Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([C:31](OC)=[O:32])[NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH2:1]([O:8][C@H:9]([CH3:35])[C@H:10]([NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:31][OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Methyl O-benzyl-N-trityl-L-threoninate (4.61 g, 9.91 mmol) was dissolved in 100 mL of anhydrous Et2O and the solution was cooled to 0° C. under N2. Lithium aluminum hydride (2.28 g, 60 mmol) was added and the mixture was stirred for 2 hours. The reaction mixture was then sequentially treated with 2.28 mL of H2O, 2.28 mL of 15% NaOH solution and 6.84 mL of H2O. After stirring for 30 minutes, the reaction mixture was filtered to remove the white solid. The solid was washed with several portions of Et2O and the combined filtrates were concentrated under reduced pressure. Chromatography (SiO2, 10-20% ethyl acetate/hexanes) gave 4.34 g of (2R,3R)-3-(benzyloxy)-2-(tritylamino)butan-1-ol as a colorless syrup.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH3:18])=[CH:8][CH:7]=1>ClCCl>[CH2:17]([C:13]1[N:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=2)[CH:16]=[CH:15][N:14]=1)[CH3:18]
Reactant: CN=C=O
Reactant: CCc1nccn1-c1ccc(N)cc1
Solvent: ClCCl
Product: CCc1nccn1-c1ccc(NC(=O)NC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g of methyl isocyanate was added to a solution of 1.5 g of 1-(4-aminophenyl)-2-ethylimidazole in 20 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours and then refluxed with stirring for 3 hours. After completion of the reaction, the reaction mixture was naturally cooled and the solvent was removed by distillation under reduced pressure. Benzene was added to the residue, and the formed solid was recovered by filtration. The recovered solid was dissolved in a small quantity of methanol and recrystallized from an ethyl ether/benzene mixed solvent. The obtained compound was converted to a hydrochloride having a melting point of 228° to 232° C. according to customary procedures. Elementary analysis values as C13H16N4O.HCl were as follows.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][C:22]([O:24]CC)=O.C(O)(=O)C.O>C1(C)C=CC=CC=1>[O:24]=[C:22]1[CH:8]([C:7]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)CC/C=C/CCCCCC/C=C/CCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)C1C/C=C/CCCCCC/C=C/CCC1=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CC=CCCCCCCC=CCCC1=O
Temperature: 25 °C

Procedure:
To a flask containing a solution of potassium t-butoxide (6.30 g, 61.1 mmole) in toluene (80 ml), heated to reflux, was added slowly (via syringe pump over 15 hours) a solution of diethyl hexadeca-4E,12E-diene-1,16-dioate (4.32 g, 12.8 mmole) in toluene (10 ml). After the addition was complete the mixture was maintained at reflux for an additional 5 hours. The reaction mixture was cooled to room temperature and to the mixture was added acetic acid and then water. To the mixture was then added diethyl ether, the layers separated and the organic layer was dried with sodium sulfate and evaporated to provide the crude ethyl 15-oxocyclopentadeca-3E,11E-dienecarboxylate which was used directly in the next step. C18H28O3 (292.42 g/mole). 1HNNR (500 MHz, CDCl3): 1.16 (m, 4H), 1.23 (t, 3H), 1.34 (m, 4H), 1.99 (m, 4h), 2.13 (m, 1H), 2.40 (m, 2H), 2.55 (m, 1H), 2.70 (m, 2H), 3.50 (dd, 1H), 4.13 (q, 2H), 5.40 (m, 4H) ppm. 13CNMR (125 MHz, CDCl3): 14.1, 26.2, 27.0, 27.4, 27.7, 28.6, 31.0, 31.1, 31.2, 43.6, 58.4, 61.3, 126.3, 129.1, 131.6, 133.6, 169.5, 204.6 ppm. IR (νmax(cm−1)): 2990, 2940, 2910, 2850, 1745, 1720, 1640, 1440, 1370, 1260, 1040, 970, 860. MS (m/z): 292(M+), 247, 163, 149, 135, 121, 107, 95, 81, 67, 55, 41.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C.O>[CH2:2]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Piperidine-4-carboxylic acid benzyl ester, hydrochloride salt (1 g, 3.9 mmol, 1e.) from step 3, was dissolved in DMF (15 ml), Triethylamine (0.55 ml, 4 mmol, 1 eq.) and methanesulfonylchloride were added. The mixture was stirred for 1 h at room temperature, then was poured in water (20 ml). The aqueous solution was extracted with Ethyl Acetate (90 ml) and the organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give a colourless oil. Yield 78%, 0.9 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:30])[N:20]1[CH2:19][C@@H:18]([NH:17][C:8]([C:6]1[S:7][C:3]([O:2][CH3:1])=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:10])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:40])([F:39])[F:41]
Reactant: COc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a 50 mL round-bottomed flask was added 5-(methyloxy)-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (148 mg, 0.62 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (242 mg, 0.63 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (356 mg, 0.76 mmol) in Chloroform (6 mL). DIEA (550 μL, 3.15 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (303 mg, 0.51 mmol, 82%): LC-MS (ES) m/z=569 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:8].O=CCCCNC(=O)C1C=CC=CC=1>>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:1])=[O:8]
Reactant: O=C(NCCCCO)NC1Cc2ccccc2C1
Agent: O=CCCCNC(=O)c1ccccc1
Product: O=CCCCNC(=O)NC1Cc2ccccc2C1

