Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1>>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][N:6]=1
Reactant: COc1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccnc(OC)c1
Yield: 59.4 %

Procedure:
According to Scheme 23 Step 1: To a solution of sodium methoxide (30% in MeOH, 2 eq, 35 mmol) was added 2-chloro-4-methoxypyridine (1 eq, 17.0 mmol, 2.50 g). The reaction was refluxed overnight. The reaction was allowed to cool, poured onto water (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to afford 2,4-dimethoxypyridine (10.1 mmol, 1.40 g, 58%) as a colorless oil. The crude product was reacted on.
Reaction SMILES: C1C2C(COC([N:18]3[C@@H:23]([CH:24]([OH:26])[CH3:25])[CH2:22][O:21][CH2:20][C@H:19]3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C(#N)C.C1(C)C=CC=CC=1>[F:34][C:29]1[CH:28]=[C:27]([C@H:19]2[NH:18][C@@H:23]([CH:24]([OH:26])[CH3:25])[CH2:22][O:21][CH2:20]2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCNCC
Product: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1
Yield: 85.4 %

Procedure:
To a solution of (3R,5R)-3-(3,4-difluorophenyl)-5-(1-hydroxyethyl)morpholine-4-carboxylic acid 9H-fluorene-9-ylmethyl ester (950 mg) in acetonitrile (16 mL) was added diethylamine (4 mL), and the resultant solution was stirred for 1 hour at room temperature. The reaction solution was then diluted with toluene (20 mL), and solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 4/1→1/1), to thereby obtain the titled compound (424 mg). The physical properties of this crude product were as follows.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCSc1ccccc1
Reactant: O=C1CCc2c(O)cccc2N1
Product: O=C1CCc2c(cccc2OCCCCSc2ccccc2)N1

Procedure:
Prepared analogous to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylmercapto-butyl bromide.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1(C(O)=O)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:34])C=CC=CC=1.C([N:46]([CH2:49]C)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([N:46]=[C:49]=[O:34])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)n1ncc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)c1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)n1ncc(CC2(N=C=O)CCN(C(=O)OC(C)(C)C)CC2)c1Br
Temperature: 25 °C
Yield: 111.1 %

Procedure:
A mixture of 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.54 g, 5.9 mmol), diphenylphosphoryl azide (1.79 g, 6.5 mmol) and triethylamine (0.91 mL, 6.5 mmol) in toluene (15 mL) was heated at reflux for 3 hours. The mixture was then cooled to room temperature and the solvent removed in vacuo. The crude product was purified by column chromatography to give tert-butyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopiperidine-1-carboxylate (2.8 g, 100%). 1H NMR (300 MHz, CDCl3, δ): 7.47 (s, 1H), 4.68 (m, 1H), 3.99 (m, 2H), 2.95 (m, 2H), 2.67 (s, 2H), 1.62 (m, 4H), 1.45 (m, 15H).
Reaction SMILES: [C:1](OC)(OC)(OC)[O:2][CH3:3].[Cl:10][C:11]1[C:20]([NH2:21])=[C:19]([NH2:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[OH-].[Na+].ClCCl>C(O)(=O)C.O>[Cl:10][C:11]1[C:20]2[N:21]=[C:1]([O:2][CH3:3])[NH:22][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Nc1c(Cl)nc2ccccc2c1N
Reactant: COC(OC)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1nc2c(Cl)nc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetramethyl orthocarbonate (1.24 mL, 9.3 mmol) was added to a suspension of 2-chloroquinoline-3,4-diamine, see U.S. Pat. No. 5,756,747 (Gerster) Example 30, (1.5 g, 7.75 mmol) in acetic acid (8 mL), and the reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the reaction was incomplete, and additional tetramethyl orthocarbonate (0.5 equivalent) was added. The reaction was stirred overnight at room temperature and diluted with water (100 mL). The mixture was adjusted to pH 7 with the addition of 2 N aqueous sodium hydroxide. Dichloromethane (100 mL) was added to the mixture, and a precipitate formed. The precipitate was isolated by filtration to provide 1.13 g of 4-chloro-2-methoxy-1H-imidazo[4,5-c]quinoline as a gray solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1>>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:25]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1ccccc1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-phenyl-methanone was prepared from phenanthridine, benzoyl chloride, and indole according to GP 2. Yield, 11%. 1H-NMR (DMSO-d6): δ=6.20 (dd, J=2.5 Hz, J=0.8 Hz, 1H), 6.36 (s, br., 1H), 6,80 (t, J=7.6 Hz, 1H), 6.99-7.08 (m, 2H), 7.11 (ddd, J=J=7.5 Hz, J=1.2 Hz, 1H), 7.19-7.31 (m, 6H), 7.37 (“t”, J≈7.1 Hz, 1H), 7.43 (“t”, J≈7 Hz, 1H), 7.54 (“t”, J≈7 Hz, 2H), 7.85-7.90 (m, 1H), 7.95 (dd, J=7.8 Hz, J=1.2 Hz, 1H), 8.10 (“d”, J≈7.5 Hz, 1H), 10.69 (s, 1H); (+)-ESI-MS: m/z=401 [M+H]+, 284 [M-indole+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=S)[CH:14]=[CH:15][C:16]=1[Cl:17].C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:7]3[CH2:8][C:2]4[S:1][CH:5]=[CH:4][C:3]=4[C:6]=3[NH:32][N:31]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: NN
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCc2sccc21
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Clc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1Cl
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 3,4-Dichloro-1-isothiocyanato-benzene (1.2 g, 7.4 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (0.4 mL, 7.9 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (3,4-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 30% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:21])=[C:7]([CH:20]=1)[CH:8]([C:13]1[N+:18]([O-:19])=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:9]=[C:10]([CH3:12])[CH3:11])#[N:2]>C(OCC)(=O)C.CCCCCC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:21][C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([C:13]3[N+:18]([O-:19])=[CH:17][N:16]=[CH:15][CH:14]=3)[C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)=CC(c1cc(C#N)ccc1O)c1ccnc[n+]1[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)CC(c2ccnc[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 4.5 %

