Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]2[N:6]([CH2:31][CH:32]3[CH2:34][CH2:33]3)[C:7]([CH2:9][O:10][CH2:11][C:12]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:8][C:4]=2[CH:3]=1.[C:37]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)#[N:38].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Pd]>[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:2]2[CH:36]=[CH:35][C:5]3[N:6]([CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:7]([CH2:9][O:10][CH2:11][C:12]4([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]4)=[N:8][C:4]=3[CH:3]=2)=[CH:41][CH:40]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(Br)ccc3n2CC2CC2)(c2ccccc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Reaction time: 0.83 h

Procedure:
Following the procedure is described in the literature (Lee, S. H. et. al. J. Org. Chem. 2004, 69, 8829-8835). tert-Butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo-[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (48 mg, 0.087 mmol) was subjected to Suzuki coupling reaction in toluene (1.0 mL) at 110° C. with p-cyanophenylboronic acid (3 equiv) and cesium carbonate (3 equiv) using Pd (dppf) (0.08 equiv) as catalyst. The crude product was purified by silica gel chromatography using a 50 min linear gradient of 12% -100% ethyl acetate in hexane. Fractions containing the required product were combined and evaporated in vacuo to give 23 mg (46%) as a gum. 1H-NMR (CD3OD, 500 MHz) δ 7.91 (s, 1H), 7.85 (d, JAB=8.5 Hz, 2H), 7.80 (d, JAB=8.5 Hz, 2H), 7.65-7.60 (m, 2H), 7.36-7.29 (m, 4H), 7.21 (m, 1H), 4.71 (s, 2H), 3.82, (d, J=7.0 Hz, 2H), 3.72 (m, 2H), 3.58 (s, 2H), 3.04 (m, 2H), 2.20 (m, 2H), 1.84 (m, 2H), 1.42 (s, 9H), 1.04 (m, 1H), 0.50-0.47 (m, 2H), 0.33-0.30 (m, 2H); 13C NMR (CD3OD, 126 MHz,) δ 155.7, 151.9, 146.5, 143.1, 142.2, 136.2, 134.3, 132.8, 128.5, 128.0, 127.3, 126.4, 122.9, 118.9, 117.6, 111.6, 110.4, 80.0, 79.9, 65.6, 41.6, 32.1, 27.7, 11.0, 3.6. Mass Spec.: 577(MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC.[ClH:30]>>[ClH:30].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:23])([OH:26])[OH:29])[P:14](=[O:15])([OH:18])[OH:21]
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccn1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(NCCCCSc1ccccn1)P(=O)(O)O
Yield: 70 %

Procedure:
A solution of tetraethyl 4-(2-pyridylthio)butylaminomethylenebisphosphonate (2.50 g) in hydrochloric acid (40 ml) was stirred for 3 hours under reflux. The reaction mixture was concentrated under reduced pressure. Acetone was added to the residue and the separated white precipitate was collected by filtration and recrystallized from water-methanol to obtain 4-(2-pyridylthio)butylaminomethylenebisphosphonic acid hydrochloride (1.46 g, 70%) as white powder.
Reaction SMILES: [CH:1]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]([OH:26])[CH2:17][CH2:18][NH:19]C(=O)C(F)(F)F)[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO>ClCCl>[NH2:19][CH2:18][CH2:17][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]#[C:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=1)[OH:26]
Reactant: O=C(NCCC(O)c1cccc(C#CC2CCCCCC2)c1)C(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCCC(O)c1cccc(C#CC2CCCCCC2)c1

Procedure:
Deprotection of N-(3-(3-(cycloheptylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide followed by flash chromatography (5% (7N NH3/MeOH)/dichloromethane) gave 3-amino-1-(3-(2-cycloheptylethynyl)phenyl)propan-1-ol as a yellow oil. Yield (0.173 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 7.18-7.30 (m, 3H), 4.91 (d, J=6.8 Hz, 1H), 3.00 (br s, 5H), 2.74-2.82 (m, 1H), 1.80-1.94 (m, 3H), 1.68-1.80 (m, 5H), 1.44-1.64 (m, 6H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[S-2:15].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=O)[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22]1>C1(C)C=CC=CC=1>[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=[S:15])[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22]1
Reactant: CN1CC(CCCl)Oc2ccccc2C1=O
Reactant: [S-2]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccccc2C1=S

