Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br.BrC1C=CC(NC(C2(C([O-])=O)CC2)=O)=C(C)C=1>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:26][CH2:25]2)=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Reactant: BrCCBr
Agent: Cc1cc(Br)ccc1NC(=O)C1(C(=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
Into a 500 milliliter three-necked round-bottom reaction flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and outlet and oil bath was added 30.0 grams (0.10 mol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared as in Example A, 34.5 grams (0.25 mol) of anhydrous potassium carbonate, 100 milliliters of anhydrous dimethylformamide and 8.6 milliliters (0.10 mol) of 1,2-dibromoethane. The resulting mixture as stirred under a nitrogen atmosphere at a temperature of 65° C. for a period of 3 hours and then at a temperature of 80° C. for a period of 3.5 hours. Following this period, high pressure liquid chromatographic analysis showed the reaction to be incomplete. An additional 13.8 grams (0.10 mol) of anhydrous potassium carbonate was added and the reaction mixture was stirred at ambient temperature for a period of 16 hours. An additional 1.7 milliliters (0.02 mol) of 1,2-dibromoethane was then added and the reaction mixture was heated at a temperature of 75° C. for a period of 3.5 hours. Anhydrous potassium carbonate (6.0 grams, 0.043 mol) was then added and heating was continued for an additional 2.5 hours. The reaction mixture was then cooled, diluted with methylene chloride and filtered to remove suspended solids. Concentration under reduced pressure gave a brown liquid which was chromatographed on silica gel using 3:1 volume/volume hexane-ethyl acetate as the eluent. Early fractions contained 17.8 grams (55.0 mmol) of 1-(4-bromo-2-methylphenylaminocabonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 87.0° C.-90.0° C. The total yield was 56.0 percent based on a 96.7 weight percent assay of the starting ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. NMR analysis of the product indicated the following:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1)[CH3:14].[CH2:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18](/[CH:21]=[C:33]2/[C:29]([NH:28][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:19][CH2:20]1)[CH3:14]
Reactant: C#CCNC1=NC(=O)SC1
Reactant: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(C=O)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(C)c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}piperidine-4-carbaldehyde (1.15 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1.00 g) in 2-propanol (16.3 mL) was added piperidinium acetate (0.473 g). The reaction mixture was stirred at 60° C. overnight, allowed to cool to room temperature, and diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), further purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (1.13 g).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[OH:7][C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)CC1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
To a solution of 1,4-cyclohexanedione (6.72 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1 M solution of phenyl magnesium bromide in THF (20 mL, 20 mmol). The mixture was stirred at room temperature for 3 hours and quenched with an NH4Cl solution. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 1:1 EtOAc/hexanes yielded 0.83 g (22%) of the title compound. MS calculated (M+H)+190. Found 173 (M+H—H2O)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][NH2:29])[CH2:24][CH2:23]1>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:15])[N:28]([CH:25]3[CH2:26][CH2:27][NH:22][CH2:23][CH2:24]3)[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Reactant: NNC1CCNCC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1000 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) are dissolved in 10.5 l of methanol. 2500 g piperidin-4-yl-hydrazine dihydrochloride, solved in 4 l of water are added rapidly. The mixture is heated to reflux and kept at reflux temperature for 4 days. The reaction mixture is cooled to 20° C., 10 l of water are added and then methanol is removed by distillation in vacuum. The aqueous solution is allowed to stand overnight at RT. The solution is cooled and aqueous sodium hydroxide (c=10 mol/l) (about 2 l) is added during 4 to 5 h by keeping the temperature below 20° C. and the pH should be higher than 13. The product crystallizes during adding of sodium hydroxide. The mixture is stirred 1 h at 10° C., filtered over a filter press and washed with 0.5 l of water. The product is dried at 50° C. in a circulating air dryer resulting in the title compound. (compound B1)
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1C[C@@H](c2ncc(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 46.2 %

Procedure:
A solution of (2S,45)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (2.25 g, 4.4 mmol) in 18 mL ethanol and 18 mL water was treated with sodium sulfite (5.59 g, 44.4 mmol) and heated at 90° C. overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with more ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulphate, filtered, concentrated, and purified by silica gel chromatography to give 766 mg (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Cl:33])=[N:5][CH:6]=[N:7]2
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cccc(F)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cccc2ncnc(Cl)c12

