Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13]/[N:14]=[C:15](\[NH2:17])/[CH3:16])=O)[S:10][C:3]=12.C1(C)C=CC=CC=1.ClC1C=CN=C2C=C(C(O)=O)SC=12>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[O:13][N:14]=[C:15]([CH3:16])[N:17]=3)[S:10][C:3]=12
Reactant: C/C(N)=N/OC(=O)c1cc2nccc(Cl)c2s1
Agent: O=C(O)c1cc2nccc(Cl)c2s1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
A 50 mL round bottom flask with a reflux condenser was charged with (1 Z)-N′-(((7-chlorothieno[3,2-b]pyridin-2-yl)carbonyl)oxy)ethanimidamide (0.282 g, 1.04 mmol) and toluene (10 ml) and heated to 110° C. and stirred for 18 hours. LC/MS analysis indicated a mixture of the product and 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid. The reaction was diluted with chloroform (30 mL) and washed with water (30 mL), sat. aq. NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield 7-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)thieno[3,2-b]pyridine (0.1128 g, 43% yield) as a light yellow solid, which was used without further purification.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:17]([CH3:33])[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=2[Cl:30])[CH:21]=1)=[O:19].C(N(CC)CC)C>C1C=CC=CC=1>[ClH:30].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH:17]([C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=3[Cl:30])[CH:21]=2)=[O:19])[CH3:33])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccccc4)CC3)ccc2c1Cl
Yield: 101.5 %

Procedure:
A mixture of N-benzyl piperazine dihydrochloride (1.5 g, 7.05 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-one (2.8 g, 8.5 mmol) and triethyl-amine (2.38 g, 23.5 mmol) in benzene (150 ml) was treated according to the general preparation 2 to obtain 2.14 g of N1-benzyl-N4-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazine dihydrochloride, yield 60%, mp 252-253° C.).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])OC[C:9]=2[CH:16]=1)=[O:4].B.C1C[O:21][CH2:20]C1>C1COCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:14])([CH3:15])[CH2:20][O:21][C:9]=2[CH:16]=1)[OH:4]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reactant: C1CCOC1
Agent: B
Product: CC1(C)COc2cc([C@@H](O)CBr)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the product of step (c) (10 g, 35.1 mmol) in 100 mL of THF was added the solid catalyst of Preparation 13, step (c)(1) (0.97 g, 3.5 mmol). The solution was cooled to between −20° C. and −10° C. and BH3-THF (35 mL, 35 mmol) diluted with 50 mL THF was added dropwise via a dropping funnel. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was quenched by slow addition of 50 mL of methanol and then concentrated to a thick oil. The oil was purified by silica gel chromatography eluted with 1:2 ethyl acetate/hexanes. The fractions were combined and concentrated to give the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:14][CH:13]=[C:12]([CH2:15]Cl)[CH2:11][N:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[CH2:14][CH:13]=[C:12]([CH2:15][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:11][N:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC=C(CCl)CN(OCc2ccccc2)C1=O
Reactant: C1COCCN1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC=C(CN2CCOCC2)CN(OCc2ccccc2)C1=O
Temperature: 65 °C

Procedure:
To a solution of 234 mg of (1-Benzyloxy-6-chloromethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-carbamic acid tert-butyl ester in 10 mL of acetonitrile was added 0.5 mL of morpholine. The mixture was heated to 65° C. for 2 hours. The reaction was cooled and the mixture was extracted with ethyl acetate. The organic layer was washed with NaHCO3(aq.) and NaCl (aq.) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers were combined and dried over Na2SO4(s). Filtration and solvent removal gave 270 mg of a clear oil. MS: 454 (M+Na), 432 (M+H).
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+].[C:17](Cl)(=O)[CH2:18][CH2:19]C>C1(C)C=CC=CC=1.CCOCC>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([C:11](=[O:14])[CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCC(=O)Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCC(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
p-Tolylboronic acid (0.150 g, 1.10 mmol), tetrakis(triphenylphosphine)pal-ladium(0) (0.064 g, 0.055 mmol), and cesium carbonate (1.80 g, 5.52 mmol) were suspended in toluene (25 mL). The reaction mixture was purged under a vigorous flow of nitrogen for 15 minutes. Butyryl chloride (0.344 mL, 3.31 mmol) was added, and the reaction mixture was heated at 100° C. under an atmosphere of nitrogen for 24 h. The reaction mixture was cooled to ambient temperature and diluted with ether (100 mL). The organic layer was extracted sequentially with water (10 mL), aqueous sodium bicarbonate (10 mL), and aqueous sodium chloride (10 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated. Purification of the residue by flash column chromatography (7.5% ether/petroleum ether) afforded 1-(4-methylphenyl)-1-butanone as a colorless oil (0.134 g, 0.827 mmol): 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, 2H), 7.25 (d, 2H), 2.92 (t, 2H), 2.41 (s, 3H), 1.76 (sx, 2H), 1.00 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([CH3:15])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (6.04 g), 3-methyl-4-nitrophenol (4.59 g) and triphenylphosphine (10.20 g) in dichloromethane (100 ml) was added dropwise diethyl azodicarboxylate (6.1 ml) in an ice bath and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1 as an eluant to give the desired compound (6.04 g, yield 60%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH2:2][CH3:3].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH2:1][CH2:2][CH3:3])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCCS(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)CCC)n1

