Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:14][CH:13]=[N:12][CH:11]=1)([O-])=O.NN>CO>[NH:14]1[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:11][N:12]=[CH:13]1
Reactant: O=[N+]([O-])c1ccccc1-c1cnc[nH]1
Agent: NN
Solvent: CO
Product: Nc1ccccc1-c1cnc[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26 %

Procedure:
To a vial were added 5-(2-nitrophenyl)-1H-imidazole (200 mg, 1.06 mmol), ferric chloride (8.6 mg, 0.35 mmol), activated carbon (2.2 mg, 1.80 mmol) and hydrazine (1.1 ml, 21.2 mmol) and methanol (9 mL). The resulting mixture was stirred at r.t. for 5 min then was heated to 70° C. for two days. The reaction was cooled to room temperature and filtered. The filtrate was concentrated and purified to give 2-(1H-imidazol-5-yl)aniline. The intermediate was dissolved in acetic acid (2 ml) and formaldehyde (37% in water, 0.3 ml) was added. The reaction was stirred for 1 h at room temperature, diluted with 30 ml ethyl acetate, and extracted with 5% HCl. The aqueous layer was basified with K2CO3 (add gradually until PH=7), then extracted with ethyl acetate (30 mL*2). The organic layer was evaporated under reduced pressure and product was obtained by column chromatography using ethyl acetate as eluent (26% yield). 1H NMR: 4.70 (s, 1H), 4.93 (s, 2H), 7.50-7.56 (m, 1H), 7.73-7.82 (m, 3H), 8.24-8.31 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH:34]=O)([CH3:29])([CH3:28])[CH3:27].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([NH:11][CH2:34][CH2:33][NH:32][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:36])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1NCCNC(=O)OC(C)(C)C
Reaction time: 23 h

Procedure:
To a solution of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-4a, 1.88 g, 5 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (1590 mg, 10 mmol) in 1,2-dichloroethane (60 ml) at room temperature was added glacial acetic acid (858 microliters, 15 mmol) and NaBH(OAc)3 (2540 mg, 12 mmol). The reaction mixture was stirred for 23 hours, then additional (2-oxo-ethyl)-carbamic acid tert-butyl ester (500 mg, 3.14 mmol) and NaBH(OAc)3 (1000 mg, 4.7 mmol) were added. The reaction mixture was stirred for an additional 24 hours, quenched with 1 N NaOH, and diluted with CH2Cl2. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The combined organic phases were washed with 0.5 M aqueous citric acid, 1 N NaOH, and saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified on a Biotage 40+M column using CH2Cl2/MeOH (100:1) to give the desired product I-4b (900 mg): +ES MS (M+1) 519.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\Cl)/[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCCCCCc1ccc(C#Cc2ccc(Br)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a 2 L flask containing a solution of 1-bromo4-[(Z)-2-chloro-2-(4-hexylphenyl) vinyl] benzene (VIb) (209.79 g; 555.37 mmol) in 1,4-dioxane (1000 mL; 4.8 vols) and MeOH (300 mL; 1.4 vols), KOH (62.32 g; 1110.73 mnmol) was added in one portion. Reaction mixture was stirred at 80° C. overnight. Volume was reduced under vacuum to 200 mL and the residue was taken up in water (2000 mL). The resulting suspension was filtered and washed with water to give a clear beige solid. Drying under vacuum at 33° C. overnight gave the title compound (m=173.34 g) in a 92% yield. Melting point: 67° C. 1H-NMR (CDlC3=7.26 ppm): 7.47 (d, J=8.66 Hz, 2H), 7.43 (d, J=8.10 Hz, 2H), 7.37 (d, J=8.28 Hz, 2H), 7.16 (d, J=8.10 Hz, 2H), 2.61 (t, J=7.81 Hz, 2H), 1.59 (quint, J=7.48 Hz, 2H), 1.42-1.21 (br s, 6H), 0.88 (t, J=6.31 Hz, 3H)
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[CH:40]=[CH:39][CH:38]=[CH:37][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH2:23]3)[N:10]=1.O.[OH-].[Li+:44]>C1COCC1.O>[C:33]([O:32][C:30]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:37]=[CH:38][CH:39]=[CH:40][C:5]=4[CH2:4][C:3]([O-:41])=[O:2])[C:14]([C:15]([F:17])([F:16])[F:18])=[CH:13][N:12]=3)[CH:21]=2)[CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35].[Li+:44]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)ccc2C1
Yield: 80.9 %