Procedure:
Thus, 5-fluoro-3,4-dihydroquinazolin-4-one (2 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-fluoro-4-chloroquinazoline (1.34 g); NMR Spectrum: (CDCl3) 7.4–7.5 (m, 1H), 7.9–8.0 (m, 2H), 9.1 (s, 1H); and
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(N(C)C)=O.[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>O>[CH2:20]([N:27]([CH2:31][CH2:32][CH2:33][CH3:34])[C:28]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCCN(Cc1ccccc1)C(=O)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCN(Cc1ccccc1)C(=O)N(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 3.89 g. of diphenylamine in 25 ml. of dimethylacetamide is added during one hour to a stirred mixture of 5.19 g. of N-benzyl-N-(n-butyl)carbamyl chloride, 0.685 g. of sodium hydride, and 65 ml. of dimethylacetamide under a nitrogen atmosphere at 45°-50° C. The mixture is stirred for 2 hours at 50° C. and then poured into water. The mixture is extracted with methylene chloride and the extract is evaporated. The residue is purified by chromatography using silica gel as the adsorbant and acetone-hexane as the eluent. After evaporation of the eluent, the residue is evaporatively distilled at 165° C. under reduced pressure (150 microns) to yield 1-benzyl-1-(n-butyl)-3,3-diphenylurea as a viscous, clear, clorless liquid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([B:21]([OH:22])[OH:20])=[CH:3][N:4]=1
Reactant: Brc1cncc2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 4-bromoisoquinoline in tetrahydrofuran is cooled to -78° C. To this solution is added dropwise n-butyllithium (1.6 M in hexane), and the resultant solu-tion is stirred for 30 minutes. To this solution is then added dropwise triisopropylborate and the reaction mixture is then stirred for 18 hours at room temperature. The reaction mixture is then partitioned between ethyl acetate and saturated aqueous sodium chloride. The phases are separated and the aqueous phase extracted well with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is sonicated in a mixture of hexane:ethyl acetate. The resulting suspension is filtered to provide isoquinolin-4-ylboronic acid.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]([C:26]#[N:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC(=O)C)C.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH:17]([C:26]#[N:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ccccc1C(C#N)CC1CCN(Cc2cccnc2OC)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccccc1C(C#N)CC1CCN(Cc2ccc[nH]c2=O)CC1

Procedure:
In ethanol (2 ml) was dissolved 191 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-cyano-2-(2-methoxyphenyl)ethyl]piperidine obtained in Example 86. To the mixture was added 0.3 ml of a 4N hydrogen chloride ethyl acetate solution, followed by heating under reflux for 2 hours. The solvent was evaporated, to give 199 mg of the title compound as colorless crystals.
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].Cl.Cl[CH2:22][C:23]1[S:24][C:25]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:35])[C:26]=2[N:36]=1>CN(C)C=O>[NH2:35][C:27]1[C:26]2[N:36]=[C:23]([CH2:22][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[S:24][C:25]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1nc2ccccc2c2sc(CCl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc2ccccc2c2sc(CON3C(=O)c4ccccc4C3=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Triethylamine (7.3 mL, 52 mmol) was added to a solution of N-hydroxyphthalimide (3.42 g, 21.0 mmol) in N,N-dimethylformamide (DMF) (50 mL). 2-(Chloromethyl)[1,3]thiazolo[4,5-c]quinolin-4-amine hydrochloride (5.0 g, 18 mmol) was added to the resulting deep red solution, and the reaction was stirred overnight at ambient temperature. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried in a vacuum oven to provide 3.34 g of 2-[(4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a tan solid. The filtrate was concentrated under reduced pressure, and the residue was mixed with dichloromethane, filtered, washed with dichloromethane, and dried in a vacuum oven overnight to provide an additional 2.06 g of product.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27].CCOC(C)=O>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1
Reactant: NCCN
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizine (0.3 g, 0.89 mmol), and ethylene diamine (0.6 mL, 8.93 mmol) in dry NMP (3 mL) at 100 ° C. for 14 h. Pour the cooled mixture onto water (30 mL) and extracte twice with EtOAc (30 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 0.5% ammonium hydroxide) to obtain the title compound as a yellow oil.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:15]>Cl.O1CCCC1>[ClH:1].[C:8]([O:9][CH2:10][C:11]([NH2:12])([CH3:14])[CH3:13])(=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC(c2ccccc2)=N1
Reactant: O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To 8.7 g (0.041 mol) 2-phenyl-4,4-dimethyl-1,3-oxazoline hydrochloride suspended in 120 ml anhydrous hydrogen chloride in tetrahydrofuran (1M) was added 3.6 ml (0.20 mol) water. The mixture was warmed to cause solution and heated under reflux with stirring for 1 hour. The tetrahydrofuran was removed under reduced pressure to afford a nearly colorless oil which crystallized at 0° following the addition of anhydrous ether. The solid was triturated with anhydrous ether overnight and isolated by filtration under a nitrogen atmosphere. After drying in vacuo over calcium sulfate, 6.9 g (0.30 mol), 73%, 2-amino-2-methyl-1-propyl benzoate hydrochloride was obtained as a white solid, mp 225°-228° (dec.) acetone:hexane, ir (KBr) 1725 (c=o) cm-1, pmr (D2O) δ 1.50 (s, 6H), 4.4 (s, 2H) and 7.0-8.3 (m, 5H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][N:6]=[C:5]2[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[C:5]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(Cc2cccnc2)c2cc(Cl)ccc12
Product: Clc1ccc2c(Cl)nnc(Cc3cccnc3)c2c1