Procedure:
A mixture of 4.8 g. 3-propylsulphinyl-1,2,4-triazole, 6.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which crystallized on trituration with petroleum ether (b.p. 60° - 80°C.). The resulting solid product was recrystallized from petroleum ether (b.p. 60° - 80°C.) to give 1-dipropylcarbamoyl-3-propylsulphinyl-1,2,4-triazole, m.p. 50° - 52°C. Elemental analysis satisfactory.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:8]=1)C.C1COCC1.[OH-].[Na+]>CCO>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[C:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[C:5]([CH3:33])[C:4]([OH:34])=[O:3])=[CH:12][CH:11]=1)=[C:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([CH3:26])=[CH:17]2
Reactant: CCOC(=O)C(C)=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(C=C(C)C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Yield: 87.9 %

Procedure:
As described above, 3-[4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-phenyl]-2-methylacrylic acid ethyl ester (219) (0.189 g, 0.418 mmol), THF (3 mL), EtOH (3 mL) and 1 N NaOH (4 mL) afforded 0.156 g (88%) of title compound (220) as a solid. 1H NMR (400 MHz, d-CDCl3): δ 2.07 (s, 3H), 2.24 (s, 3H), 3.93 (s, 3H), 6.61 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=2.5 Hz, J2=9.2 Hz, 1H), 7.12-7.14 (m, 3H), 7.17-7.21 (m, 2H), 7.23-7.27 (m, 3H), 7.56 (s, 1H), 7.64 (s, 1H), 7.74 (d, J=9.1 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:27][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:20])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:27][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:20])=[CH:17][C:12]=3[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)c1ccccn1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc3cc(NC(=O)c4ccccn4)ncc3[nH]2)cc1
Yield: 88.6 %

Procedure:
A solution of amide 21 (0.80 g, 0.222 mmol) in THF/MeOH (5 ml/5 ml) was stirred with Raney Nickel (0.150 ml) under H2 atmosphere at room temperature for 2 h. The amine was freed from catalyst by filtration through celite to give 22 (0.065 g, 88%) dried and used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11](I)[S:12][C:3]=12.[CH3:14][N:15]([CH3:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.O>COCCOC.C(=O)(O)[O-].[Na+].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>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[C:11]([C:19]3[CH:20]=[CH:21][C:16]([N:15]([CH3:25])[CH3:14])=[CH:17][CH:18]=3)[S:12][C:3]=12
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: N#Cc1cnc2cc(I)sc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1ccc(-c2cc3ncc(C#N)c(Cl)c3s2)cc1
Yield: 59.6 %