Procedure:
In an analogous manner to that described in the first paragraph of Example 8, from 0.22 g of 6-[5-cyano-2-hydroxy-α-(2-methylpropenyl)benzyl]pyrimidine 1-oxide there was obtained 0.01 g of 6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyrimidine 1-oxide in the form of an off-white solid (from ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.C[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[C:40]([CH3:39])=[CH:41][CH:36]=[CH:37][C:38]=2[CH3:42])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(C)c1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4c(C)cccc4C)cc3)c2cc1OC
Yield: 109.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2,6-dimethylphenol (32 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (82 mg, yield 100%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C([O:8][C:9](=O)[CH:10]([NH2:34])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[CH:13]=1)C.C([N:38](CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:34][CH:10]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:13]=1)[C:9]([NH2:38])=[O:8])(=[O:4])=[O:3]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(N)Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NC(Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12)C(N)=O
Temperature: 30 °C
Reaction time: 48 h

Procedure:
2-Methane sulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide (39) was prepared as follows: MeSO2Cl (0.3 g, 2.6 mmol) was added to a solution of compound 33 (0.2 g, 0.5 mmol) prepared in Example 8 and triethylamine (0.5 mL) in CHCl3 (15 mL) at 0° C. The resulting mixture was shaken at 30° C. for 48 hours, and then washed with water (4 mL). The solvent was removed to give crude compound 38 (LC/MS: m/z=479.2 [M+H]+ (Calc: 478.2)), which was dissolved in NH3 (2 mL 28% aqueous and 4 mL 7N in MeOH), and heated to 120° C. for 2 hours under microwave. The reaction mixture was diluted with CHCl3 (45 mL), washed with water (10 mL), concentrated and purified by column (Silica gel, TCM/MeOH 10/1) to give compound 39 as a brown solid (60 mg, 30% in two steps): 1H-NMR (400 MHz, CDCl3) δ: 7.61-7.63 (m, 1H), 7.41-7.42 (m, 1H), 7.3-7.34 (m, 4H), 7.0-7.18 (m, 8H), 6.13 (br, 1H, NH), 5.57 (br, 1H, NH), 5.2 (d, 1H, 7.9 Hz), 4.19-4.25 (m, 1H), 3.32-3.37 (m, 1H), 3.19-3.25 (m, 1H), 2.54 (s, 3H); LC/MS: m/z=450.1 [M+H]+ (Calc: 449.5).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]O)[CH2:3][CH2:2]1.[C:10]([O:14][C:15]([O:17]C(OC(C)(C)C)=O)=O)([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:49]I>ClCCl>[I:49][CH2:8][CH2:7][CH:4]1[CH2:3][CH2:2][N:1]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:17])[CH2:6][CH2:5]1
Reactant: OCCC1CCNCC1
Reactant: II
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a mixture of 2-piperidin-4-ylethanol (10 g, 77 mmol) and dichloromethane (190 mL) at 0° C. was added di-(tert-butyl)dicarbonate (17.7 g, 81.3 mmol). The reaction was warmed to ambient temperature and stirred 4 hours. The reaction was washed with water, 10% aqueous potassium hydrosulfate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to 20 g of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil. This clear oil was dissolved in dichloromethane (90 mL) and added dropwise over 20 minutes at 0° C. to a suspension of triphenylphosphine (20 g, 77 mmol), imidazole (5.3 g, 77 mmol), iodine (22 g, 85 mmol), and dichloromethane (300 mL). The reaction was stirred 5 hours at ambient temperature. The reaction was filtered and the filtrate was quenched with sodium bisulfite and diluted with water. The layers were separated. The aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a brown oil. This oil was purified by chromatography (SiO2, 20% hexanes/ethyl acetate) to obtain 22 g of tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][C:15]3([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:23][C:24]([NH2:26])=[NH:25])=[N:4][CH:3]=1.Cl.NC(N)=N.