Procedure:
A mixture of 18.5 g (0.0834 mole) of phosphorus pentasulfide and 18.5 g potassium sulfide was ground together and added to a solution of 100 g (0.417 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in dry toluene, the mixture refluxed 24 hr. and filtered. The filtrate was concentrated and partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was concentrated and the residue was crystallized several times from ethanol. Yield of product was 55 g (52%), m.p. 105°-108° C.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[CH:8]1([C:11](=[O:13])[CH3:12])[CH2:10][CH2:9]1.C[O-].[Na+].Cl>CS(C)=O.C1(C)C=CC=CC=1>[CH:5]1([C:3](=[O:4])[CH2:12][C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:13])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CC1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
Methylcyclopropanecarboxylate (20.2 ml, 286.3 mmol) was added to a stirred solution of 1-cyclopropylethanone (9 ml, 152.4 mmol) in dimethylsulfoxide (25 ml). Sodium methoxide powder (10.8 g, 200 mmol) was added, and the reaction was stirred at 55° C. for 8 hours. The mixture was cooled, diluted with toluene, neutralised with 6M hydrochloric acid, and then extracted with toluene. The combined extracts were washed with sodium carbonate, dried over magnesium sulphate and evaporated in vacuo to provide the title compound (14.9 g, 78%) as a mixture 2:1 enol:ketone forms. 1H NMR (CDCl3, 400 MHz): δ=0.79-0.87 (m, 4H), 0.98-1.01 (m, 4H), 1.46-1.51 (m, 2H-enol), 1.93-1.97 (m, 2H-keto), 3.70 (s, 2H-keto), 5.65 (s, 1H-enol); LRMS: APCl+: m/z 153 [MH+]; APCl− m/z 151 [M−H]−.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:36])=[N:33][CH:34]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[N:33][CH:34]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1

Procedure:
Neat TFA (0.04 mL, 0.55 mmol) was added to a DCM solution (1 mL) of tert-butyl 3-(5-(2-(((4′-chloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (34 mg, 0.06 mmol). After 16 h the resulting mixture was concentrated in vacuo, dissolved in DCM and 1N HCl in ether was added. The resulting solution was concentrated in vacuo and the DCM/HCl process was repeated 2×. The resulting solid was characterized as the corresponding HCl salt of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl.FC1C=CC(C(C2CCN(CCCC3C4C(=CC=CC=4)NC=3)CC2)=O)=CC=1>>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]([OH:7])[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCc2c[nH]c3ccccc23)CC1
Agent: Cl
Product: OC(c1ccc(F)cc1)C1CCN(CCCc2c[nH]c3ccccc23)CC1

Procedure:
A sample of 3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl}indole, free base of Example 22, is reduced and treated by the method described in Example 2 to give 3-{3-[4-(4-fluorophenylhydroxymethyl)piperidyl]propyl}indole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([C:23]1([CH2:30][CH3:31])[CH2:28][C:27](=[O:29])[O:26][C:24]1=[O:25])[CH3:22]>N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([NH:17][C:27](=[O:29])[CH2:28][C:23]([CH2:30][CH3:31])([CH2:21][CH3:22])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCC1(CC)CC(=O)OC1=O
Reactant: Nc1cccc(OCc2ccc3ccc(Br)cc3n2)c1
Solvent: c1ccncc1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3ccc(Br)cc3n2)c1)C(=O)O
Reaction time: 0.5 h

Procedure:
2 g of 3-(7-bromo-2-quinolinylmethoxy)aniline and 1.9 g of 2,2-diethylsuccinic acid anhydride (purified by distillation) are stirred in 28 ml of pyridine for 72 hours at 20° and concentrated by evaporation. The residue is suspended in 25 ml of 2N aqueous hydrochloric acid and the suspension is stirred for 30 min. at 20° and filtered. The precipitate is washed with water and crystallised from ethanol to give the title compound in the form of colourless crystals of m.p. 175°, IR (Nujol): inter alia 3600-2100, 3308, 1710, 1670, 1610, 1600, 1497 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O.C(O)C>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:12][CH:13]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1ccc(Br)nc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Brc1ccc(-c2cccnc2)nc1
Temperature: 25 °C
Yield: 70.6 %

