Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:15])=[O:4].[CH2:16](O)[CH:17]([OH:19])[CH3:18].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH3:13][C:12]1([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:15])[C:6]=2[NH:5][C:3](=[O:4])[CH2:2][Cl:1])[O:19][CH:17]([CH3:18])[CH2:16][O:14]1
Reactant: CC(O)CO
Reactant: CC(=O)c1cccc(C)c1NC(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cccc(C2(C)OCC(C)O2)c1NC(=O)CCl

Procedure:
N-chloroacetyl-2-methyl-6-acetylaniline (from Example 1), 4.51 g, 1,2-propanediol, 3.7 ml, and a dash of toluene sulfonic acid were combined in 50 ml toluene and refluxed. The distilled water by-product was collected in a Dean-Stark trap. After water ceased to distil, methylene chloride was added and the mixture was extracted successively with bicarbonate solution and water, then dried (MgSO4) and evaporated to yield 3.3 g brown oil. The oil was purified on a silica gel column (Hexane:ethyl acetate eluant) to yield the title product (Compound No. 2 in Table A).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[N:7]=1
Reactant: NCc1ccccc1Cl
Reactant: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CN1CCN(c2nccn3c(-c4cccc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 39 supra) (0.187 g, 0.5 mmol), 2-chloro-benzylamine (71 mg, 0.5 mmol), Pd2(dba)3 (30 mg), Davephos (40 mg), NaOtBu (70 mg, 0.73 mmol) and dioxane (20 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 100° C. for 15 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC. The obtained product was dissolved in ethanol and then concentrated HCl (1 mL) was added and stirred for 1 h. The mixture was concentrated under reduced pressure. The resulting solid was suspended in dichloromethane and concentrated to give (2-chloro-benzyl)-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl}-pyridin-2-yl]-amine; hydrochloride. (Yield 47 mg). 1HNMR (300 MHz, CD3OD): δ 8.39 (d, 1H, J=5.4 Hz), 8.17 (s, 1H), 7.73 (t, 1H, J=7.8 Hz), 7.40-7.36 (m, 2H), 7.22-7.09 (m, 4H), 6.87 (d, 1H, J=8.4 Hz), 5.43 (brs, 2H), 4.64 (s, 2H), 3.86-3.66 (m, 4H), 3.41-3.37 (m, 2H), 2.91 (s, 3H). LC-MS: [M+H]+ 435.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([OH:8])[CH:7]=1.Br[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([O:8][CH:18]([CH3:20])[CH3:19])[CH:7]=1
Reactant: CC(C)Br
Reactant: Oc1cc(I)ccc1OCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc(I)ccc1OCCN1CCCC1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A suspension of 0.15 g (0.45 mmol) of 5-iodo-2-(2-pyrrolidin-1-ylethoxy)phenol (Example 33.1c), 52 μL (0.55 mmol) of 2-bromopropane, and 186 mg (1.35 mmol) of potassium carbonate in 2 mL of acetonitrile was stirred for 2 hours at 75° C. The reaction mixture was diluted with water and the aqueous phase exhaustively extracted with DCM. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 77 mg (46% of theoretical); C15H22INO2 (M=375.245); calc.: molpeak (M+H)+: 376; found: molpeak (M+H)+: 376; HPLC-MS: 5.86 minutes (method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]=2[CH:26]=O)=[CH:5][CH:4]=1>C(O)(=O)C.[Zn]>[CH3:23][O:22][C:17]1[C:16]([O:24][CH3:25])=[CH:15][C:14]2[C:13]3[CH:26]=[N:9][C:7]4[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[C:12]=3[CH:21]=[CH:20][C:19]=2[CH:18]=1
Reactant: COc1ccc(-c2ccc3cc(OC)c(OC)cc3c2C=O)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)ncc1c3cc(OC)c(OC)cc3ccc21
Yield: 7.7 %

