Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1(B(O)O)[CH2:15][CH2:14][CH2:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:11]1([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: COc1ccc(F)cc1Br
Reactant: OB(O)C1=CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(F)cc1C1=CCCC1
Yield: 49.2 %

Procedure:
A microwave vial was charged with 2-bromo-4-fluoro-1-methoxybenzene (500 mg, 2.44 mmol), 1-cyclopentenylboronic acid (273 mg, 2.44 mmol), and Pd(dppf)Cl2 (199 mg, 0.24 mmol). The solids were dissolved in acetonitrile (7 mL) and 2 M Na2CO3 (5 mL) and the mixture heated under microwave irradiation for 20 min at 110° C. The reaction was diluted with dichloromethane (50 mL) and the layers separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10-30% ethyl acetate/hexane) provided 2-cyclopentenyl-4-fluoro-1-methoxybenzene (231 mg, 49% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.01 (dd, J=3.1, 10.0 Hz, 1H), 6.92-6.82 (m, 1H), 6.54 (dd, J=2.4, 6.5 Hz, 1H), 6.54 (s, 1H), 3.87 (s, 3H), 2.78-2.73 (m, 2H), 2.62-2.57 (m, 2H), 2.03-1.95 (m, 2H).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([OH:19])(=O)=[O:17])=[O:6].P(Cl)(Cl)([Cl:22])=O>CO>[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:16]([Cl:22])(=[O:19])=[O:17])=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 17.3 g (0.27 mol) of potassium hydroxide (88% strength) and 100 ml of methanol is added carefully with vigorous stirring to a solution of 70.9 g (0.27 mol) of 2-methoxycarbonyl-5-nitrobenzenesulfonic acid in 300 ml of methanol. The mixture is cooled to 0° C. and the salt which is precipitated is filtered off, dried and then suspended in 150 ml of sulfolane, 150 ml of acetonitrile and 10 ml of dimethylformamide. After the dropwise addition of 100 ml (1.07 mol) of phosphorus oxychloride, the mixture is heated at boiling for 2.5 h. The reaction mixture is then poured into ice-water. The 2-methoxycarbonyl-5-nitrobenzenesulfonyl chloride (60.1 g, 70% of theory) which has precipitated is filtered off with suction through a Buchner funnel and freed from traces of solvent under reduced pressure. Melting point: 86°-88° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:23])[C:12]3[C:17]([S:18](=[O:22])(=[O:21])[C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:23])[C:12]3[C:17]([S:18](=[O:22])(=[O:21])[C:19]=2[CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=S(Cl)Cl
Reactant: CN1c2ccccc2S(=O)(=O)c2cc(CO)ccc21
Solvent: ClC(Cl)Cl
Product: CN1c2ccccc2S(=O)(=O)c2cc(CCl)ccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
Thionyl chloride (5 ml) was added to a mixture of 3-hydroxymethyl-10-methylphenothiazine-5,5-dioxide (1.23 g, 4.47 mmol) and chloroform (15 ml), and the mixture was stirred for 1 hour. The reaction mixture was concentrated under a reduced pressure, water was added to the residue, and the reaction product was extracted with chloroform. The extract was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure to give the title compound (1.32 g, 100%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:25])[N:15](COCCOC)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:26]#[N:27])[CH:8]=2)[O:3]1>[Zn+2].[Br-].[Br-].ClCCl>[CH3:1][C:2]1([CH3:28])[CH:11]([OH:12])[CH:10]([C:13]2[C:14](=[O:25])[NH:15][CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:26]#[N:27])[CH:8]=2)[O:3]1
Reactant: COCCOCn1cccc(C2c3cc(C#N)ccc3OC(C)(C)C2O)c1=O
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(C#N)cc2C(c2ccc[nH]c2=O)C1O
Reaction time: 16 h

Procedure:
A mixture of 384 mg of 2,2-dimethyl-4-[1-(2-methoxyethoxymethyl)-1,2-dihydro-2-oxo-3-pyridyl]-6-cyano-3-chromanol [obtainable from 1-(2-methoxyethoxy-methyl)-1,2-dihydro-2-oxopyridine and 2,2-dimethyl-3,4-epoxy-6-cyanochroman], 600 mg of finely powdered ZnBr2 and 4 ml of dichloromethane is stirred at 25° for 16 hours. The mixture is washed with saturated NaHCO3 solution, then with saturated NaCl solution, the wash solutions are extracted with ether, and the organic phases are combined and further worked up in the customary manner. 2,2-Dimethyl-4-(1,2-dihydro-2-oxo-3-pyridyl)-6-cyano-3-chromanol is obtained; m.p. 246°-247°.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@H:27]1[C@H:32]([NH:33][C:34](=[O:41])[O:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH2:31][CH2:30][N:29]([C:42]2[CH:47]=[C:46]([C:48]#[N:49])[CH:45]=[C:44]([NH:50][C:51]3[N:56]=[C:55]([NH:57][CH:58]4[CH2:60][CH2:59]4)[C:54]4=[N:61][CH:62]=[C:63]([C:64]#[N:65])[N:53]4[N:52]=3)[C:43]=2[Cl:66])[CH2:28]1)(C(C)(C)C)(C)C>C1COCC1>[Cl:66][C:43]1[C:44]([NH:50][C:51]2[N:56]=[C:55]([NH:57][CH:58]3[CH2:60][CH2:59]3)[C:54]3=[N:61][CH:62]=[C:63]([C:64]#[N:65])[N:53]3[N:52]=2)=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:42]=1[N:29]1[CH2:30][CH2:31][C@@H:32]([NH:33][C:34](=[O:41])[O:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])[C@H:27]([OH:26])[CH2:28]1
