Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([S:11]([C:14]([CH3:36])([CH3:35])[C:15]([NH:17][C:18]2[O:22][N:21]=[C:20]([C:23]([CH3:34])([C@@H:25]([O:27]C3CCCCO3)[CH3:26])[CH3:24])[CH:19]=2)=[O:16])(=[O:13])=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.O>[OH:27][C@@H:25]([CH3:26])[C:23]([C:20]1[CH:19]=[C:18]([NH:17][C:15](=[O:16])[C:14]([S:11]([CH:8]2[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]2)(=[O:12])=[O:13])([CH3:36])[CH3:35])[O:22][N:21]=1)([CH3:34])[CH3:24]
Reactant: C[C@H](OC1CCCCO1)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCN(S(C)(=O)=O)CC2)on1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCN(S(C)(=O)=O)CC2)on1
Yield: 100 %

Procedure:
A solution of 192 mg (0.35 mmol) of 2-(1-methanesulfonylpiperidine-4-sulfonyl)-2-methyl-N-{3-[(3S)-2-methyl-3-(oxan-2-yloxy)butan-2-yl]-1,2-oxazol-5-yl}propanamide in DCM/methanol (1/1, 4 mL) is treated with 241 mg (1.40 mmol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 18 h. The resin is removed by filtration and washed alternating with DCM and methanol. The combined filtrates are concentrated under reduced pressure and the resulting residue is purified by column chromatography (silica, eluent: heptanes, 50-100% ethyl acetate) to yield 163 mg of N-{3-[(3S)-3-hydroxy-2-methylbutan-2-yl]-1,2-oxazol-5-yl}-2-(1-methanesulfonylpiperidine-4-sulfonyl)-2-methylpropanamide. Yield 78%; ES-MS: m/z 466 [M+H]
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](C(OCC)=O)[C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12])=[C:6]([CH3:23])[CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH3:23][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:9]=[CH:8][C:7]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cnc([N+](=O)[O-])cc1C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cnc([N+](=O)[O-])cc1C
Reaction time: 12 h

Procedure:
tert-Butyl ethyl (6-nitro-4-methylpyridin-3-yl)propanedioate (7.4 g, 22.8 mmol) was dissolved in DCM (100 mL) and treated with trifluoromethanesulfonic acid (25 mL). The reaction mixture stirred 12 h, then was concentrated in vacuo and dried under high vacuum. The resulting residue purified by flash chromatography (eluted with 2−>10% hexanes/ethyl acetate) to provide title compound.
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=[N:3]1.Cl.CN(C)CCCN=C=NCC.[NH:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])[C:30](O)=[O:31])[C:24]([CH3:26])=[O:25].O.NN>CN(C)C=O>[NH:23]([C:27]1[CH:28]=[C:29]([C:30]([NH:2][NH2:3])=[O:31])[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])[C:24]([CH3:26])=[O:25]
Reactant: COC(=O)c1ccc(C(=O)O)cc1NC(C)=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
1-Hydroxybenzotriazole (HOBt) (270 mg, 2 mmol) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (WSC) (498 mg, 2.6 mmol) were added to a solution of 3-acetamino-4-methoxycarbonylbenzoic acid (474 mg, 2 mmol) in dimethylformamide (10 mL), and the mixture was stirred at room temperature for 3 hours. Hydrazine monohydrate (485 μL, 10 mmol) was further added at 0° C., and the mixture was stirred overnight at room temperature. The precipitated solid was filtered, and then washed with water to obtain 400 mg of the desired product as a white solid (yield 80%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26](OC(=S)C)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.OO.[S:48]([O-:51])([OH:50])=[O:49].[Na+]>C(O)(=O)C>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:24][CH2:25][CH:26]([S:48]([OH:51])(=[O:50])=[O:49])[CH2:27][CH2:28]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:45])([F:1])[F:44])[CH:8]=1
Reactant: CC(=S)OC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1-c1cc(N2CCC(S(=O)(=O)O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a suspension of 0.16 g (0.24 mmol) thioacetic acid 5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl ester in 1 ml acetic acid were added 0.12 ml (1.2 mmol) of a 30% aqueous solution of hydrogen peroxide at room temperature. After heating to 60° C., a clear solution was obtained. Stirring was continued at this temperature for 20 h. After cooling to room temperature an aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Acidification with 1 N aqueous hydrochloride solution to pH 1 was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.13 g (83%) of the title compound as a light yellow solid.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[N:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:12][N:13]([S:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:14](F)=[O:15]>>[CH3:12][N:13]([S:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C:14]([O:2][N:1]=[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[N:7][CH2:6][CH2:5][S:4]1)=[O:15]
