Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](O)=[O:34])=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:44]([NH:48][C:33]([C:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:16]3[C:17]4[C:22](=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)[N:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]4)[N:15]=3)[N:25]=2)[N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=1)=[O:34])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In a 10 ml round-bottomed flask, 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (85 mg, 0.14 mmol) was dissolved in DMF (1.5 ml) and tert-butylamine (0.06 ml, 0.57 mmol) and HATU (59 mg, 0.155 mmol) were added. The light yellow suspension was stirred at room temperature overnight then water and petroleum ether were added. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum. The residue was chromatographed over 8 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 47 mg (51%) of 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][NH:13][C:12](=[O:16])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CO>CN(C=O)C.C(Cl)Cl>[CH2:24]([O:23][C:21]([CH2:20][N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11][C:12]1=[O:16])=[O:22])[CH3:25]
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc(NC(=O)c2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a stirred suspension of 6 (1.92 g, 9 mmol) in dry DMF (100 mL) at 0° C., NaH (0.43 g, 18 mmol) was added and the mixture was stirred at room temperature for 1 h. Ethyl bromoacetate (1.5 g, 9 mmol) was added dropwise at 0° C. and stirred for 1 h. Methanol (2 mL) was added to quench the reaction, and the solvents were removed under reduced pressure. The residue obtained was dissolved in DCM, washed with water (3×50 mL), dried over Na2SO4, and the solvent was evaporated to give 7 as a white solid (1.38 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([F:34])[CH:26]=4)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:35][C:36]1C=C(S(Cl)(=O)=O)C=C(C)C=1>>[CH2:35]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:4]4[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=4)(=[O:11])=[O:10])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][C:27]=1[F:34])[CH3:36]
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCOc3ccc(C(=O)Nc4ccc(C(=O)O)c(F)c4)cc32)c1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CCO3)cc1F

Procedure:
4-{[4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=483.3 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3,5-dimethyl-benzenesulfonyl chloride and yielded 4-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1.C(N(CC)C(C)C)(C)C.[N:40]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:30])[CH2:11][C:12]1[C:21]([CH3:22])=[C:20]([CH:23]2[CH2:24][CH2:25][N:26]([S:45]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)(=[O:47])=[O:46])[CH2:27][CH2:28]2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:29])[CH:18]=2)[CH:13]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)N3CCCC3)CC2)c1C
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 81.4 %

Procedure:
To a 0° C. solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 102 mg, 0.237 mmol) and N,N-diisopropylethylamine (124 μL, 0.711 mmol) in methylene chloride (10.0 mL) was added pyrrolidine-1-sulfonyl chloride (80.4 mg, 0.474 mmol). The reaction mixture was stirred at 0° C. for 25 minutes, and then warmed to room temperature and stirred overnight. During this time period the solvent evaporated to dryness. Additional methylene chloride (10 mL) was added in the morning. The reaction mixture was diluted with water (25 mL). The resulting mixture was extracted with ethyl acetate (2×30 mL). The organic phase was dried over MgSO4, filtered, and concentrated. Silica gel chromatography (33% ethyl acetate in hexanes) provided {6-fluoro-3-methyl-4-[1-(pyrrolidine-1-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (86.5 mg, 81%). MS cald. for C23H30FN2O4S [(M+H)+]: 449, obsd. 449.2.
Reaction SMILES: NN1N=[CH:5][CH:4]=[N:3]1.C[Al](C)C.C.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34](OC)=[O:35])(=[O:27])=[O:26])=[O:23])[N:15]=1.Cl.[S:39]1C=C[N:41]=[CH:40]1>C(Cl)Cl.C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([NH:41][C:40]2[S:39][CH:5]=[CH:4][N:3]=2)=[O:35])(=[O:26])=[O:27])=[O:23])[N:15]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Reactant: c1cscn1
Reactant: Nn1nccn1
Agent: C
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)Nc2nccs2)n1

Procedure:
To a solution of 2-aminotriazole (2.1 g) in 100 ml of methylene chloride was added 10 ml of a 2M solution in toluene of trimethylaluminum (1.44 g of Al(CH3)3) by syringe. Evolution of methane gas was seen and the solution became homogeneous. To this mixture was added 4.0 g of N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide and the homogeneous solution was heated at reflux for 18 hours. The reaction mixture was then heated with aqueous hydrochloric acid and the precipitated product isolated by filtration, 1.42 g, m.p. 185°-187° C. IR: 1690 cm-1 and 1700 cm-1 unresolved double carbonyl, NMR: in TFA 2.7 ppm s, CH3 pyrimidine, 4.2 ppm s, OCH3 on pyrimidine, 6.7 ppm s, proton in 5-position on pyrimidine, 7.8-8.0 ppm and 8.4-8.5 ppm M, aromatic, 7.6, 7.7 ppm D, thiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH:13]1([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14]1>>[CH:13]1([C:16]([NH:18][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=2)=[O:17])[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: NC(=O)C1CC1
Product: COC(=O)c1cc(C)nc(NC(=O)C2CC2)n1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (2.70 g, brown oil) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.00 g, 16.1 mmol) and cyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[C:22]1([NH:32][C:33](=[O:44])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>ClCCl.C(OCC)C>[C:22]1([NH:32][C:33](=[O:44])[O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([CH:42]=[O:43])=[CH:40][CH:41]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1cccc2ccccc12)OCc1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(COC(=O)Nc2cccc3ccccc23)cc1
Reaction time: 5 h
Yield: 85.7 %