Procedure:
tert-Butyl 6-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I80) (520 mg, 0.91 mmol) was dissolved in THF (20 mL) and a solution of lithium hydroxide hydrate (76 mg. 1.8 mmol) in water (5 mL) was added. After 18 hours the THF was removed under reduced pressure, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulfate) and evaporated to give the title compound (I81) (414 mg, 81% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.36 (s, 1H), 8.65 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.20-7.02 (m, 5H), 4.45 (5, 2H), 3.54 (t, J=5.8 Hz, 2H), 3.17 (s, 2H), 3.14-2.98 (m, 4H), 2.76 (t, J=5.7 Hz, 2H), 1.43 (s, 9H). LCMS Method C: rt 6.51 min; m/z 557.1 [M−Li+2H] 501.1 [M−tBu−Li+3H]+, 457.1 [M−Li−Boc+3H]+; m/z 555.1 [M−Li]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[CH:13]=[O:14].CC(=CC)C.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(OCC)(=O)C.C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[C:13]([OH:25])=[O:14]
Reactant: [O-][Cl+][O-]
Reactant: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde from Step 1 (492 mg, 0.001726 mol) and 2-methyl-2-butene (300 μL, 0.002832 mol) were stirred in test-butyl alcohol (2.0 mL). A solution of sodium chlorite (400 mg, 0.003538 mol) and sodium dihydrogenphosphate (450 mg, 0.003751 mol) in water (3.0 mL) was added and reaction mixture was stirred for 12 hours at room temperature. Solvent was evaporated and resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over MgSO4 and evaporated to give the title compound (340 mg, 65.5%) as white solid. This material was used in the next step without further purification.
Reaction SMILES: C1(=O)OCCC1.[C:7]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[C:10]([O:12][CH2:13][CH3:14])(=[O:11])/[CH:9]=[CH:8]\[C:7]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCC(=O)OCC
Solvent: O=C1CCCO1
Product: CCOC(=O)/C=C\C(=O)OCC

Procedure:
In EP-A-0255400 there is described a process for the production of substantially pure gamma-butyrolactone from a feed mixture containing a major molar amount of gamma-butyrolactone and a minor amount of diethyl succinate. Such a feed mixture may result from hydrogenation of diethyl maleate according to the teachings of EP-A-0143634, WO-A-86/03189, and/or WO-A-86/07358. In EP-A-0255400 which was published on Feb. 3, 1988, there is described a process in which the "light ends", i.e. a mixture of tetrahydrofuran, ethanol, water, and n-butanol, are stripped off in a first distillation column which is operated under vacuum at a pressure of 0.27 bar with a head temperature of 48° C. The "light ends" which are recovered overhead are passed to a second distillation column which is operated at 1.2 bar at a head temperature of 58° C. A first tetrahydrofuran/water azeotrope is recovered overhead from this second distillation column which is passed to a third distillation column operated at 7.0 bar with a head temperature of 126° C. Essentially pure tetrahydrofuran is recovered as a bottom product from the third distillation column, whilst the overhead product therefrom is a second tetrahydrofuran/water azeotrope which is markedly richer in water than the first tetrahydrofuran/water azeotrope from the second column. This second azeotrope is recycled to the second column.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][C:24]1[S:28][C:27]([C:29](Cl)=[O:30])=[C:26]([CH2:32][CH2:33][Cl:34])[CH:25]=1>C1COCC1>[CH3:14][N:13]([CH3:15])[C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:27]3[S:28][C:24]([Br:23])=[CH:25][C:26]=3[CH2:32][CH2:33][Cl:34])=[O:30])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C(Cl)c1sc(Br)cc1CCCl
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3sc(Br)cc3CCCl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of [(R)-1-(4-Amino-phenyl)-pyrrolidin-3-yl]-dimethyl-amine (349 mg) and triethylamine (0.25 mL) in THF (4 mL) a solution of 5-Bromo-3-(2-chloro-ethyl)-thiophene-2-carbonyl chloride (489.6 mg) in THF (3 mL) added dropwise. The mixture was stirred for 2 h at room temperature. Then the solvent was removed in vacuum and then water and ethyl acetate were added to the residue. The aqueous phase was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 456.84 (C19H23BrClN3OS); MS (ESI): 456, 458 (M+H+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:21])([C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[O:11][C:12]([F:16])=[C:13]([F:15])[F:14])[C:5]([O:7]C)=[O:6].[Na].S(=O)(=O)(O)O>O>[F:3][C:4]([F:21])([C:9]([F:19])([F:20])[C:10]([F:18])([F:17])[O:11][C:12]([F:16])=[C:13]([F:14])[F:15])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)OC(F)=C(F)F
Reaction time: 1.5 h
Yield: 313.3 %