Procedure:
A mixture of 7-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (321 mg, 1.0 mmol), 4-(dimethylamino)phenylboronic acid (248 mg, 1.5 mmol) and 58 mgs of tetrakis(triphenylphosphine)palladium(0) in 13 mL of ethylene glycol dimethyl ether and 11 mL of aqueous saturated sodium bicarbonate is heated at reflux for 6 hours. 4-(dimethylamino)phenylboronic acid (105 mg) and tetrakis(triphenylphosphine)palladium(0) (29 mg) are added and the reaction mixture is heated at reflux for 6 hours. The mixture is treated with water and extracted into dichloromethane and the organic phase is washed with brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to provide 187 mg (60%) of 7-chloro-2-[4-(dimethylamino)phenyl]thieno[3,2-b]pyridine-6-carbonitrile as an orange solid, mp 270-272° C.; 1H NMR (CDCl3) δ 3.07 (s, 6H), 6.73 (d, J=5 Hz, 2H), 7.58 (s, 1H), 7.63 (d, J=5 Hz, 2H), 8.74 (s, 1H); HRMS found: 314.05127.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH2:10][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:3]=1[C:10](=[O:12])[CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(O)cc(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
1.62 g (9.75 mmol) of 1-(2,6-dihydroxy-4-methylphenyl)ethanone (35) are dissolved in 30 ml of dimethylformamide, and 4.0 ml (33.7 mmol) of benzyl bromide and 13.8 g (100 mmol) of potassium carbonate are added. The reaction mixture is stirred at room temperature for 3 hours. This is followed by addition of water and extraction twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in a rotary evaporator. 1.35 g (40%) of compound 36 are obtained as a colorless crystalline product. C23H22O3 (346.2) MS (ESI+): 347.15 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C[N:13]1CCOCC1.ClC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(Cl)nc1Cl
Reaction time: 0.08 h
Yield: 109.9 %

Procedure:
A mixture of 2,6-dichloro-3-carboxypyridine (5.73 g, 30 mmole) and N-methylmorpholine (3.6 ml, 33 mmole) in dichloromethane (100 ml) was stirred in an ice-bath for 5 min. Isopropyl chloroformate (4.28 ml, 33 mmole) was added the reaction mixture at 0° C. The reaction mixture was stirred for 30 min and then bubbled with pure ammonia gas for 2 min. and stirred overnight at room temperature. The crude was concentrated under reduced pressure and sodium bisulfate (0.5 M, 35 ml) was added with stirring. The aqueous solution was extracted with ethyl acetate (3×40 ml). The organics was washed with water and brine and dried with sodium sulfate to give yellow crude product (6.3g, 50% pure).
Reaction SMILES: Cl[C:2]1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.C[C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[C:46]4[C:51]=3[N:50]=[CH:49][CH:48]=[CH:47]4)[C:37]2=[O:52])[S:31][C:32]=1[C:33]([OH:35])=O.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>>[CH3:2][SH:31]1[C:32]([C:33]([NH:53][CH2:54][C:55]2[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=2)=[O:35])=[CH:28][N:29]=[C:30]1[N:36]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[C:46]3[C:51]=2[N:50]=[CH:49][CH:48]=[CH:47]3)[C:37]1=[O:52]
Reactant: Cc1nc(N2CCN(Cc3cccc4cccnc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Product: C[SH]1C(C(=O)NCc2cccnc2)=CN=C1N1CCN(Cc2cccc3cccnc23)C1=O
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(quinolin-8-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 44% yield: mp 225-228° C. (methanol); 1H NMR (300 MHz, DMSO-d6) δ 8.98-8.96 (m, 1H), 8.59-8.53 (m, 2H), 8.46-8.39 (m, 2H), 7.96-7.93 (m, 1H), 7.72-7.70 (m, 2H), 7.63-7.58 (m, 2H), 7.38-7.33 (m, 1H), 5.09 (s, 2H), 4.40 (d, J=5.8 Hz, 2H), 4.07-4.01 (m, 2H), 3.63-3.58 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 459.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:41]([F:44])([F:43])[F:42])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[F:48].O.ClCCl>O1CCOCC1>[F:48][C:19]1[CH:20]=[C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:45])([C:37]([F:38])([F:39])[F:40])[C:41]([F:43])([F:44])[F:42])=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[CH:46]=[CH:47][C:18]=1[NH:17][C:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccncc1)Nc1ccc(CN2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 130 °C
Yield: 14.1 %