Procedure:
1-Indan-2-yl-3-(4-oxobutyl)urea (60C) is prepared from 60B as described for 1E.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([OH:15])[C:8](=[CH:10][C:11](=[CH:13][CH:14]=1)[OH:12])[CH3:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[CH3:16][S:17]([CH:9]([S:17]([CH3:16])(=[O:19])=[O:18])[C:8]1[C:7]([OH:15])=[CH:14][CH:13]=[C:11]([OH:12])[CH:10]=1)(=[O:19])=[O:18]
Reactant: Cc1cc(O)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)C(c1cc(O)ccc1O)S(C)(=O)=O

Procedure:
In 500 ml. of pyridine was dissolved 124 g. of toluhydroquinone and then 170 ml. of methanesulfonyl chloride was added dropwise to the solution while stirring at a temperature below 25° C. Thereafter, the mixture was further stirred for one hour at room temperature. After the reaction was over, 500 ml. of chloroform was added to the reaction mixture and the resultant mixture was washed several times with water, then with 10% hydrochloric acid and finally once with water. The chloroform layer formed was recovered and dried over anhydrous sodium sulfate. After filtering, the solvent was distilled off from the filtrate and the residue formed was recrystallized from methanol to provide 230 g. of the desired compound of a melting point of 80° to 82° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>C1COCC1.Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(-c3cccc(C)c3)cc(=O)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(=O)oc3cc(C(=O)O)ccc23)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(3-methylphenyl)-2-oxo-2H-chromene-7-carboxylate (610 mg, 2.1 mmol) in THF (21 mL) a solution of lithium hydroxide (10.3 mL, 10.3 mmol) was added. The solution was then heated at 65° C. for 2 hours. After cooling, volatiles were removed under reduced pressure and the residue obtained was diluted with THF (20 mL) and 2N HCl (40 mL). After 1 h stirring, the solid formed was collected by filtration to afford the title compound. 1H NMR (400 MHz, DMSO-d6): 13.5 (bs, 1H), 7.90 (d, 1H), 7.87 (dd, 1H), 7.59 (d, 1H), 7.48 (t, 1H), 7.43-7.33 (m, 3H), 6.55 (s, 1H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN(CC)CC.[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)=[C:20]([S:22](Cl)(=[O:24])=[O:23])[CH:21]=1)#[N:15]>C(Cl)Cl>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:26][C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)=[C:20]([S:22]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:23])=[O:24])[CH:21]=1)#[N:15]
Reactant: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)Cl)c1
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of N1,N1-dimethyl-ethane-1,2-diamine (74.0 mg, 0.84 mmol) and Et3N in dry CH2Cl2 (3 ml) was added the solution of 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (90%, 282 mg, 0.7 mmol) in dry CH2Cl2 (6 ml) dropwise. The resulting solution was stirred at room temperature for 1 hour. CH2Cl2 (60 ml) was added and the mixture was washed with water, brine, and dried over MgSO4. The solvent was evaporated, and the residue was purified by column chromatography (CH2Cl2/CH3OH=10:1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide as white solid (220 mg, 75.9%): HPLC-MS (ESI): Calcd for C19H21Cl2N3O4S [M+H]+ 414, Found: 414
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][CH:7]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9][N:8]2[CH:21]=1)=[O:4].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:21][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=[O:13])[CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)C1=CN2CCN(Cc3ccccc3)C(=O)C2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC2C(=O)N(Cc3ccccc3)CCN2C1
Yield: 95.1 %