Procedure:
(1') An aqueous solution containing 40 g (0.1 mole) of sodium hydroxide dissolved in 160 ml of water was added to 306 g (0.1 mole)of methyl perfluoro(4-vinyloxybutyrate) at 0°-5° C. over 5 hours, and the mixture was returned to room temperature with stirring over 1.5 hours and then left standing for 12 hours. By distilling off water and heating the residue to dryness under reduced pressure, sodium perfluoro(4-vinyloxybutyrate) was quantitatively obtained. 100 g of the sodium salt was suspended in excess amount of concentrated sulfuric acid and the suspension was distilled under reduced pressure, whereby 91.5 g of perfluoro(4-vinyloxybutyric acid) was obtained as a fraction having a boiling point of 80°-81.5° C./20 mmHg (yield:93%). ##STR16##
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:9]1[CH:14]=[C:13]([CH:15]=O)[C:12]([CH:17]=O)=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[CH:11]1[C:12]2[C:13](=[CH:15][C:6]3[C:1](=[O:8])[C:2]4[C:3]([C:4](=[O:7])[C:5]=3[CH:17]=2)=[CH:15][C:13]2[C:12](=[CH:11][CH:10]=[CH:9][CH:14]=2)[CH:17]=4)[CH:14]=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)CC1
Reactant: O=Cc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Temperature: 47 °C

Procedure:
A solution of 62.7 grams (0.559 mmoles, 1.0 equivalents) of cyclohexan-1,4-dione and 150 grams of o-phthalaldehyde (1.12 mmoles, 2.0 equivalents) in 2000 mL of ethanol was heat to 28° C. To this solution was added 220 mL of a 1M aqueous solution of sodium hydroxide. The reaction temperature increased to 47° C. during the addition. The mixture was then heated at 40° C. for 4 hours. The mixture was cooled and a yellow solid precipitate was collected. The solid was stirred in 2000 mL of N,N-dimethylformamide and heated to 50° C. for 2 hours. The mixture was cooled to room temperature (i.e., 20° C. to 25° C.) and the yellow solid was collected and washed with N,N-dimethylformamide, then with acetone and dried to give 108.3 grams (62 mole percent yield) of a bright yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[C:4]1=[CH:11][N+:12]([O-])=O)[CH3:2]>[Ni].CO>[CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH2:12])[CH3:2]
Reactant: CCN1CC2CCCC2C1=C[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCN1CC2CCCC2C1CN

Procedure:
54 parts of N-ethyl-2-nitromethylene-3-azabicyclo (3,3,0) octane, in solution in 500 parts of anhydrous methanol were reduced in presence of 20 parts of Raney Nickel at 5 kg/m2 pressure. After filtration and washing of the catalyst by methanol, the filtrate was evaporated under vacuo then distilled. There were obtained 30 parts of N-ethyl-2-aminomethyl-3-azabicyclo (3,3,0) octane, B.P./0.25-0.30 mmHg : 88°-90° C. This reduction can be easily carried out with lithium aluminium hydride too.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.S(=O)(=O)(O)O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)(O)O
Product: ClCc1csc(-c2ccc(Cl)cc2)n1

Procedure:
In analogy to the procedure described in example 4 a], 4-chlorothiobenzamide was reacted with 1,3-dichloroacetone followed by treatment with concentrated sulfuric acid to obtain 4-chloromethyl-2-(4-chloro-phenyl)-thiazole as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:5]([N:7]1[CH:13]2[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:6].[Cl-:21].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:21][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:2]([F:1])[CH:3]=1
Reactant: [Cl-]
Reactant: C#CCOc1ccc(C(=O)N2C3CCCCC32)cc1F
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1ccc(C(=O)NC2CCCCC2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2 ml of chloroform and 229 mg of zinc (II) chloride was stirred at room temperature for 5 minutes. Then, a mixture of 230 mg of 7-[3-fluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 0.20 g of N-(2-chlorocyclohexyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 110 of the present invention) represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O.[OH-].[Li+].[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[OH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])[S:3][C:4]=2[CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
To a solution of 2-amino-1,3-benzothiazol-6-ol (3.43 g, 20.6 mmol) in pyridine (50 mL) were added cyclopropanecarbonyl chloride (4 mL, 44.1 mmol) and N,N-dimethylpyridine-4-amine (220 mg, 1.80 mmol), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added lithium hydroxide monohydrate (2.06 g, 49.1 mmol) in water (50 mL) and the mixture was stirred at the same temperature for 1 hr. 5N Aqueous sodium hydroxide solution (50 mL) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dilute hydrochloric acid (300 mL, pH 2.0), and extracted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (150 mL). The earlier aqueous layer was extracted with ethyl acetate (150 mL), and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (100 mL). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.67 g, 76%) as a pale-gray solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].Cl.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.C(O)(=O)C.Cl>C(O)C>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH2:10][C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[N:29]2)=[CH:24][CH:23]=1
Reactant: O=C(C=Cc1ccc(F)cc1F)C(F)(F)C(F)(F)F
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2ccc(Br)cc2)c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (3.8 g, 13.3 mmol) prepared in Step 3 of Preparation 14, 4-bromophenylhydrazine hydrochloride (3.3 g, 13.5 mmol), acetic acid (15.0 mL) and conc. hydrochloric acid (20.0 mL) were added to ethanol (35.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 5.4 g of the titled compound as a yellow liquid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[Cl:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][N:18]=1.C(#N)C.[OH-].[Na+]>O.CC(O)C>[Cl:12][C:13]1[C:14]2[N:15]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:19]=2)[CH:16]=[CH:17][N:18]=1
Reactant: Nc1nccnc1Cl
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CC(C)O
Product: Fc1ccc(-c2cn3ccnc(Cl)c3n2)cc1
Temperature: 45 °C
Yield: 56 %

