acetate in iso-hexane to afford impure methyl 2-(4-(1,3-dioxolan-2-yl)phenyl)acetate (0.84 g). This material was dissolved in THF (15 mL) and cooled to −78° C. A solution of lithium aluminium hydride (1.0 M in THF, 6.00 mL, 6.00 mmol) was added drop-wise. The reaction mixture was allowed to warm to RT over 18 hours. The mixture was sequentially treated with water (0.228 mL), 2M aqueous sodium hydroxide (0.228 mL) and water (3×0.228 mL). The mixture was diluted with ethyl acetate and magnesium sulfate added. The mixture was stirred at RT for 1 hour and then filtered through celite. The filter cake was washed with further ethyl acetate and the filtrates combined. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (0.315 g, 17%).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=1)=O.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][CH:2]([F:19])[C:3]1[N:22]2[N:23]=[CH:24][C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([CH3:17])[CH:8]=2)[CH:4]=1
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)F)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(-c4ccncc4)c3n2)ccc1C(F)(F)F
Yield: 69.2 %

Procedure:
Reaction of 4,4-difluoro-1-(3-methyl-4-trifluoromethyl-phenyl)-butane-1,3-dione (140 mg, 0.5 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (140 mg, 69%). MS (ISP) 405.4 [(M+H)+]; mp 236° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:28]([N:30]3[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1>>[NH2:16][C:17]1[C:22]2[CH:23]=[C:24]([CH2:26][CH:27]([NH:37][S:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[C:28]([N:30]3[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]3)=[O:29])[S:25][C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: COCCOc1ccc(S(=O)(=O)Cl)cc1
Product: COCCOc1ccc(S(=O)(=O)NC(Cc2cc3c(N)nccc3s2)C(=O)N2CCC(C)CC2)cc1

Procedure:
This compound was prepared from 0.6 mmol 4-(2-methoxy-ethoxy)-benzenesulfonyl chloride and 210 mg (0.5 mmol) of 30a using the procedure described for 58c . Yield: 30 mg (white crystals), m.p. 210° C. (decomp.), EI-MS: 532 (M+).