Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:26])=[CH:11][CH:12]=[C:13]([S:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](O)(=O)[CH3:28].[Cl-].[Na+]>Cl>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([S:15][C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][N:20]=[CH:21]4)[CH:12]=[CH:11][C:10]=2[N:26]=[C:27]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Sc2cccc3cnccc23)cc1NCc1ccccc1
Reactant: CC(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: Cc1nc2ccc(Sc3cccc4cnccc34)cc2n1Cc1ccccc1
Yield: 43.3 %

Procedure:
N2-Benzyl-4-(5-isoquinolylsulfanyl)-1,2-benzenediamine 730 mg (2.0 mmol) was dissolved in 4N hydrochloric acid 20 ml, acetic acid 0.3 ml was added, and the mixture was heated and refluxed overnight. 40% sodium chloride was added to obtain an alkaline solution, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: acetone=5:1), and 1-benzyl-6-(5-isoquinolylsulfanyl)-2-methyl-1H-benzo[d]imidazole 330 mg (43.3%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27]([NH:29][CH:30]([CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([C:42](=[O:44])[NH2:43])=[CH:37][C:36]=1[CH3:45])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][CH:30]([CH2:34][C:35]1[C:36]([CH3:45])=[CH:37][C:38]([C:42](=[O:44])[NH2:43])=[CH:39][C:40]=1[CH3:41])[C:31](=[O:32])[N:13]1[CH:12]([C:9]2[NH:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 220 mg (0.8 mmol) of 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline, 269 mg (0.8 mmol) of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid, 216 mg (1.6 mmol) of of hydroxybenzotriazole hydrate and 184 mg (0.96 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 3 mL of dimethylformamide. The resulting mixture was allowed to stir overnight at room temperature under argon. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and concentrated. The product {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester was taken to the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:14][C:15]([CH2:17][NH:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH3:20])=O)C>O>[OH:14][CH2:15][CH2:17][NH:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH3:20]
Reactant: CCOC(=O)CNC(C)c1ccccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(C)NCCO
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a mixture of 3.8 g of lithium aluminium hydride (0.1M) and 150 ml of tetrahydrofuran, 23.3 g of the compound (0.105M) prepared in Step 2 above was dropwise added at room temperature and stirred for 30 minutes. The resultant was added with water and solids produced were filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, to give 13.8 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([CH3:17])=[CH2:16]>Cl.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)([CH3:17])[CH3:16])=[CH:19][CH:20]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Solvent: Oc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 180 °C
Reaction time: 2 h
Yield: 378.5 %

Procedure:
Ten grams of aniline was added to a mixture consisting of 13.0 g of phenol, 3.4 g of p-isopropenyl phenol monomer, 8.5 g of a linear dimer of p-isopropenyl phenol, 1.1 g of a linear trimer of p-isopropenyl phenol and 0.8 g of a linear tetramer and higher polymers of p-isopropenyl phenol (1.05 mole of aniline per mole of the p-isopropenyl phenol monomeric unit). The mixture was stirred at 180° C. Then, 0.2 g of 10% hydrochloric acid (0.0053 mole per mole of the p-isopropenyl phenol monomeric unit) was added, and the reaction was performed for 2 hours. Gas-chromatographic analysis of the reaction mixture showed that 0.38 g of bisphenol A and 21.8 g (yield 93%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane were formed.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:27]=[O:28])C.Cl>C1COCC1>[CH:10]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:27]=[O:28])([CH3:12])[CH3:11]
Reactant: COc1cc(Br)cc(C(C)C)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(C(C)C)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-bromo-3-isopropyl-5-methoxy-benzene (1.06 g, 4.63 mmol) in dry THF (10 mL) was cooled to −78° C. under nitrogen atmosphere. A 1.6 M solution of nBuLi in hexane (2.9 mL, 4.63 mmol) was added at once, followed within 1 min by DMF (0.356 mL, 4.63 mmol). After 1 min the mixture was poured onto 10 mL 1N aq. HCl, stirred for 5 min and extracted with TBME. The organic phase was washed with brine, dried with MgSO4 and evaporated to give the title compound sufficiently pure for further use: TLC (AcOEt-hexane 1:9) Rf=0.40; HPLC RtH1=2.97 min; ESIMS [M+H]+=179; 1H NMR (400 MHz, CDCl3): δ 9.95 (s, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.05 (s, 1H), 3.85 (s, 3H), 2.96 (heptet, 1H), 1.29 (d, 6H).