Procedure:
A mixture of 40.0 g (140 mmol) of 7-methoxycarbonyl-2-phenylmethyl-1,2,3,4,8,8a-hexahydro-pyrrolo[1,2-a]pyrazin-1-one (Preparation 8) and 10 g of 5% Pd on charcoal in 600 mL of ethyl acetate was shaken in a Parr apparatus under 50 psi of hydrogen gas for 6.5 h. The mixture was filtered through Celite, and the filtrate was evaporated to give 38.4 g (95%) of the title compound. 13C NMR (CDCl3): δ 31.8, 41.4, 44.8, 46.5, 49.6, 52.1, 55.2, 64.0, 127.5, 128.1, 128.7, 128.8, 136.6, 169.6, 174.8. HRMS calcd for C16 H22N2O3 (MH+): 289.1552, found: 289.1549.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH3:17])[C:15]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:18]1[C:15]2[N:16]([CH3:17])[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:13][C:14]=2[CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCc1nc2cccc(Cl)c2n1C
Reactant: Ic1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cn1c(CCC#Cc2ccccn2)nc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
In a dry reaction tube containing copper iodide (1 mg, 0.0055 mmol) and triethylamine (0.50 mL, 0.1 mmol), were added 2-iodopyridine (22 mg, 0.11 mmol) and Pd(PPh3)2Cl2 (2.4 mg, 0.0055 mmol). A yellow suspension was obtained and after a few minutes of stirring at room temperature, 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (compound 191(E), 24 mg, 0.11 mmol) in triethylamine (0.2 mL) was added. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 50° C. for 3 h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 2 g, DCM/MeOH: 98/2 as eluent) to afford 2 mg g of 7-chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 6%) as brown solid.
Reaction SMILES: [C:1]([S:20][C@@H:21]1[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]1[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]=[C:34]=[O:35]>CN(C)C=O>[C:1]([S:20][C@@H:21]1[O:29][C@H:28]([CH2:30][O:31][C:34](=[O:35])[NH:33][CH3:32])[C@@H:26]([O:27][C:34](=[O:35])[NH:33][CH3:32])[C@H:24]([O:25][C:34](=[O:35])[NH:33][CH3:32])[C@H:22]1[O:23][C:34](=[O:35])[NH:33][CH3:32])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CN(C)C=O
Product: CNC(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(=O)NC)[C@@H](OC(=O)NC)[C@@H]1OC(=O)NC
Temperature: 65 °C
Reaction time: 2 h

Procedure:
S-Trityl-1-thio-β-D-glucopyranose (0.70 g., 1.6 mmole) is dissolved in 20 ml. of dry dimethylformamide. Methyl isocyanate (1.5 ml.) is added and the mixture is stirred for 1.5 hours at room temperature and for an additional two hours at 65° C. The solvent is evaporated at reduced pressure, the residue is triturated with water and neutralized to pH 4 with dilute hydrochloric acid. Extracting the organic materials into chloroform, evaporating the chloroform extract and chromatographing the residue on a silica column with ethyl acetate eluant gives S-trityl-2,3,4,6-tetra-O-(N-methylcarbamoyl)-1-thio-β-D-glucopyranose.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:5]([C:7]2[C:8]([F:29])=[C:9]([N:14]([CH2:26][O:27][CH3:28])[S:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=2[F:13])[N:6]=1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CC(N(C)C)=O>[CH:36]1([NH:42][C:2]2[S:3][C:4]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:5]([C:7]3[C:8]([F:29])=[C:9]([N:14]([CH2:26][O:27][CH3:28])[S:15]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=4[F:25])(=[O:17])=[O:16])[CH:10]=[CH:11][C:12]=3[F:13])[N:6]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCCCC1
Reactant: COCN(c1ccc(F)c(-c2nc(Br)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Solvent: CC(=O)N(C)C
Product: COCN(c1ccc(F)c(-c2nc(NC3CCCCC3)sc2-c2ccncc2)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 110 °C
Reaction time: 16 h