Procedure:
Phenyl pyridin-4-ylcarbamate (0.461 mmol, 0.099 g) was added to a stirred solution of 2-(4-((4-(4-amino-3-fluorobenzyl)piperazin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.279 mmol, 0.139) in dioxane (7 mL) and mixture heated in a microwave reactor for 10 minutes at 130° C. Water (10 mL) was added to the reaction followed by dichloromethane (10 ml). The organic layer was separated, washed with water (3×10 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC giving the title compound (0.023 g). MS (ESI) m/z 586.3 [M+H]+
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=NO)[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C:26](=[O:41])[CH2:25][CH2:24]5)=[C:18]([C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: O=C(CN1CCOCC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCc2cc(-c3oc(C4CCN(C(=O)CN5CCOCC5)CC4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
A solution of the product of Step 1 (0.15 g, 0.35 mmol) in dry dichloromethane (3 ml) was treated with morpholine (0.060 ml, 0.76 mmol) and triethylamine (0.11 ml, 0.76 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to afford the title compound (0.05 g, 29%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.S(OC)(OC)(=O)=O.[NH3:18]>C(#N)C.CO>[NH:1]1[C:5]2=[N:6][C:7]([NH2:18])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: N
Reactant: [O-][n+]1cccc2cc[nH]c21
Solvent: CC#N
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: Nc1ccc2cc[nH]c2n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide, 3-chlorobenzoic acid complex (1.5 g, 5.16 mmol) was suspended in acetonitrile (10 mL). Dimethyl sulfate (0.54 mL, 5.68 mmol) was added and the reaction mixture was warmed to 60° C. After 16 h, the mixture was transferred to a thick-walled pressure tube and 7M ammonia in methanol solution (11 mL) was added. The tube was sealed and warmed to 55° C. After 16 h, the solvent was evaporated and the residue was taken up in dichloromethane and 10% sodium carbonate solution. The aqueous layer was extracted with dichloromethane, and then the combined organic layers were washed successively with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried (sodium sulfate), filtered, and concentrated in vacuo. Purification by chromatography (silica, 10 to 80% ethyl acetate in hexanes) gave 1H-pyrrolo[2,3-b]pyridin-6-ylamine (316 mg, 46%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.73 (br. s., 1H) 7.70 (d, J=8.3 Hz, 1H) 6.99 (d, J=3.5 Hz, 1H) 6.38 (d, J=8.3 Hz, 1H) 6.36 (d, J=3.5 Hz, 1H) 3.82 (br. s., 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C)cccc32)cc1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of 4-methyl-1H-indole (2.53 g) in N,N-dimethylformamide (20 mL) was added 55% sodium hydride (0.88 g) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To this mixture was added p-toluenesulfonyl chloride (4.04 g) at the same temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 4-methyl-1-(toluene-4-sulfonyl)-1H-indole (4.99 g). This material was dissolved in dichloromethane (100 mL). To the solution was added bromine (26% dichloromethane solution, 12.62 g) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1). The purified material was crystallized from n-hexane-diethyl ether, and the crystals were collected by filtration. The crystals were washed with n-hexane and dried under reduced pressure to give the title compound (4.8 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH3:7][O:8][C:9](=[O:22])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=2)[CH:14]=[N:13][CH:12]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu]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>[CH3:7][O:8][C:9](=[O:22])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:19]=2)[CH:14]=[N:13][CH:12]=1
Reactant: COC(=O)Cc1cncc2ccc(Br)cc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cncc2ccc(C#C[Si](C)(C)C)cc12
Temperature: 45 °C

Procedure:
Trimethylsilylacetylene (0.17 ml, 1.23 mmol) is added to a suspension of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (0.325 g, 1.03 mmol) in DMF (1.75 ml) and triethylamine (10 ml), follwed by copper(I) iodide (40 mg, 0.20 mmol) and (Ph3P)2PdCl2 (73 mg, 0.10 mmol). The reaction is heated at 45° C. for 40 minutes, cooled to ambient temperature and diluted with ethyl acetate. After washing with water and brine, the organic phase is dried over magnesium sulfate, evaporated and purified by flash column chromatography (1:1 ethyl acetate-hexane elution) to afford (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester, [MH]+ 298. This intermediate (0.221 g, 0.74 mmol) is dissolved in methanol (7.5 ml) and treated with potassium carbonate (75 mg, 0.54 mmol). The reaction is stirred for 30 minutes at ambient temperature, evaporated and purified by flash chromatography (5:1 dichloromethane-methanol elution) to afford (6-ethynyl-isoquinolin-4-yl)-acetic acid, [MH]+ 212.