Reaction SMILES: O.[OH:2][N:3]1[C:7](=[O:8])[CH2:6][CH:5]([S:9]([OH:12])(=[O:11])=[O:10])[C:4]1=[O:13].C(Cl)CCl.[Na+:18].[Cl-]>Cl.C(O)C(O)C.C1N(CCS(O)(=O)=O)CCOC1>[CH2:6]1[C:7](=[O:8])[N:3]([OH:2])[C:4](=[O:13])[CH:5]1[S:9]([O-:12])(=[O:11])=[O:10].[Na+:18]
Reactant: O=C1CC(S(=O)(=O)O)C(=O)N1O
Agent: Cl
Agent: O=S(=O)(O)CCN1CCOCC1
Agent: [Cl-]
Solvent: CC(O)CO
Solvent: O
Solvent: ClCCCl
Product: O=C1CC(S(=O)(=O)[O-])C(=O)N1O

Procedure:
Recombinant rat PDGF-AA was purchased from R&D Systems (Minneapolis, Minn., USA) and dissolved in 4 mM HCl with 10% 1,2-propanediol at a concentration of 400 μg/ml (40 μg/100 μl). The water-soluble carboimide, 1-ethyl-3-(3-dimethylaminopropyl) carboimide hydrochloride (EDC, 50 μl; Sigma-Aldrich) and N-Hydroxysulfosuccinimide (sulfo-NHS, 50 μl; Pierce) in 0.1 M 2-(N-morpholino)ethanesulfonic acid (MES) buffer, 1 M NaCl, pH 6 (reaction buffer) were added to the PDGF-AA solution to obtain a final concentration of 11 mM EDC and 12 mM sulfo-NHS. After mixing and reacting the above reagents at room temperature for 15 min, Alexa Fluor 350 hydrazide sodium salt (5 mM) in dimethyl sulfoxide (DMSO) and 4-(4-N-maleimidophenyl) butyric acid hydrazide (MPBH, 7 mM) in 0.1 M sodium acetate pH 5.5 (200 μl) were added to the PDGF-AA for 75 min at room temperature. After adding 20 mM HCl (80 μl), the modified PDGF-AA (MI-PDGF-AA) was purified with AKTA-FPLC (Amersham Pharmacia) using Sephadex G-25 (Sigma-Aldrich) column (10×200 mm) (Amersham Pharmacia) equilibrated in 4 mM HCl pH 2.3, 150 mM NaCl, 5% propanediol. Elution of MI-PDGF-AA was monitored at 280 nm using UV-Vis monitor (UPC-900 Pharmacia Biotech) equipped on the FPLC. Fluorescently tagged MI-PDGF-AA was confirmed by measuring fluorescent emission at 445 nm on a fluorescence plate reader (345 nm excitation, Molecular Device). The concentration of MI-PDGF-AA was determined using the PDGF-AA enzyme-linked immunosorbent assay (ELISA; R&D Systems). Assays were performed according to the manufacturer's instructions. The yield of MI-PDGF-AA was determined to be 30.4 μg (7.6 μg/ml), yielding 76% recovery. To confirm the conjugation of MPBH to PDGF-AA, the reaction described above, excluding the addition of Alexa Fluor 350 was performed. The molecular weight of conjugated PDGF-AA-MPBH was determined using MALDI-TOF.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:18]3[C:9](=[C:10]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=4)[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=4)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:37]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:37][C:17]1[C:18]2[C:9]([C:10]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[C:11]3[C:16]=1[CH:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=[CH:12]3)=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:20][CH:19]=2
Reactant: c1ccc(-c2ccc3c(-c4ccc5ccccc5c4)c4cc(-c5ccccc5)ccc4cc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2cc(-c3ccccc3)ccc2c(-c2ccc3ccccc3c2)c2cc(-c3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