Reactant: CN(C)CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
TBAF (1M in THF, 0.059 mL, 0.059 mmol) was added to a solution of (+/−)-2-(dimethylamino)ethyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (34 mg, 0.049 mmol) in THF (1 mL) and the resulting solution was stirred at room temperature overnight. Solvent was evaporated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate. The layers were separated and aqueous layer was extracted with dichloromethane/methanol (4/1) two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 2-12% 2 N ammonia in methanol/dichloromethane). (+/−)-2-(dimethylamino)ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (22 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:32][CH:33]4[CH2:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NC1Cc2ccccc2C1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-aminoindan as in General Procedure 10 to give the title compound. LCMS: m/z=562.96 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:27]1([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].C1COCC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CO.O.CC(O)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:18])([CH3:17])[C:14]([C:19]4[CH:20]=[CH:21][C:22]([CH2:23][N:30]5[CH2:31][CH2:32][N:27]([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:28][CH2:29]5)=[CH:25][CH:26]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(C=O)cc1
Reactant: OCCOCCN1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1ccc(CN2CCN(CCOCCO)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (55 mg, 0.16 mmol), 2-(2-(piperazin-1-yl)ethoxy)ethanol (56 mg, 0.32 mmol) and 4 Å molecular sieves (100 mg) in anhydrous DMF (3 mL) was stirred at room temp for 16 hours. To this stirred mixture was added AcOH (10 mg), 1M sodium cyanoborohydride in THF solution (0.32 mL, 0.32 mmol) and 3 mL of anhydrous methanol. The reaction mixture was stirred at room temp for 5 hours and poured into 100 mL of water. Saturated NaHCO3 solution was then added until pH=9. The precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3 to give (3E)-6-fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 45 mg, 56%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])(C)(C)C.C(O[C:25](=[O:41])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:29]=1)(C)(C)C>>[N:39]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[C:30]1[CH:29]=[C:28]([C:27]2[CH2:26][C:25](=[O:41])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (138 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (164 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (75 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:15]4[CH:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:18]=[CH:17][N:16]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH:27]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([C:15]4[CH:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:18]=[CH:17][N:16]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1)[CH3:27]
Reactant: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4)ccn3)cccc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-methyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.3 g, 15.76 mmol) was dissolved in 130 mL of THF. This solution was cooled in a dry ice bath to −78° C. Lithium diisopropylamide in THF (9.85 mL, 19.69 mmol) was added dropwise to the reaction mixture over a 10 minute period maintaining the temperature below −73° C. The reaction mixture was stirred at −78° C. for 2 hours. Iodomethane (3.35 g, 23.63 mmol) was dissolved in 20 mL of THF then was added dropwise via syringe to the cold reaction mixture. Stirring was continued as the reaction mixture gradually warmed to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride then was extracted 2×300 mL ethyl acetate. The organics were combined, were washed with aqueous LiCl then were dried over magnesium sulfate. These organics were then filtered and concentrated under vacuum. The crude residue was dissolved in DCM and was loaded onto a silica gel column. The column was eluted with 5-8% ethyl acetate/DCM. The main set of product fractions were combined and concentrated under vacuum yielding 2-ethyl-8-(4-phenylpyridin-2-yl)benzofuro[2,3-b]pyridine (5.15 g, 14.70 mmol, 93% yield)