[CH2:32](OC(=O)C1(CCCC1)NC(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)=O)[CH3:33]>CC(O)(C)C>[CH2:32]([O:21][C:20](=[O:22])[C:15]1([CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:14][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[NH:23][C:24]([NH2:26])=[NH:25])=[CH:10][CH:9]=1)=[O:13])[CH3:33]
Reactant: CCOC(=O)C1(NC(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC3(C(=O)O)CCCC3)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(NC(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 15.2 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]cycloleucine ##STR62## NaH (45 mg, 60% dispersion in mineral oil, 1.13 mmol) was added to t-BuOH and the mixture heated at 50° C. for 15 min. Guanidine hydrochloride (105 mg, 1.10 mmol) was added and the mixture heated at 50° C. for an additional 15 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]cycloleucine ethyl ester (350 mg, 0.92 mmol) was added and the mixture heated at reflux for 17 h. The solvents were evaporated in vacuo and the residue purified by column chromatography on silica gel using CH2Cl2 -MeOH-0.880NH3 (90:10:1) as eluant, followed by trituration with CH2Cl2 -i-Pr2O, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]cycloleucine ethyl ester (55 mg, 0.14 mmol) as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1.IC1C=C(NC(=O)C2C=CC(N3CCOCC3)=NC=2)C=CC=1C>>[F:20][C:21]1([F:25])[CH2:24][N:23]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:22]1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: FC1(F)CNC1
Agent: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(N3CC(F)(F)C3)nc2)cc1I
Yield: 40 %

Procedure:
6-(3,3-Difluoro-azetidin-1-yl)-N-(3-iodo-4-methyl-phenyl)-nicotinamide was prepared from 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide and 3,3-difluoroazetidine hydrochloride in a manner similar to the one described in the synthesis of N-(3-Iodo-4-methyl-phenyl)-6-morpholin-4-yl-nicotinamide above. The product was isolated after silica gel column purification with 20-30% EtOAc in hexanes to afford the product (23 mg. Yield: 40%). HRMS m/z calcd for C16H14N3OFI [M+H]+: 430.0223. Found: 430.0224.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].N[CH2:22][CH2:23][SH:24].C(O)C>O>[S:24]1[CH2:23][CH2:22][N:2]=[C:1]1[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15]
Reactant: NCCS
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: CCO
Solvent: O
Product: O=S(=O)(Nc1cccc2cc(C3=NCCS3)[nH]c12)c1cccs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.54 g), 2-aminoethanethiol (0.14 g) and ethanol (20 mL) was stirred at 60° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (0.19 g, yield 29%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 189-190° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N-:7]=[C:8]=[O:9].Cl[CH2:11]Cl>>[CH3:11][NH:7][C:8]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:9]
Reactant: [N-]=C=O
Reactant: C1CNCCN1
Reactant: ClCCl
Product: CNC(=O)N1CCNCC1