First, 9.09 g of 2,6-diphenyl-9-(2-naphthyl)anthracene were dissolved in 100 mL of N,N-dimethylformamide under heat, and then a solution of 3.91 g of N-bromosuccinimide in 10 mL of N,N-dimethylformamide was added to the solution. The mixture was stirred at 60° C. for 6 hours under heat. After having been cooled to room temperature, the reaction solution was poured into 500 mL of water. The resultant solid was sequentially washed with methanol, water, and methanol. After that, the solid was repeatedly recrystallized with toluene and hexane and washed. Thus, 8.55 g of 9-bromo-2,6-diphenyl-10-(2-naphthyl)anthracene were obtained (in 80% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]1)[CH3:3]>Cl>[CH3:3][N:2]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CN(C)C[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-1, tert-butyl trans-4-[(dimethylamino)methyl]cyclohexylcarbamate (1.1 g, 4.30 mmol) was reacted with 3 M hydrochloric acid (10 mL) to afford the desired product (1.0 g, >99%) as a glass: ESI MS m/z 230 [C9H20N2+H]+.
Reaction SMILES: C(S(N[C@@H](C([NH:19][C@H:20]([C:25]([NH:27]CC1C=CC(C#N)=CC=1)=[O:26])[CH2:21][CH2:22][S:23][CH3:24])=O)[C@@H](CC)C)(=O)=O)C1C=CC=CC=1.Cl.ON>C(O)C.N1C=CC=CC=1>[NH2:19][C@H:20]([C:25]([NH2:27])=[O:26])[CH2:21][CH2:22][S:23][CH3:24]
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)NCc1ccc(C#N)cc1
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Solvent: CCO
Product: CSCC[C@H](N)C(N)=O
Reaction time: 16 h
Yield: 0 %

Procedure:
N-(Benzylsulfonyl)-D-isoleucyl-N1-(4-cyanobenzyl)-L-methioninamide (100 mg, 0.19 mmol) was dissolved in ethanol (6 ml) and pyridine (0.6 ml), to which hydroxyamine hydrochloride (120 mg) was then added and stirred for 16 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethanol, filtered and then purified by preparative HPLC to give N-(benzylsulfonyl)-D-isoleucyl-N1-[4-(E)-amino(hydroxyimino)methyl]benzyl]-L-methioninamide (1.6 mg, 0.00003 mmol; yield 1.5%).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].O.Cl>C1COCC1>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4])=[CH2:24]
Reactant: C=COCCON
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[NH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Temperature: 22 °C
Reaction time: 0.92 h
Yield: 73.6 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (221 g, 0.53 mol) and O-(2-vinyloxyethyl)-hydroxylamine (63 g, 0.61 mol) in THF (2.85 L), under nitrogen, was added 1M lithium bis(trimethylsilylamide) solution in hexanes (1431 g), over 55 minutes, keeping the temperature between −14.7 and −12.4° C. After 2 hours at −15° C., water (165 mL, 9.2 mol) was added to the mixture, followed by 2M HCl solution (1.98 L), which was added over 20 minutes. The mixture was then allowed to warm to 22° C. and the lower aqueous phase (2.25 L) was separated and discarded. The organic phase was washed with sodium chloride solution (15% w/w, 1100 mL) and the volume was reduced to approximately 1.75 L by distillation of 2.25 L of solvent at ambient pressure. Iso-hexane (3.35 L) was added to the mixture over 2.5 hours with the temperature held at approximately 58° C. After a further 1 hour at this temperature the mixture was cooled to 20° C., held for 1 hour and then cooled to 0° C. and held at this temperature overnight. A further quantity of iso-hexane (500 mL) was added and the mixture was held for 1 hour, then more iso-hexane (500 mL) was added. After 45 minutes at 0° C. the slurry was filtered and the solid was washed with chilled iso-hexane (1.1 L) then dried in vacuum oven at 30° C. to provide 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (190 g, 0.39 mol, 74% yield). 1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.52 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.55-6.46 (m, 2H, ArH/OCH═CH2), 4.18 (dd, 1H, J 14, 2 Hz, OCH═CH2), 3.99 (dd, 1H, J 7, 2 Hz, OCH═CH2), 3.90-3.88 (m, 2H, OCH2), 3.81-3.79 (m, 2H, OCH2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, ArCH3).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[C:5]2[CH2:18][CH:19]([CH2:21][OH:22])[O:20][C:4]=2[CH:3]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][O:10][C:6]=2[C:5]2[CH2:18][CH:19]([C:21]([OH:25])=[O:22])[O:20][C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2c(cc(Cl)c3c(-c4ccccc4F)noc23)O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(cc(Cl)c3c(-c4ccccc4F)noc23)O1