Procedure:
Into a 1-Neck round-bottom flask was added 2-bromo-1-(4-fluorophenyl)ethanone (125 g, 564 mmol) and 3-chloropyrazin-2-amine (128.9 g, 965.2 mmol) followed by ACN (750 mL). The mixture was stirred at reflux for about 24 h. The reaction mixture was cooled to about 45° C. before the solvent was removed in vacuo to yield a brown solid. The brown solid was suspended in water (500 mL) and basified, whilst stirring, with 2.5N NaOH (500 mL). The mixture was then stirred for about 30 min then re-acidified with 5N HCl (300 mL) and extracted with DCM (5×1000 mL). The combined organic layers were filtered from the insoluble material, washed with water (750 mL), followed by washing with 2.5N HCl (4×750 mL), 2.5N NaOH (500 mL) and water (2×500 mL), then dried over MgSO4 and filtered. The filtrate was eluted through a Florisil® pad (3 inch diameter×3 inch depth), washing with repeated amounts of DCM until no product detected by TLC. The organic solvent was removed in vacuo to yield a yellow solid, which was suspended in 2-propanol (500 mL) at about 80° C. for about 15 min and then cooled to about 30° C. The solid was filtered, washing with petroleum ether [bp 30-60° C.] (2×100 mL) and heptane (2×100 mL) to remove impurities, dried in vacuo at 45° C. to yield the title compound (78.2 g, 55.4%): LC/MS (Table 1, Method g) Rt=2.48 min; MS m/z: 248.2 (M+H)+.
Reaction SMILES: O.[NH3:2].[F:3][C:4]([F:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17])[C:5]([F:8])([F:7])[F:6]>C(Cl)Cl>[F:3][C:4]([F:20])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:2])(=[O:18])=[O:17])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)C(F)(F)F
Reactant: N
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F

Procedure:
To a mixture of 250 ml of methylene chloride, 250 ml of water and 250 ml of 30% ammonia solution is slowly added a solution of the crude 2-pentafluoroethoxyphenylsulfonyl chloride obtained in Example 1(a), in 50 ml of methylene chloride. After the exothermic reaction has subsided, the reaction mixture is refluxed for 2 hours. The organic phase is washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from methanol yields 65 g of 2-pentafluoroethoxyphenylsulfonamide with a melting point of 145°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[O:20][C:19]([CH2:21][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:18][CH:17]=4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1
Reactant: CS(=O)(=O)CCN
Solvent: O
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(F)c4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.36 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H), obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Cl:11].[N-:12]=[N+:13]=[N-:14].[Na+].C(=O)([O-])O.[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[N:12]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Cl:11])=[N+:13]=[N-:14]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])c(Cl)c1
Yield: 99.4 %

Procedure:
A mixture 8.0 g (0.035 mol) of 4-bromomethyl-3-chlorobenzonitrile (J. Pharm. Sci., (1986) 75, 410), 2.7 g (0.042 mol) of sodium azide, 1.2 g (3.4 mmol) of tetrabutylammonium hydrogen sulfate, 0.30 g (3.4 mmol) of sodium hydrogen carbonate, 7 mL of water and 20 mL of toluene was stirred vigorously for 3 days. The phases were separated and the aqueous layer was extracted three times with ether. The combined organic phase was washed with water, dried over sodium sulfate and evaporated to give 6.7 g (100%) of the sub-title compound.