Reactant: CC(C)C1=NCCSC1=NO
Reactant: CN(SN1CCOCC1)C(=O)F
Product: CC(C)C1=NCCSC1=NOC(=O)N(C)SN1CCOCC1

Procedure:
2-Oxo-5,6-dihydro-3-isopropyl-2H-1,4-thiazine oxime is reacted with N-methyl-N-morpholinosulphenylcarbamoyl fluoride as described in Example 25 to yield 2-oxo-5,6-dihydro-3-isopropyl-2H-1,4-thiazine O-(N-methyl-N-morpholinosulphenylcarbamoyl)oxime, m.p. 127°-128.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[NH:6][C:5]2=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[NH:6][C:5]3=[O:19])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2c(c1)c(=O)[nH]n2Cc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Product: O=c1[nH]n(Cc2ccc(F)cc2)c2ccc(NS(=O)(=O)c3cccc(Cl)c3)cc12
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.9 %

Procedure:
To a solution of 5-amino-1-(4-fluoro-benzyl)-1,2-dihydro-indazol-3-one (0.100 g) in pyridine (1 mL) was added 3-chlorobenzenesulfonylchoride (0.082 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired 3-chloro-N-[1-(4-fluoro-benzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl]-benzenesulfonamide (0.087 g) as a brown solid. MS (ESI+): 432.4 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][Li].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([OH:16])[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CC1(c2ccc(Cl)c(Cl)c2)CCCCC1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(3,4-dichlorophenyl)cyclohexanecarbaldehyde (440 mg, 1.71 mmol) in anhydrous THF (17 mL) at 0° C. was added slowly methyl lithium (1.6 M in Et2O, 3.21 mL, 5.14 mmol). The solution was allowed to warm to RT and was stirred for 16 h. It was then quenched with MeOH (5 mL). The crude reaction mixture was poured into 2M HCl (15 mL) and washed with EtOAc (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give 1-(1-(3,4-dichlorophenyl)cyclohexyl)ethanol. HPLC Rt=11.28 min; 1H NMR (400 mHz, CDCl3) 7.44-7.41 (m, 2H), 7.20 (dd, J=2.2, 8.4 Hz, 1H), 3.63-3.58 (m, 1H), 2.39-2.35 (m, 1H), 2.14-2.10 (m, 1H), 1.67-1.48 (m, 5H), 1.31-1.16 (m, 3H), 0.92 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CN(c2cccc(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of alcohol 103 (6.33 g, 30.0 mmol) in CH2Cl2 (60 mL) was treated with TEA (6.07 g, 8.36 mL, 60 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before MsCl (3.78 g, 2.55 mL, 33.0 mmol, 1.1 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (40 mL) and CH2Cl2 (40 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with H2O (2×40 mL) and saturated aqueous NaCl (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (SR)-methanesulfonic acid 3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 109 (7.69 g, 88.7% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H12FNO5S, LCMS (EI) m/e 290 (M++H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Mg].O(CC)CC.Br[CH2:22][CH:23]=[CH2:24]>O1CCCC1>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:24][CH:23]=[CH2:22]
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: C=CCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCc1ccc(-c2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 89 parts of 4-(chloromethyl)-1,1'-biphenyl and 12.5 parts of magnesium in 350 parts of 1,1'-oxybisethane, is added dropwise a solution of 60 parts of 3-bromo-1-propene in 180 parts of tetrahydrofuran. Upon completion, stirring is continued for 2.50 hours at reflux temperature. The reaction mixture is cooled and poured onto water. The layers are separated and the aqueous phase is extracted with 1,1'-oxybisethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is filtered and the filtrate is evaporated, yielding 60 parts of 4-(3-butenyl)-1,1'-biphenyl as a residue.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[C:16]12([NH2:21])[CH2:20][CH:18]([CH2:19]1)[CH2:17]2.CCN(C(C)C)C(C)C>C(O)C.O>[C:16]12([NH:21][C:2]3[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=3)[CH2:20][CH:18]([CH2:19]1)[CH2:17]2
Reactant: NC12CC(C1)C2