Procedure:
A mixture of 2-(4-methoxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (30 mg, 0.81 mmol) in acetic acid (3 ml) and zinc dust (100 mg, 1.5 mmol) was heated to reflux for 3 hours. Acetic acid was evaporated in vacuo and the residue extacted with chloroform. The chloroform solution was filtered through a celite bed. The filtrate was washed successively with saturated sodium bicarbonate solution and brine and evaporated to dryness. The residue obtained was chromatographed on 75 g silica using a 1:1 mixture of hexanes:ethyl acetate as eluent to give the title compound (20 mg, 77%); IR (KBr) 1615, 1518, 1272; 1H NMR (CDCl3) δ4.02 (3H, s), 4.08 (3H, s), 4.18 (3H, s), 7.33 (1H, s), 7.37 (1H, dd, J=9.1, 2.6 Hz), 7.54 (1H, d, J=2.6), 8.05 (1H, d, J=8.7), 8.42 (1H, d, J=8.7), 8.56 (1H, d, J=9.1), 10.05 (1H, s); 13C NMR δ56.1, 56.5, 56.6, 102.2, 108.6, 109.5, 119.0, 119.2, 119.3, 120.6, 124.1, 125.8, 127.6, 131.4, 131.7, 146.7, 148.4, 150.1, 151.1, 160.3; HRMS calcd for C24H12NO3; 319.1208; found 319.1209.
Reaction SMILES: [I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[NH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>CN(C=O)C.O>[I:1][C:2]1[C:6]2=[N:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][CH:10]=[C:5]2[N:4]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: O=C(O)c1ccc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodo-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid (0.549 g, 1.906 mmol) in DMF (9.5 mL) at 0° C. was added NaH (60% in mineral oil, 0.191 g, 4.76 mmol). After 30 min at 0° C., p-toluenesulfonyl chloride (0.436 g, 2.287 mmol) was added and the reaction was warmed to RT. After 1 h at RT, the mixture was poured into H2O and the mixture was acidified with 5 M HCl (aq.). The precipitate was collected by filtration, washed with H2O and dried in a vacuum oven overnight to afford 3-iodo-1-((4-methylphenyl)sulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid. (0.663 g, 1.499 mmol, 79%) as a tan solid. MS (ESI, pos. ion) m/z: 442.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.35 (3H, br s), 7.44 (2H, d, J=8.22 Hz), 7.96-8.01 (2H, m), 8.10 (1H, d, J=8.80 Hz), 8.47 (1H, d, J=8.80 Hz), 8.54 (1H, s).
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][N:38]([CH3:44])[C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:41]4[CH2:42][CH2:43][C@@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C(F)(F)F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.76 (s, 1H), 3.83 (t, 1H), 3.75 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 2.12 (m, 2H), 1.85-1.72 (m, 4H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 499 [M+H]
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([F:30])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([O:18]C)[C:15]([F:20])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22])[CH:9]=[C:8]([C:24]([O:26]CC)=[O:25])[C:7]2=[O:29].Br>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([F:30])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:20])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22])[CH:9]=[C:8]([C:24]([OH:26])=[O:25])[C:7]2=[O:29]
Reactant: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2[N+](=O)[O-])c2c(Cl)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2cc(O)c(F)cc2[N+](=O)[O-])c2c(Cl)c(F)c(F)cc2c1=O
Yield: 47.5 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(4-fluoro-5-methoxy-2-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (510 mg) was added to a mixed liquid (1:1, v/v; 5 ml) of 47% hydrobromic acid and acetic acid, aid the mixture was stirred and heated under reflux for 46 hours. The reaction mixture was concentrated under reduced pressure. A process of adding distilled water (5 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Distilled water (5 ml) was added to the resultant residue, and deposits were collected by filtration. The deposits were dispersed in ethanol (2 ml) and heated to reflux. The reaction mixture was allowed to cool, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (220 mg) as a pale brown powder.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[C:4]=1C#C.[CH2:18]1COC[CH2:19]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:18]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[CH:4]=1)#[CH:19]
Reactant: C#Cc1c([Si](C)(C)C)ccc(C(=O)OC)c1O
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C#Cc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3.07 g (12.4 mmol) of methyl 4-trimethylsilanyl-ethynyl-2-hydroxybenzoate are mixed, in a 500 ml three-necked flask, with 50 ml of THF, and 13.7 ml of a tetrabutylammonium fluoride solution (1 M/THF) are added dropwise. The reaction medium is stirred for 1 h at room temperature and is then poured into water and extracted with ethyl ether. After separation of the phases by settling, the organic phase is dried over magnesium sulphate and concentrated. 2.48 g (100%) of a beige-coloured powder are obtained. m.p.=62° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:28]([C:27]1[C:31]([CH3:35])=[CH:32][CH:33]=[CH:34][C:26]=1[Cl:25])=[O:29]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 64.5 %