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2([CH2:11][NH:10][CH2:9]2)[CH2:7][N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5]1.C=O.[C:21]([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(O)C>[CH2:12]([N:6]1[CH2:5][C:4](=[N:3][O:2][CH3:1])[C:8]2([CH2:11][N:10]([CH3:21])[CH2:9]2)[CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON=C1CN(Cc2ccccc2)CC12CNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CON=C1CN(Cc2ccccc2)CC12CN(C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
550 mg of 6-benzyl-2,6-diazaspiro[3,4]octane-8-one-O-methyloxime was added to 10 ml of ethanol and thereto 0.4 ml of acetic acid and 176 mg of paraformaldehyde were added and the resulting mixture was stirred for 30 minutes at room temperature and thereto 370 mg of sodium cyanoborohydride was added. The resulting mixture was stirred for 16 hours at room temperature, neutralized with aqueous solution of potassium carbonate and distilled under the reduced pressure and the obtained residue was added into 50 ml of dichloromethane, washed with 50 ml of water, dried with magnesium sulfate, filtered and concentrated under the reduced pressure. The residue was purified by silicagel column chromatography(methanol:normal hexane:dichloromethane=1:10:8) to give 350 mg of the titled compound(yield: 60.1%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)=[O:8].Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[OH-].[Na+].O>CS(C)=O>[F:1][C:2]([F:16])([F:17])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)=[O:8]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(CCCCC(F)(F)F)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(CCCCC(F)(F)F)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of 3-(6,6,6-trifluorohexanoyl)phenol (6.8 g, 27 mmol) and 2-chloromethylquinoline (4.4 g, 25 mmol) in DMSO (75 ml) containing 2N NaOH solution (14 ml) was stirred at room temperature overnight (13 hrs.). The dark reaction mixture was poured into water (200 ml) and the aqueous solution was extracted with ethyl acetate (4×30 ml). The organic extract was washed with 1N NaOH solution, water and brine and then dried over MgSO4. After removal of all volatiles, a dark liquid was obtained which solidified on standing (7.2 g). This solid was chromatographed (3% ethanol in toluene on silica gel) to obtain a beige color solid (4.5 g; mp 83°-4° C.), which was chromatographed again (15% acetone in hexanes on silica gel) to get a white solid (3.1 g; mp 86°-87° C.). This pure material was recrystallized from hexanes-acetone (trace) to leave the desired compound as a colorless, crystalline solid (2.4 g), mp 88°-88.5° C. (first crop; second crop mp 87°-88° C.).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Reactant: C1COCCN1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CN4CCOCC4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with morpholine. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.09 (s, 2H, CH2), 3.27-3.31 (m, 4H, CH2), 3.62-3.64 (m, 4H, CH2), 7.04 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.54 (d, 2H, J=8.8 Hz, Ph-H), 7.67 (d, 2H, J=8.8 Hz, Ph-H), 8.48 (d, 1H, J=4.9 Hz, pyridinyl-H), 9.59 (s, 1H, NH). MS (ESI+) m/z 425.01 [M+H]+ (C21H24N6O2S requires 424.52).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:17].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]2=[O:17])(=[O:21])=[O:20]
Reactant: COC(=O)CN1C(=O)c2ccc(N)cc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Yield: 108.6 %

Procedure:
To a solution of methyl 2-(5-amino-1,3-dioxoisoindolin-2-yl)acetate (380 mg, 1.622 mmol) in pyridine (10 ml), methanesulfonyl chloride (190 μl, 2.434 mmol) was added, and the mixture was reacted overnight at room temperature. The solvent was evaporated and the resulting crude was partitioned between 1N HCl (10 ml) and EtOAc (10 ml); aqueous phase was extracted with EtOAc (3×20 ml) and the organic phase was dried over sodium sulfate. The solvent was removed affording title compound as a brown solid (550 mg, MS/ESI+ 312.9 [MH]+). It was used in the next step without any additional purification.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH2:33][CH3:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1O)[CH3:17].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH2:33][CH3:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)/C(=C/c1ccc(O)c(OCC)c1)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
808 μL (4.8 mmol) of triflic anhydride are added to a solution of 1.5 g (4 mmol) of ethyl 2-[1-(3-ethoxy-4-hydroxyphenyl)meth-(E)-ylidene]butyrate and 1.6 mL (12 mmol) of triethylamine in 20 mL of dichloromethane at 0° C. The reaction mixture is stirred at room temperature for 1 hour. The reaction medium is hydrolyzed in sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 1.7 g (100%) of ethyl 2-[1-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)meth-(E)-ylidene]butyrate are obtained in the form of a brown oil.