Procedure:
6-Chloro-4-(3-pyridylmethyl)-1(2H)-phthalazinone (0.86 g) was suspended in 10 ml of phosphorus oxychloride. The obtained suspension was heated under reflux for 2 hours and freed from the phosphorus oxychloride by vacuum distillation. The residue was dissolved in tetrahydrofuran. The obtained solution was neutralized with triethylamine, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The residue was purified by silica gel column chromatography to give 0.49 g of the title compound as a pale yellow crystal.
Reaction SMILES: Br[C:2]([F:33])([F:32])[C:3](F)([F:30])[O:4][C:5]1[CH:29]=[CH:28][CH:27]=[C:7]2[C:8]([N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20](F)([F:25])[C:21]([F:24])([F:23])Br)=[CH:15][CH:14]=3)[C:11](=[O:12])[C:6]=12)=[O:9].BrC(F)(F)C(F)(F)OC1C=CC(N)=CC=1.BrC(F)(F)C(F)(F)OC1C=CC=C2C(OC(=O)C=12)=O.C1(C)C=CC=C(C)C=1>CN1CCCC1=O>[F:30][C:3]([O:4][C:5]1[CH:29]=[CH:28][CH:27]=[C:7]2[C:8]([N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:25])=[C:21]([F:23])[F:24])=[CH:17][CH:18]=3)[C:11](=[O:12])[C:6]=12)=[O:9])=[C:2]([F:33])[F:32]
Reactant: O=C1c2cccc(OC(F)(F)C(F)(F)Br)c2C(=O)N1c1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: Nc1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: O=C1OC(=O)c2c(OC(F)(F)C(F)(F)Br)cccc21
Solvent: Cc1cccc(C)c1
Solvent: CN1CCCC1=O
Product: O=C1c2cccc(OC(F)=C(F)F)c2C(=O)N1c1ccc(OC(F)=C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
3-(2-Bromotetrafluoroethoxy)-N-(4-(2-bromotetrafluoroethoxy)phenyl)phthalimide Into a 250 ml round bottomed flask fitted with a mechanical stirrer and a Dean-Stark trap is placed 4-(2-bromotetrafluoroethoxy)aniline (3.4 g, 0.0118 mole) in 40 ml of N-methylpyrrolidinone (NMP). In a separate flask, 3-(2-bromotetrafluoroethoxy)phthalic anhydride (3.0 g, 0.00874 mole) is dissolved in 20 ml of NMP and is added slowly drop wise over 15 minutes to the stirring solution of 4-(2-bromotetrafluoroethoxy)aniline in NMP. The mixture is stirred for 30 minutes at room temperature, after which m-xylene (6 ml) is added and the suspension is heated to 40° C. After heating at 40° C. for 1 hour the is heated to reflux (181° C.) and is refluxed for 6.5 hours to remove water azeotropically. Upon cooling the solvent is removed by evaporation under vacuum and the solid precipitate is recrystallized from dichloromethane/hexane solution (2:1) to provide the product as a light yellow crystalline solid (4.37 g, 81.5 percent yield) with a melting point of 172°-172.5° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:19][C:18]2=[O:33]>N1C=CC=CC=1>[O:33]=[C:18]1[C:17]2[C:22](=[C:13]([NH:12][S:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)(=[O:10])=[O:9])[CH:14]=[CH:15][CH:16]=2)[O:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:32])([F:30])[F:31])=[CH:19]1
Reactant: Nc1cccc2c(=O)cc(-c3ccccc3C(F)(F)F)oc12
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cc(-c2ccccc2C(F)(F)F)oc2c(NS(=O)(=O)c3cccnc3)cccc12
Temperature: 80 °C
Yield: 31.4 %