Procedure:
To a suspension 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.5 mmol, 0.180 g), 2-chloro-6-methylbenzoic acid (0.55 mmol, 0.084 g) and HBTU (0.6 mmol, 0.227 g) in DMF (4 mL) was added diisopropylethylamine (3.0 mmol, 0.52 mL) at room temperature. After 1 min, everything went into solution and the yellow clear solution was stirred 15 h at room temperature. By this time, it turned to a brown solution was diluted with ethyl acetate (25 mL). The ethyl acetate layer was washed successively with water (2×20 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel column chromatography to afford 151.5 mg (72% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as a white solid: mp 155-157° C. EI-HRMS m/e calcd for C24H24N3O5Cl (M+) 470.1483, found 470.1484.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][NH:5][C:6](=[O:8])[CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[Cu]I.O>[OH:1][C:2]1[C:3]([C:9]#[N:10])=[CH:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: N#Cc1c[nH]c(=O)cc1O
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C#N)c(O)cc2=O)cc1
Temperature: 190 °C
Yield: 5.7 %

Procedure:
A mixture of 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile (200 mg, 1.469 mmol, Medinoah), 1-bromo-4-(methylsulfonyl)benzene (345 mg, 1.469 mmol), 4,7-dimethoxy-1,10-phenanthroline (70.6 mg, 0.294 mmol), copper(I) iodide (56.0 mg, 0.294 mmol) and potassium carbonate (609 mg, 4.41 mmol) in DMSO (3 mL) was heated at 190° C. To the reaction mixture was added H2O (10 mL) and the pH adjusted to ˜2 using with 1N HCl. The resulting aqueous mixture was extracted with EtOAc (40 mL, 2×). The combined extracts were dried over Na2SO4 and concentrated to give a brown oil. The crude oil was purified by flash chromatography (SiO2, 0-5% MeOH/CH2Cl2) to give a yellow solid (35 mg, 0.084 mmol, 5.74%). MS (ESI) 291 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].N.[N:16]1C=CC=CC=1>S(Cl)(Cl)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:16])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: c1ccncc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1F
Agent: N
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-3-sulphamoylbenzoic acid (5.4 mmol) in thionyl chloride (10 mL) is refluxed for 4 hours. The reagent is then removed by distillation under reduced pressure and the residue is re-dissolved in dry toluene (10 mL). The solvent is removed by distillation under reduced pressure. This operation is repeated twice, and then the residue is dissolved in dry dioxane (10 mL), and ammonia (6 mmol) and pyridine (6 mmol) are added. After one hour, the solvent is removed under reduced pressure and the residue is taken up in methanol (5 mL), and then water (30 mL) is added. The precipitate obtained is collected by filtration, washed with water and dried.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].CCCCCC>C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: NC(=O)c1ccccc1N
Reactant: N#Cc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2ccccc2C(N)=O)cc1
Yield: 86.8 %

Procedure:
Following the general procedure, 4-bromobenzonitrile (91 mg, 0.5 mmol) was coupled with 2-aminobenzamide (102 mg, 0.75 mmol) with the reaction time of 17 h. Chromatography on silica gel column with 1:1 hexane:ethyl acetate gave 103 mg (87%) of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:22][S:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:37][CH3:38].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:21][CH2:22][S:23][CH2:24][C:25]#[C:26][C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCSCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCSCC#Cc1cccs1)C(C)(C)C)CC2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 505 mg of 9h in 6 ml of dioxane and a solution of 180 mg of KOH in 1 ml of water were mixed and stirred for 3 h at 50° C. The reaction mixture was cooled and diluted with 20 ml of water and acidified to pH 3 by addition of 0.5 N HCl and extracted with ethyl acetate. The extract was once washed with water, dried and concentrated, to provide 480 mg of crude and unstable 91, which was used without further purification directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.C(O[CH:13]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)(=O)C>C1C=CC=CC=1>[N:4]1([CH2:3][CH2:2][NH:1][CH:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: NCCn1ccnc1
Solvent: c1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NCCn1ccnc1