Procedure:
PDC (2.1 g, 5.6 mmol) was added to a stirred mixture of alcohol 7 (1.72 g, 5.6 mmol) and activated 4 Å molecular sieves (1.0 g) in anhydrous dichloromethane (20 mL). The resulting mixture was stirred for 5 h; then it was diluted with diethyl ether (20 mL). The resulting suspension was filtrated through a pad of silica gel. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (hexanes/ethyl acetate=5:1) to provide aldehyde 6 (1.46 g, 4.8 mmol) as a white solid in 85% yield: m.p.: 153-154° C.; IR (thin film): 3272, 1691, 1609, 1544, 1504, 1257, 1206 cm−1; 1H NMR (500 MHz, CDCl3): δ 10.01 (s, 1H), 7.93-7.81 (m, 5H), 7.68 (d, J=8.2 Hz, 1H), 7.57 (s, 1H), 7.55-7.40 (m, 4H), 5.32 (s, 2H) ppm; 13C NMR (101 MHz, CDCl3): δ 192.07, 192.03, 154.26, 143.05, 136.09, 134.16, 132.34, 130.94, 130.08, 128.82, 128.28, 126.74, 126.41, 126.20, 125.83, 125.47, 120.68, 119.36, 66.35 ppm. HRMS (m/z): [M+Na]+ calcd. for C19H15NNaO3, 328.0944; found, 328.0938.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C(O)(=O)C.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2cnc3ccccc3c2n1CCCCNC1CCOCC1
Reaction time: 0.17 h

Procedure:
To a suspension of 4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl) butan-1-amine obtained in step VI of example I in tetrahydrofuran was added acetic acid (1 eq.) and tetrahydro-pyran-4-one (1.1 eq.). Resulting reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (2.2 eq.) was added to reaction mixture over a period of 1 hrs and resulting suspension was then stirred for 4-5 hrs. Reaction was then quenched with methanol and concentrated to dryness. Reaction mixture was basified using aq.sodium hydroxide solution and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky solid. Product was then purified by silica gel column chromatography to afford N-[4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-amine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCC[CH2:8]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[C:23](=[O:40])[CH:24]([OH:39])[C@@H:25]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:26][CH3:27])C>O>[CH2:12]([NH:19][C:23](=[O:40])[CH:24]([OH:39])[C@@H:25]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[CH:26]([CH3:27])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(O)[C@H](CC)NC(=O)OCc1ccccc1
Reactant: C1CCOC1
Reactant: NCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)NCc1ccccc1
Temperature: 25 °C

Procedure:
A suspension containing lithium aluminum hydride (1.2 g) and tetrahydrofuran (200 ml) is stirred under reflux for 1.5 hour. The reaction solution is cooled to room temperature, and thereto is added dropwise benzylamine (17.3 g). Then, to the mixture is added dropwise tetrahydrofuran (150 ml) containing (3S)-3-benzyloxycarbonylamino-2-hydroxy-4-methylbutyric acid ethyl ester (10 g), and the mixture is stirred at room temperature for 12 hours. Water is carefully added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is removed by evaporation under reduced pressure. The residue is purified by silica gel column chromatography [solvent; n-hexane:ethyl acetate (1:1)] to give the desired (1S)-3-benzylamino-1-benzyloxycarbonylamino-1-isopropyl-2-hydroxy-3-oxopropane (9.2 g) as colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=1>>[CH3:9][C:10]1[CH:11]=[CH:12][C:13](=[O:16])[N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Cc1ccc(I)cc1
Reactant: Cc1ccc(=O)[nH]c1
Product: Cc1ccc(-n2cc(C)ccc2=O)cc1
Yield: 89 %

Procedure:
The reaction of p-iodotoluene with 5-methyl-2-(1H)-pyridone by the reaction of Example 1, affords 5-Methyl-1-p-tolyl-2-(1H)-pyridone in 89% yield.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH2:20][OH:21])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:20]=[O:21])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2]
Reactant: COC(=O)c1ccc(CCC(CO)CCCCC#N)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)CCCCC#N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 117.9 %

Procedure:
A solution of 2.23 g (7.71 mmol) of methyl 4-(7-cyano-3-hydroxymethylheptyl)benzoate from Example 93A in 100 ml of dichloromethane is mixed with 1.99 g (9.26 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 6 hours. After conversion is complete, the solvent is concentrated to dryness in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 1.50 g (9.09 mmol, 68% yield) of an oil are obtained.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC(=O)CBr
Yield: 70 %