Procedure:
Into a 1 l flask, 20 g of 3-pyridine boronic acid, 50 g of 2,5-dibromopyridine, 5.5 g of Pd(PPh3)4, 33.9 g of sodium carbonate, 500 ml of toluene, 150 ml of ethanol, and 150 ml of pure water were put, and the solution was stirred at reflux temperature for 3.5 hours. After heating, the reaction liquid was cooled to room temperature and the organic layer was extracted. The organic layer was concentrated in an evaporator, the concentrates were purified by column chromatography, then, recrystallized in heptane, and thus 27 g of 5-bromo-2,3′-bipyridine was obtained.
Reaction SMILES: [OH:1][CH:2]([C:31]([NH:33][O:34][CH3:35])=[O:32])[CH:3]([NH:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.C([O-])(O)=O.[Na+]>CS(C)=O.ClCCl.O.CO>[CH3:35][O:34][NH:33][C:31](=[O:32])[C:2](=[O:1])[CH:3]([NH:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:20]1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CONC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of N-(3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide (2000 mg, 4.24 mmol) in DMSO (25 ml) at 20° C. 2-iodoxybenzoic acid (IBX) (3959 mg, 6.36 mmol) was added. More IBX (400 mg, 0.643 mmol) was added 2 times over an interval of 2 h, the mixture was stirred overnight, another 500 mg of IBX were added and stirring was continued. After the reaction was completed (tlc: CH2Cl2+5% (v/v) methanol) 100 ml of a saturated solution of NaHCO3 was added dropwise, 200 ml of water and 200 ml of dichloromethane were then added and the precipitate was filtered off with suction. The dichloromethane layer was dried, filtered and concentrated to give 1.9 g of a yellowish amorphous solid, which was crystallized from ethyl acetate and dried in vacuo to give 1.1 g of the title compound. ESI-MS [M+H]+: 470.2
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14](=[CH2:20])[CH2:15][N+](C)(C)C)=[CH:9][CH2:8][CH2:7]2.[CH3:21][OH:22]>[Ag]=O.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([CH2:15][C:13]1([CH3:12])[C:21](=[O:22])[CH2:6][CH2:5][C:4]1=[O:3])=[CH2:20])=[CH:9][CH2:8][CH2:7]2
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ccc21
Reactant: CO
Agent: O=[Ag]
Agent: [I-]
Solvent: O
Product: C=C(CC1(C)C(=O)CCC1=O)C1=CCCc2cc(OC)ccc21
Reaction time: 2 h

Procedure:
To a solution containing 13.3 parts of 2-(6-methoxy-3,4-dihydro-1-naphthyl)-2-propen-1-yl trimethylammonium iodide in 200 parts by volume of methanol and 1 part by volume of water is added 4.1 parts of silver oxide and the resulting reaction mixture is stirred for approximately 2 hours. At the end of that time the mixture is filtered into a container holding 4 parts of 2-methylcyclopentane-1,3-dione. The resulting solution is concentrated to a small volume and 500 parts by volume of xylene, 5 parts by volume of hexamethylphosphoramide and 5 parts by volume of triethylamine are added. Approximately 50 parts by volume of solvent is removed by distillation and the resulting mixture is heated gently at the reflux temperature for about 20 hours, then allowed to cool. That solution is washed successively with water, 5% hydrochloric acid, water, 5% aqueous sodium bicarbonate and water again, after which time the mixture is dried over anhydrous sodium sulfate and concentrated to a small residue. Crystallization of that crude product from methanol affords 2-(6-methoxy-3,4-dihydro-1-naphthyl)-3-(2-methylcyclopentane-1,3-dione-2-yl)propene, melting at about 81°-82° and displaying an ultraviolet absorption at about 274 millimicrons with a molecular extinction coefficient of approximately 10,400.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14][C@H:13]2[O:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC)C3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)O)c4s3)C[C@H]2OC)nc1Cl
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (1h) (95 mg, 0.19 mmol) was dissolved in methanol (5 mL) and dichloromethane (2 mL). A 2 N aqueous lithium hydroxide solution (3 mL) was added, and the mixture was stirred at 70° C. for 1.5 hours. The organic solvent was evaporated under reduced pressure and 1 N hydrochloric acid was added until the pH of the solution was about 4. The resulting solid was collected by filtration and washed with distilled water to obtain 75 mg of the title compound as a white solid (84%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][C:7]=1[OH:13].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][C:7]=2[OH:13])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: Oc1ccc(SCCCCl)c(O)c1
Product: Oc1ccc(SCCCN2CCOCC2)c(O)c1