Procedure:
A solution of 1.86 g. of 1-(2-aminoethyl)imidazole and 4.0 g. of 9-acetoxyxanthene dissolved in 100 ml. of dry benzene was refluxed for 24 hours. After cooling the solution was washed with 5% aqueous sodium carbonate solution and water, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was redissolved in ether and deposited white crystals which were filtered and recrystallized from benzene-hexane to give N-[2-(1-imidazolyl)ethyl]-9-xanthenylamine, m.p. 90°-92° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH-:13].[K+].Cl>C(O)(C)(C)C>[Cl:8][C:7]1[C:2](=[O:13])[NH:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]cc(C(F)(F)F)cc1Cl
Yield: 75.3 %

Procedure:
4.5 g of 2,3-dichloro-5-trifluoromethylpyridine was added to a solution of 2.7 g of potassium hydroxide dissolved in 40 ml of t-butanol, and the mixture was reacted at the reflux temperature for one hour while stirring. After completion of the reaction, the reaction product was allowed to cool and made acidic with concentrated hydrochloric acid. The contents were concentrated under reduced pressure to obtain a solid which was then purified to obtain 3.1 g of the titled compound having a melting point of 165° to 166° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1>CN(C)C=O.O>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (151 g, 88 mmol) in dry N,N-dimethylformamide (40 mL) at 0° C. was added diethyl malonate (10.3 g, 64.3 mmol) and the mixture was stirred at room temperature for 30 minutes. A solution of 4-fluoro-2-methoxy-1-nitrobenzene (10 g, 58.5 mmol) was added and the mixture was stirred at 90° C. overnight. The mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 1/20 to 1/10 ethyl acetate/petroleum ether to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]=[CH:18][C:19]3[N:28]=[C:27]4[C:22]([CH2:23][CH2:24][C:25](=[O:29])[NH:26]4)=[CH:21][CH:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[N:28]=[C:27]4[C:22]([CH2:23][CH2:24][C:25](=[O:29])[NH:26]4)=[CH:21][CH:20]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)n1
Yield: 1.1 %

Procedure:
7-{5-[4-(6-Methyl-pyridin-2-yl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.343 g, 0.876 mmol) was hydrogenated using 20% Pd/C in EtOH for 103 h. The reaction was filtered and concentrated. Purification by liquid chromatography (Biotage 12 SiO2 column, CH2Cl2 to 1% MeOH/CH2Cl2) followed by recrystallization from Et2O gave the title compound as a white powder (42 mg, 0.01 mmol, 12%). MS: APCI: M+1: 394.2 (Exact Mass: 393.25).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CN(C)C=O.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:32][C:29]4[CH:28]=[CH:27][C:26]([Br:25])=[CH:31][N:30]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.38 g, 11.5 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (2.5 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at 60° C. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 7 mL of anhydrous pyridine. This solution was then slowly added to a solution of 5-bromo-pyridin-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 mL of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110° C. The mixture was then evaporated to dryness, suspended in 100 mL of dichloromethane, and washed with three 25 mL portions of 1N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified by silica gel column chromatography utilizing dichloromethane as the eluent to yield the pure product (3.46 g, 83%) ESI-MS m/z calc. 361.2. found 362.1 (M+1)+; Retention time 3.40 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.21 (m, 2H), 1.44-1.51 (m, 2H), 6.07 (s, 2H), 6.93-7.02 (m, 2H), 7.10 (d, J=1.6 Hz, 1H), 8.02 (d, J=1.6 Hz, 2H), 8.34 (s, 1H), 8.45 (s, 1H).