Reaction SMILES: CC(C)(OC([NH:7][NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:17])[CH:16]=1)=[O:10])=O)C.FC(F)(F)C(O)=O>>[O:17]=[C:15]1[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][NH:12][C:11]([C:9]([NH:8][NH2:7])=[O:10])=[CH:16]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.7 %

Procedure:
1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide (69 g, 0.191 mol) was added at 0° C. to 370 ml of trifluoroacetic acid. The mixture was stirred for 1 hour at room temperature, then evaporated. The remaining syrup was treated with ether to yield 68.2 g of crude 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, hydrazide, trifluoroacetate (1:2) salt as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:11][C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17]
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
87.5 g of 2,4-dichlorobenzaldehyde are added slowly to a solution of 50 g of pinacolone in 200 ml of ethanol and 1 ml of sodium hydroxide solution (50% by weight), keeping the internal temperature at 30° C. or below. The mixture is stirred at 20° C. for 24 hours and then the precipitate is filtered off with suction and dried. 105.5 g (82%) of tert-butyl 2,4-dichlorostyryl ketone are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C(C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C2C=CC=CC=2)C=CC=CC=1.[C:38](=O)([O-:40])[O-:39].[K+].[K+].[C]=O>[Pd](Cl)Cl.O>[C:38]([OH:40])(=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: CC(C(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 210 °C
Reaction time: 3 h

Procedure:
In an autoclave made of metal were placed 11.2 g of chlorobenzene, 17.5 mg of palladium chloride, 427 mg of bisdiphenylphosphinobutane and 3.1 g of potassium carbonate. The air in the autoclave was replaced with carbon monoxide introduced thereinto in several times, after which carbon monoxide was further introduced to its pressure therein to 50 kg/cm2. The reaction was carried out with stirring for 3 hours on a salt bath at a bath temperature of 210° C. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added. The aqueous layer was separated, after which acid was added thereto and the deposited crystals were collected by
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=O)[CH2:15]1)=[O:13].F[B-](F)(F)F.C([O+](CC)CC)C.[S:33]1[C:37]([C:38]([NH:40][NH2:41])=O)=[N:36][CH:35]=[N:34]1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:38]([C:37]3[S:33][N:34]=[CH:35][N:36]=3)=[N:40][N:41]=[C:16]2[CH2:15]1)=[O:13]
Reactant: NNC(=O)c1ncns1
Reactant: O=C1CN(C(=O)c2cccc(C(F)(F)F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-piperazinone (I1) (0.307 g, 1 mmol) in dry Dichloromethane (DCM) (3 ml) was added triethyloxonium tetrafluoroborate (0.209 g, 1.100 mmol). The solution was then stirred at room temperature and under argon for 30 minutes. 1,2,4-Thiadiazole-5-carbohydrazide (I80) (0.144 g, 1.000 mmol) was then added and the solution was stirred for 1 hour, before the solvent was concentrated and n-BuOH (3.00 ml) was added. The solution was then stirred under argon and reflux for a further 3 hours. The solution was then allowed to cool to room temperature before the solvent was evaporated in vacuo.