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A portion (4.3 g) of the 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol obtained in Example 22 was dissolved in 120 ml of acetone. To the solution, a mixture of chromium (VI) oxide (6.5 g), water (15 ml) and concentrated sulfuric acid (9.3 g) was added dropwise under stirring. The stirring was continued at room temperature for 2 hours, then the mixture was left to stand overnight. The insolubles were filtered off by suction, and the solvent was distilled off. Water was added to the residue, followed by extraction with ether. The ether layer was washed with water and dried, and the solvent was distilled off. The residue was recrystallized from acetone/water to yield 2.7 g of 4-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 191°-193° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([OH:22])=[O:21])=[CH:3]1.FC(F)(F)C(O[C:28]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:29]=1[F:38])=O.N1C=CC=CC=1>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([O:22][C:28]2[C:29]([F:38])=[C:30]([F:37])[C:31]([F:36])=[C:32]([F:35])[C:33]=2[F:34])=[O:21])=[CH:3]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cn1cc(C(=O)O)c(Nc2ccc3ccccc3c2)cc1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc3ccccc3c2)cc1=O
Yield: 97 %

Procedure:
1-Methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate (97%). 1H NMR [400 MHz, (CD3)2SO]δ 9.06 (s, 1H), 8.97 (s, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.92 (t, J=9.0 Hz, 2H), 7.85 (d, J=1.9 Hz, 1H), 7.56-7.46 (m, 3H), 5.73 (s, 1H), 3.51 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11](Cl)=[C:10]([C:19]#[N:20])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:10]([C:19]#[N:20])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Reactant: C1CNCCN1
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (8) (530 mg, 1.79 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (463 mg, 5.37 mmol) in dichloromethane at room temperature. The solution was further stirred overnight at room temperature and diluted by dichloromethane. The solution was subsequently washed with saturated NaHCO3 solution, water and brine, then dried over Na2SO4 and evaporated to yield 610 mg (98%) of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (9) as white solids. MP: 211° C.; 1H-NMR (DMSO-d6): δ 2.93 (m, 4H), 3.57 (m, 4H), 5.53 (s, 2H), 7.20-7.27 (m, 5H), 7.34 (dd, J=4.8, 8.0 Hz, 1H), 8.26 (dd, J=1.6, 8.0 Hz, 1H), 8.65 (dd, J=1.6, 8.0 Hz, 1H); EIMS: 296 (M+1). EIMS: 346 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24]C)=[C:17]([CH:26]([CH3:28])[CH3:27])[CH:16]=1)=O)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:30][C:10]1[S:9][C:8]2[CH:1]=[C:15]3[C:20](=[C:13]([C:15]4[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:24])=[C:17]([CH:26]([CH3:27])[CH3:28])[CH:16]=4)[C:12]=2[C:11]=1[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16]3
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1sc2cc3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C

Procedure:
Using (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (4.3 g, 10.1 mmol), boron tribromide (3.1 mL, 32.4 mmol), and methylene chloride (60 mL) the title compound was prepared according to the procedure in Example 2, step 2 to give 1.2 g (30%) as a yellow foam; NMR (DMSO-d6) δ 8.42 (s, 1 H), 8.24 (s, 1 H), 7.94 (d, 1 H), 7.48-7.32 (m, 3 H), 6.90 (s, 2 H), 3.45-3.35 (m, 2 H), 2.38 (s, 3 H), 1.57 (s, 3 H), 1.15 (d, 12 H). MS(-ESI), [M-H] 387.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])[CH3:2].CO[C:14]1C(OC)=C[C:17]2[NH:18][C:19](CCCNC)=N[C:16]=2[CH:15]=1>>[CH2:1]([O:3][C:4]1[C:5]2[N:11]=[C:14]([CH2:15][CH2:16][CH2:17][NH:18][CH3:19])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(N)c1N
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CCOc1cccc2[nH]c(CCCNC)nc12

Procedure:
Prepared from 3-ethoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][C:11]1[CH:30]=[C:29]([N:31]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[N:32]2)[CH:28]=[CH:27][C:12]=1[O:13][CH:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl>C(OCC)(=O)C.C1COCC1>[CH3:10][C:11]1[CH:30]=[C:29]([N:31]2[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[N:32]2)[CH:28]=[CH:27][C:12]=1[O:13][CH:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:23])=[CH:25][CH:26]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)CCN
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 72 h
Yield: 53.1 %

Procedure:
To a mixture of ethyl 3-aminopropanoate hydrochloride (46 mg, 0.3 mmol), 4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzoic acid (84 mg, 0.2 mmol), HOBt hydrate (34 mg, 0.22 mmol), and DIPEA (0.133 ml, 0.8 mmol), and THF (3 ml) was added EDCl hydrochloride (62 mg, 0.32 mmol) in one portion at the ambient temperature and the reaction was stirred at the same temperature for three days. The mixture was diluted with 3 ml of ethyl acetate, 3 ml of heptanes, and washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 10% to 50% of ethyl acetate in heptane gave the target product as a colorless gum (55 mg, 53%). 1H NMR (500 MHz, CDCl3) δ 8.01 (s, 1H), 7.84 (s, 1H), 7.75 (d, J=8.29 Hz, 2H), 7.45 (d, J=2.68 Hz, 1H), 7.40 (d, J=8.05 Hz, 2H), 7.20 (dd, J=2.68, 8.78 Hz, 1H), 6.81-6.87 (m, 1H), 6.61 (d, J=8.78 Hz, 1H), 5.21 (dd, J=5.12, 7.56 Hz, 1H), 4.18 (q, J=7.16 Hz, 2H), 3.73 (q, J=6.02 Hz, 2H), 2.64 (t, J=5.85 Hz, 2H), 2.40 (s, 3H), 2.00-2.10 (m, 1H), 1.81-1.90 (m, 1H), 1.52-1.61 (m, 1H), 1.44-1.51 (m, 1H), 1.28 (t, J=7.20 Hz, 3H), 0.98 (t, J=7.44 Hz, 3H). MS (M+1): 5182.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:11][OH:12])[CH3:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:12][N:11]=[C:9]([C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(=NO)c1c(O)cccc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)ON=C(C)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To 1-(2,6-dihydroxyphenyl)ethanone oxime (Intermediate 8, 588 mg), acetic anhydride (1.97 ml, 20.8 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. After the removal of the volatiles, water was added and the solid obtained was filtered and dried under high vacuum affording 437 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:39]1[CH:44]=[CH:43][CH2:42][CH2:41][CH2:40]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:21])[CH2:19][O:20][CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44][O:39]4)[CH2:16][CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(CO)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C(COC1CCCCO1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (730 mg) was reacted with 17 mg para-toluenesulfonic acid and 245 μL of 3,4-dihydro-2H-pyran in ethyl acetate overnight to yield 1-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)ethanone.