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride 12 (280 mg, 1.3 mmol) was added to a solution of 8-amino-2-(2-(trifluoromethyl)phenyl)-4H-chromen-4-one 11 (100 mg, 0.328 mmol) in pyridine (5 mL). The reaction mixture was heated at 80° C. for 12 h. The pyridine was removed en vacuo. The residue was taken up in CH2Cl2, washed with sat. aq NaHCO3, dried (MgSO4) and concentrated. The crude residue was purified by MPLC eluting with CH2Cl2/MeOH (0-10%) followed by recrystallization from CH3CN to give Compound 326 (46 mg, 31% yield). MS (ESI) calcd for C21H13F3N2O4S: 446.1. found: 447 [M+H].
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[I:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(-c2ccccc2)on1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(-c2ccccc2)c1I
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.9 %

Procedure:
Large Scale: A mixture of ethyl 5-phenylisoxazole-3-carboxylate (3.05 g, 14.0 mmol) and N-iodosuccinimide (3.79 g, 16.9 mmol) in trifluoroacetic acid (78 mL) was stirred at room temperature for 3.5 h. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was washed with a 1N aqueous solution of sodium hydroxide (150 mL), washed with a 3% aqueous solution of sodium bisulfite (2×150 mL), washed with brine (150 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 4-iodo-5-phenylisoxazole-3-carboxylate (4.69 g, 13.7 mmol, 97% yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:22][OH:23])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[C:8]2=[C:7]([NH:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[N:6]=1.[C:36]([NH:43][C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.ClC(OC(C)=C)=O>C(Cl)Cl>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:22][O:23][C:48](=[O:49])[CH:44]([NH:43][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH:45]([CH3:47])[CH3:46])[N:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[C:8]2=[C:7]([NH:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:28])=[O:29])[N:6]=1
Reactant: CS(=O)(=O)CCNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1cc(F)ccc1F)nn2CO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C=C(C)OC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCn1nc(-c2cc(F)ccc2F)c2c(NCCS(C)(=O)=O)nc(Oc3ccc(F)cc3F)nc21
Temperature: 0 °C
Yield: 51.2 %

Procedure:
[6-(2,4-Difluoro-phenoxy)-3-(2,5-difluoro-phenyl)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-methanol (170 mg, 0.33 mmol) was dissolved in methylene chloride, and Boc-(L)-Valine (216 mg, 0.99 mmol), dimethylamino pyridine (81 mg, 0.66 mmol), and triethylamine (0.23 mL, 1.6 mmol) were added. The reaction mixture was cooled to 0° C. and stirred under nitrogen, and isopropenyl chloroformate (54 uL, 0.49 mmol) was added. The reaction mixture was stirred for 10 minutes and then partitioned between water and methylene chloride. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography through silica (1:1 hexanes/EtOAc) to give 120 mg of 2-tert-butoxycarbonylamino-3-methyl-butyric acid 6-(2,4-difluoro-phenoxy)-3-(2,5-difluoro-phenyl)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl ester as an oil.