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1NC12CC(C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (200 g, 0.86 mol), bicyclo[1.1.1]pentan-1-amine hydrochloride (171 g, 1.11 mol; prepared according to Org. Lett., 13(17): 4746-4748 (2011)) and DIEA (278 g, 2.15 mol) in ethanol (2.4 L) was stirred overnight at room temperature. After completion of the reaction, the solvents were concentrated under reduced pressure to give the crude product, which was diluted with water (1 L). The aqueous layer was extracted with chloroform (2×1 L) and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents afforded the desired compound (231 g, 0.83 mol, 96% yield) as a pale brown oil which was contaminated with trace amounts of DIEA. This product was used in the next reaction without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 8.61 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 2.51 (s, 1H), 2.20 (s, 6H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.Cl.[CH3:9][N:10]1[C:19]2[NH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]([C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:28]([CH3:42])[CH:27]=3)=[O:25])[CH2:14][C:13]=2[CH:12]=[N:11]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:39]1[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][CH2:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([C:24]([N:15]3[CH2:14][C:13]4[CH:12]=[N:11][N:10]([CH3:9])[C:19]=4[NH:18][C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]3=4)=[O:25])=[CH:27][C:28]=2[CH3:42])[CH2:37][CH2:38]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCNCC1
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Acetic acid (0.05 ml) and 3,3-dimethylbutyraldehyde (0.024 ml, 0.19 mmol) were added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperidin-4-yl-propoxy)-phenyl]-methanone hydrochloride from Example E68.5 (60 mg, 0.12 mmol) in methanol (2.45 ml) and triethylamine (0.026 ml, 0.19 mmol). The mixture was stirred at room temperature for 1 h then sodium triacetoxyborohydride (40 mg, 0.19 mmol) was added. The mixture was stirred at room temperature for 18 h, diluted with dichloromethane, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white fluffy solid identified as the title compound (33 mg, 48%).
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>O.C(OCC)C>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:18]=[CH:19][C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:9][CH:10]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A solution of 3.0 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine dihydrochloride (Example 2) is dissolved in 100 ml H2O and while stirring 3.5 ml of 10N NaOH, and then 2.6 g of 4-(t-butyl)benzenesulfonyl chloride in 100 ml of diethyl ether are added. The mixture is stirred at room temperature for 4 hours. The precipitate is collected, washed with 50 ml of water and 50 ml of diethyl ether, and air dried. Recrystallization from 50% aqueous ethanol gives 2.6 g of the title compound, m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5].C(Cl)(=O)C([Cl:25])=O.CN(C)C=O.O>C(Cl)Cl>[Cl:25][C:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:17][C:2]=1[Cl:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)C2C(=O)CCCC2=O)c(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)C2=C(Cl)CCCC2=O)c(Cl)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
2-(2-Chloro-4-methanesulfonylbenzoyl)-cyclohexane -1,3-dione [9.8 grams (g.), 30 millimole (mmol)] was dissolved in 100 milliliters (ml) methylene chloride and stirred at room temperature. To this solution was added oxalyl chloride (5.7 g., 45 mmol) followed by dimethylformamide (0.5 ml) in portions small enough to control effervescence. The resulting solution was stirred for 4 hours and then poured into water and extracted with methylene chloride. The organic layer was washed again with water, saturated K2CO3 solution and then dried with MgSO4 and the solvent evaporated to yield 3-chloro-2(2-chloro-4-methanesulfonylbenzoyl) cyclohex-2-enone (7.3 g., 70%) as an oil which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:30]=[CH:29][N:28](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]=3[N:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=3)[N:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>CO>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[CH:30]=[CH:29][NH:28][C:12]=3[N:13]=[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:27])[C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=3)[N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(CN)c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3cccc(CN)c3)c3cc[nH]c3n2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of N-(4-(4-(3-(aminomethyl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (27 mg, 0.049 mmol) in MeOH (3 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. The mixture was stirred at 60° C. for 3 h. It was concentrated in vacuo. The residue was acidified with HOAc (1 mL) before being purified by HPLC to give the titled compound (15 mg). MS 402.3 (M+H); UV 202.6, 282.9, 315.0 nm.