Procedure:
4 g of 4-(3-chloropropylthio)resorcin and 8 ml of morpholine are heated for two hours at 100° C. The mixture is poured into ice-cold water and extracted with ethyl acetate. The organic phases are washed, dried and concentrated under vacuum. The yellow oil is crystallized from ethyl acetate to lead to white crystals having a melting point of: 99° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C1(=O)OC(=O)CCC1>O1CCOCC1>[C:11]([OH:13])(=[O:12])[C:4]1[C:5](=[CH:9][CH:10]=[CH:2][CH:3]=1)[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(C(=O)O)c1
Agent: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)O

Procedure:
65.1 g (0.36 mol) of 4-aminophthalic acid in 500 ml of dioxane are reacted with 43.12 g (0.38 mol) of glutaric anhydride, in the manner described in Example 9, to give 4-glutaramidyl)-phthalic acid, and the latter is subsequently cyclised. 70 g (75% of theory) of 4-(glutarimidyl)-phthalic anhydride of melting point 220°-222° C. are obtained.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:20][NH2:21]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:21][CH3:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CN
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: CNc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
200 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.115 ml (5 equivalents) of methylamine, and the mixture is then heated at 120° C. for approximately 18 hours. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride. Partial drying and drying under vacuum at 50° C. are carried out. 190 mg of expected product are obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[S:14][C:13]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][NH:17][N:16]=2)=[CH:12][CH:11]=1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:18]1[NH:17][N:16]=[C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2n[nH]c(Br)c2-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
N-Bromosuccinimide (1 eq, 0.38 mmol) was added to a solution of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 0.38 mmol) in 2 mL of N,N-dimethylformamide. The mixture was then stirred at 80° C. for 2 h. Further N-Bromosuccinimide (0.3 eq, 0.12 mmol) was added and the mixture was stirred for one more hour. After cooling to room temperature, ethyl acetate was added and the organic layer was washed with water, dried over MgSO4, filtered and evaporated. The residue was suspended in diisopropylether and dichloropethane, filtered and dried in a vacuum oven at 50° C. to afford 0.16 g of 4-[5-bromo-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
3,4-Dihydroxybenzaldehyde (30.2 g, 219 mmol) is dissolved in DMF (300 mL) and added to a suspension of NaH (60% oil, 17.2 g, 430 mmol) in DMF (500 mL) at RT. The mixture is stirred for 30 minutes and benzyl chloride (17.3 mL, 150 mmol) is added at 0° C. The reaction is stirred overnight. The solvent is removed by evaporation and the residue is dissolved in water (500 mL). The mixture is extracted three times with CH2Cl2. The aqueous layer is acidified with HOAC (100 mL). The product is precipitated and filtered, washed with water to provide 3-benzyloxy-4-hydroxybenzaldehyde.
Reaction SMILES: BrC1C=CC=CN=1.C([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N+]([O-])=O)[C:14]2=[N:13]1)CC#C>>[N:13]1[NH:12][N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=12
Reactant: C#CCCn1nc2cccc([N+](=O)[O-])c2n1
Agent: Brc1ccccn1
Product: c1ccc2n[nH]nc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (76 mg, 0.48 mmol) and 2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH-99:1) to yield 40 mg (0.14 mmol, 31%) of 4-nitro-2-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Product: O=c1[nH]cc(N2CCOCC2)c(=O)[nH]1
Yield: 76 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 10 (Step1), starting from 5-bromouracil (0.10 g, 052 mmol) and 20 equivalents of morpholine. The crude was purified by precipitation in acidic water (10 mL, pH 5) to afford the title compound (0.08 g, 76%) as white, powder. 1H NMR (400 MHz, DMSO-d6): δ 2.74-2.84 (m, 4H), 3.64 (t, J=4.6 Hz, 4H), 6.72 (s, 1H), 10.47 (s, 1H), 11.05 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:39]#[N:40])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:45])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:41][OH:42])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:39]([NH2:40])=[O:45])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CN1CCN(c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)CC1
Solvent: O
Product: CN1CCN(c2ccc3c(C(N)=O)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (43 mg, 76.0 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (2.00 mg, 4.66 μmol, Eq: 0.0613) were combined with ethanol (1.00 ml) and water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (35 mg, 97%, [M+H]+ 584).