Procedure:
N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in Example 3, 50 mg, 0.09 mmol) was dissolved in 3 mL of dimethylacetamide and 74 μL (0.85 mmol) of cyclohexylamine were added. The mixture was stirred at 110° C. for 16 h. The solvent was evaporated under reduced pressure and the residue was taken up with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated, giving N-{3-[2-(cyclohexylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide. The latter, without any further purification, was treated with 4 mL of TFA and 1 mL of water and stirred at 75° C. for 8 h. The solvent was then removed, the residue taken up with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated. The crude was purified by flash chromatography eluted with cyclohexane-ethanol 9/1, affording 20 mg (42%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:20]([O:21][C:22]([O:24]C3C=CC=CC=3)=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:31])=[N:7]2.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(OC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:20]([O:21][C:22]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]1=[O:31])=[N:7]2
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2c(Cl)ccnc2n1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3c(Cl)ccnc3n2)CC1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
The procedure of Example 11 is followed but starting with 2-(5-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (6.7 g.), 4-methylpiperazine (15.8 g.) and dimethylformamide (32 cc.) and stirring for 15 minutes at 23° C. The reaction mixture is then diluted by adding diisopropyl ether (320 cc.). The precipitate is filtered off, washed with diisopropyl ether (3 × 30 cc.) and then dried. A product (3.8 g.) is obtained which is recrystallised from acetonitrile (300 cc.) to yield 2-(5-chloro-1,8-naphthyridin-2yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (2.9 g.) melting at 240° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1)#[N:2].[C:19](OCC)(=O)C>S(=O)(=O)(O)O.CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([O:16][CH3:19])=[O:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CC(C)CC(=O)Nc1ccc(C#N)cc1
Yield: 56 %

Procedure:
A solution of 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (940 mg, 3.82 mmol) and conc. sulfuric acid (1 drop) in methanol (25 mL) was heated with reflux for 14 hr. The reaction solution was cooled, and ethyl acetate was added thereto. The solution was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give methyl 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoate (557 mg, 2.139 mmol, 56.0%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CN1C(=O)CCC1>C(OCC)(=O)C.O>[OH:26][CH2:25][CH2:24][C:23]1[CH:27]=[CH:28][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Cc1cccc(Nc2nc(Cl)ncc2C(N)=O)c1
Reactant: Nc1ccc(CCO)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(Nc3ccc(CCO)cc3)ncc2C(N)=O)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A mixture of 2.0 g of 2-chloro-4-{(3-methylphenyl)amino}pyrimidine-5-carboxamide, 1.25 g of 4-aminophenethyl alcohol, 1.99 ml of diisopropylethylamine and 10 ml of NMP was stirred overnight at 110° C. The reaction mixture was cooled down to room temperature and mixed with water and ethyl acetate, and the thus precipitated solid was collected by filtration and recrystallized (methanol) to obtain 560 mg of 2-{[4-(2-hydroxyethyl)phenyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as pale yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C1
Reaction time: 8 h

Procedure:
A solution of 3α-hydroxy-5α-pregnane-11,20-dione (1 g) in pyridine (ca 5 ml) was treated with acetic anhydride (2.5 ml) and allowed to stand overnight. The reaction mixture was poured into water and the solid collected by filtration and dried to give the title compound m.p. 150°-151°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.I[C:16]1[CH:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[N:20][CH:21]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: O=c1ccc(I)c[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3ccc(O)nc3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
5-methoxybenzofuran boronic acid (230 mg, 1.2 mmol), 5-iodo-2-pyridone (221 mg, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol) and NEt3 (317 μL, 2.4 mmol) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The solvent was removed under vacuum, water was added and the solution was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The crude substance was purified by preparative HPLC to afford the title compound as a white solid (20 mg). 1H NMR δ ppm 11.95 (br. s., 1 H) 7.94 (dd, 1 H) 7.88 (s, 1 H) 7.44 (d, 1 H) 7.00-7.20 (m, 2 H) 6.84 (dd, 1 H) 6.48 (d, 1H) 3.78 (s, 3 H); MS m/z 242 (M+H).