Procedure:
A solution of bromoacetyl bromide (44.4 g; 0.22 mol) in CH2Cl2 (50 mL) was added dropwise in 2.5 h at 20° C. to a mixture of octadecylamine (59.3 g; 0.22 mol) and K2CO3 (30.4 g; 0.22 mol) in CH2Cl2 (600 mL) and H2O (600 mL). After 16 h at room temperature the organic layer was separated, washed with H2O, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (CH2Cl2/MeOH=100/1 (v/v)) to give the desired product (60 g; 0.154 mol). Yield 70%. GC: 96% (area %), K.F.: <0.1%; 1H-NMR, 13C-NMR and MS spectra were consistent with the postulated structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Br[CH2:23][C:24](=O)[CH3:25].C(O)C.CN(C)C(=O)C>O>[CH3:25][C:24]1[N:20]=[C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[S:21][CH:23]=1
Reactant: CC(=O)CBr
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: Cc1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.30 g), bromoacetone (0.10 mL), ethanol (2 mL) and N,N-dimethylacetamide (2 mL) was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.24 g, yield 72%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 181-183° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:20])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.C[Si]([C:37]#[N:38])(C)C>C(#N)C>[NH2:20][C:9]1[N:10]=[CH:11][N:12]=[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:32])([F:31])[F:21])[CH:24]=3)[C:37]#[N:38])[CH2:16][CH2:15]2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: N#CC(c1cccc(C(F)(F)F)c1)N1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
In a round bottom flask equipped with a stir bar was dissolved 5-(4-Fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (1 eq) and 3-trifluoromethyl-benzaldehyde (1.05 eq) in acetonitrile. The vial was sealed with a rubber septa, then evacuated and backfilled with argon. To this sealed vessel was added trimethylsilyl cyanide (1.05 eq) and the reaction was allowed to stir at room temperature until complete. The reaction is quenched by addition of an equal amount of ammonium chloride (saturated, aqueous solution), then extracted with ethyl acetate. The organic layers are then dried over sodium sulfate, filtered and concentrated to give the title compound. LC-MS: (M+1=457, obsd.=457).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.N1CCCCC1>C(Cl)Cl.CO>[N:26]1([C:33]([N:1]2[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]3[CH2:14][CH2:13][N:12]([C:15]4[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][C:16]=4[F:25])[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:35])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCN(C(=O)N4CCCCC4)CC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 63a (135 mg, 0.35 mmol) and pyridine (85 μL, 1.05 mmol) in DCM (5 mL) was added to a solution of triphosgene (37 mg, 0.123 mmol) in DCM (6 mL) and stirred at r.t. for 1 h. 0.5 mL of this solution was transferred to a vial, piperidine (0.01 mL) was added and the mixture stirred at r.t. for 2 h, diluted with methanol and purified by HPLC yielding 73-1. LC-MS 481.4 (MH+).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[CH3:14][C:15]1[N:16]=[C:17]([CH2:20][C:21]([CH3:23])=O)[S:18][CH:19]=1.[NH2:24]/[C:25](/[CH3:29])=[CH:26]\[C:27]#[N:28]>C(O)(C)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[C:20]([C:17]3[S:18][CH:19]=[C:15]([CH3:14])[N:16]=3)=[C:21]([CH3:23])[NH:24][C:25]([CH3:29])=[C:26]2[C:27]#[N:28])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)c2ccccc12
Reactant: CC(=O)Cc1nc(C)cs1
Reactant: C/C(N)=C/C#N
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc(F)c3ccccc23)C(c2nc(C)cs2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.861 mmol) of 4-fluoro-1-naphthaldehyde, 134 mg (0.861 mmol) of the compound from example 4A and 70 mg (0.861 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 14 mg (4% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[C:4]([O:30]C)[C:3]=1[F:32].B(Br)(Br)Br.C(=O)(O)[O-:38].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH:11]2[NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][NH:17][C:18]3=[O:38])=[C:4]([OH:30])[C:3]=1[F:32]
Reactant: COc1c(C(C)(C)CC(O)(C=Nc2cccc3cnccc23)C(F)(F)F)ccc(Cl)c1F
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2cc(Cl)c(F)c(O)c21
Temperature: 25 °C
Yield: 31.6 %

Procedure:
80.3 mg (0.166 mmol) of (rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-[1(2H)-one is mixed at room temperature with 1.7 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for two and one-half hours at room temperature. The reaction mixture is mixed with ice, and then saturated sodium bicarbonate solution is added in drops (pH 8). After the ethyl acetate is added and after ten minutes of vigorous stirring at room temperature, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and the residue is chromatographed on a Flashmaster after the solvent is spun off. 24.6 mg (31.6%) of the desired compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S([CH:28]([N+]#[C-])[N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]2[O:13][CH:30]=[N:29][CH:28]=2)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]C([N+]#[C-])S(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(-c2cnco2)c1Cl

Procedure:
25 g (0.09 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate (Ex. A.1.), 17.6 g (0.09 mol) of tosylmethylene isocyanide and 6.2 g (0.045 mol) of finely pulverulent potassium carbonate are stirred together with 450 ml of methanol at reflux temperature for 5 hours. The solvent was subsequently stripped off, the residue was taken up in ethyl acetate, and the mixture was extracted with water. The ethyl acetate phase was dried using sodium sulfate and concentrated.