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][C:10]=1[F:34])[O:6][CH2:7][CH3:8])C.C1COCC1.CO.O[Li].O>O>[F:15][C:14]1[CH:13]=[C:12]([OH:16])[CH:11]=[C:10]([F:34])[C:9]=1[CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC(C(=O)O)c1c(F)cc(O)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of (RS)-[4-(tert-butyl-diphenyl-silanyloxy)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester (10.4 g) in a THF (50 ml), MeOH (50 ml) and H2O (20 ml) mixture was added LiOH.H2O (1.75 g) and it was stirred 2 h at 60° C. After cooling water (240 ml) was added and the solution was washed with TBME (240 ml). The aqueous layer was collected, TBME was added (240 ml) and the mixture was acidified with 1 N HCl sol. The aqueous layer was extracted with one more portion of TBME. The combined organic layers were dried (MgSO4) and the solvent was evaporated to obtained an oil. Solid (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid (4.6 g, 95%) was obtained after addition of AcOEt, evaporation of it and drying on the high vacuum over night. Off-white solid. MS 231.1 ([M−H]−).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH2:14][CH2:15][CH2:16][C@H:17]([CH2:19][CH2:20][CH2:21][C@H:22]([CH2:24][CH2:25][CH2:26]/[C:27](=[CH:29]/[CH2:30][OH:31])/[CH3:28])[CH3:23])[CH3:18])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C:27]([CH2:26][CH2:25][CH2:24][CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH:17]([CH3:18])[CH2:16][CH2:15][CH2:14][CH:12]([CH3:13])[CH3:11])=[CH:29][CH:30]=[O:31]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=CC=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 17.4 mL (202 mmol) of oxalyl chloride was dissolved in methylene chloride (300 mL). 36 mL (0.51 mol) of dimethyl sulfoxide was slowly added dropwise to the mixture at −78° C. After the mixture was stirred for 15 min, 50 g (0.17 mol) of phytol was added, followed by stirring for 1 hour at the same temperature. After addition of 94 mL (0.68 mol) of triethylamine, the reaction mixture was allowed to warm up to room temperature. The mixture was concentrated with methylene chloride, and the residue was diluted with diethylether, and the solution was washed saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain 3,7,11,15-tetramethylhexadec-2-en-1-al as a crude product.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CN1CCOCC1>CO>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccc(Cl)cc1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(Cl)cc3)cc2s1
Yield: 16.1 %

Procedure:
the title compound (21 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-chlorobenzylamine (74 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 434.4 (Cl35 M+1, 100%), 436.4 (Cl37 M+1, 40%). Yield=16%.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.C(O)C>[O:9]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=[N:2][OH:3])[CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NO
Reactant: CC(=O)COc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(COc1ccc(Oc2ccccc2)cc1)=NO
Reaction time: 1 h

Procedure:
Over about 1 hour, a solution of 22 g of hydroxylamine hydrochloride and 26 g of anhydrous sodium acetate in 110 ml of water is added dropwise at room temperature to a solution of 64 g of 4-phenoxyphenoxyacetone in 260 ml of ethanol. After the slightly exothermic reaction has subsided, the mixture is stirred for a further 3.5 hours at reflux temperature. Subsequently, the ethanol is distilled off from the reaction mixture by rotary evaporation, the aqueous residue is extracted three times with a 2:1 mixture of ether and hexane, the combined organic phases are washed with water and with 10% sodium bicarbonate solution and then dried over sodium sulfate. The solvent is then distilled off. Recrystallisation from a mixture of diethyl ether and pentane affords 4-phenoxyphenoxyacetone oxime with a melting point of 59°-61° C.