Procedure:
To the solution of piperazine (3 g) in dichloromethane (30 ml) was addedmethyl isocyanate (2.16 ml) in an ice water bath with stirring. After 10 minutes the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo. The residue was diluted with acetonitrile (15 ml) and crystals were filtered off. The filtrate was evaporated in vacuo. To the residue was added xylene and the solvent was azeotropically removed in vacuo to give N-methyl-1-piperazinecarboxamide (2.43 g) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:25])[N:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:17][CH2:18][O:19][CH2:20][C:13]=4[C:12]([C:26]4[S:30][CH:29]=[N:28][CH:27]=4)=[C:9]3[C:10]=2[CH:11]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Sn](CCCC)(CCCC)CCCC)[N:35]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([N:16]1[C:15](=[O:25])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:31][CH3:32])[C:2]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([F:33])[N:35]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:26]3[S:30][CH:29]=[N:28][CH:27]=3)[C:13]=2[CH2:20][O:19][CH2:18][CH2:17]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cccc(F)n1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Yield: 72.7 %

Procedure:
A solution of 80 mg of 11i, 90 mg of 2-fluoro-6-tributylstannylpyridine and 25 mg of Pd(PPh3)4 in 5 ml of degassed toluene was heated at 110° C., under N2 atmosphere, during 48 hr. The reaction mixture was applied to a silica gel column and eluted with a gradient of heptane/acetone. The isolated product was treated with diethyl ether and provided 60 mg of 11k as white crystalline material; Mp: 232-234° C.; Rf 0.45 (heptane/acetone 1/1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]Cl)=[CH:13][CH:12]=1.C(Cl)Cl>CCOCC>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: COC(=O)c1cc[nH]c1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Methyl pyrrole-3-carboxylate (2.5 g., 20 mmole) was dissolved in 35 ml. of methylene chloride p-Chlorobenzenesulfenyl chloride (4.0 g., 22 mmoles) was added dropwise over approximately 2 minutes, and the reaction mixture was stirred at room temperature for 1 hour. Two volumes of ether were added, the mixture extracted twice with 20 ml. portions of water and the organic layer evaporated in vacuo. The resulting oil was chromatographed on 100 g. of silica gel with approximately 25 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 19 to 36 were combined and concentrated to yield methyl 5-(4-chlorophenylthio)pyrrole-3-carboxylate (1.4 g., m.p. 122°-124° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].O.Br[C:9]1[N:13]([C:14]2[C:22]3[C:18](=[N:19][O:20][N:21]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[N:11][N:10]=1>C(Cl)(Cl)Cl>[N:19]1[O:20][N:21]=[C:22]2[C:14]([N:13]3[C:12]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[N:11][N:10]=[C:9]3[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[CH:15][CH:16]=[CH:17][C:18]=12
Reactant: CNCCOC
Reactant: Brc1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCCN(C)c1nnc(-c2ccc(-c3ccccc3)nc2)n1-c1cccc2nonc12
Temperature: 160 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
In a sealed tube, N-(2-methoxyethyl)methylamine (3 ml) and water (3 ml) were added to 4-[3-bromo-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzooxadiazol (336 mg) prepared in the Production Example 5, and stirred at 160° C. for 6 hours. After the reaction solution was cooled to ambient temperature, chloroform was added to the solution, which was then washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from ethyl acetate, to afford the entitled compound as white crystal (66 mg, 19%). The physico-chemical values are as follows.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][C:4]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C(O)(=O)C.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+]>CO>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][C:4]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:33]([CH3:35])[CH3:32])[CH2:17][CH2:16]1
Reactant: CC(C)=O
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)c(Cl)cc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
64 mg (0.23 mmol) of 7-chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one-hydro-chloride (54) were dissolved in 5 mL of methanol. 41.4 mg (0.41 mmol) of triethyl amine were added and the mixture stirred at room temperature for 10 minutes. After adding freshly dried molecular sieves, 122.4 mg (2.04 mmol) acetic acid, 26.7 mg (0.46 mmol) of acetone and 43.3 mg (0.69 mmol) of sodium cyanoborohydride, the reaction mixture was refluxed for 8 h. After the addition of 2 equivalents acetone and 2 equivalents of sodium cyanoborohydride at room temperature, the reaction was refluxed for another 2 h to complete conversion. For working up, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane, washed twice with 2 N NaOH and water and dried over MgSO4. After evaporation of the solvent and purification by preparative HPLC, 13 mg of the title compound were obtained as trifluoroacetate. Rt=0.96 min (Method B). Detected mass: 321.1/323.2 (M+H+).