Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.ClC1C=CC(CBr)=NC=1.[Cl:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: BrCc1cccnc1
Agent: Clc1ccc(CBr)nc1
Product: O=[N+]([O-])c1ccc(OCc2cccnc2)c(Cl)c1

Procedure:
In like manner, each of 3-bromomethylpyridine and 5-chloro-2-bromomethylpyridine is reacted with 2-chloro-4-nitrophenol to give 3-(2-chloro-4-nitrophenoxy)methylpyridine and 5-chloro-2-(2-4-nitrophenoxy)methylpyridine, respectively, each of which is reduced. The resulting 3-(2-chloro-4-aminophenoxy)methylpyridine and 5-chloro-2-(2-chloro-4-aminophenoxy)methylpyridine is each reacted with 3,4,5,6-tetrahydrophthalic anhydride to yield, respectively, N-3-chloro-4-(3-pyridylmethoxy)phenyl-3,4,5,6-tetrahydrophthalimide and N-3-chloro-4-[2-(5-chloropyridyl)methoxy]phenyl-3,4,5,6-tetrahydrophthalmide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>CN(C=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([N:19]1[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)[CH2:21][CH2:20]1)(=[O:33])=[O:34]
Reactant: O=C(CN1CCN(c2ccncc2)CC1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 22 %

Procedure:
Using an analogous procedure to that described in Example 2 except that DMF was used in place of methylene chloride as the reaction solvent, 1-{2-[4-(4-pyridyl)piperazin-1-yl]acetyl}piperazine was reacted with 2-naphthylsulphonyl chloride to give 1-(2-naphthylsulphonyl)-4-{2-[4-(4-pyridyl)piperazin-1-yl]acetyl}-piperazine in 22% yield;
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:10])#[N:2].[OH:30]S(O)(=O)=O>>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:7]2[S:6][N:5]=[C:4]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[C:3]=2[C:1]([NH2:2])=[O:30])=[O:10])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 45 °C
Yield: 100 %

Procedure:
A mixture of 1-(4-cyano-3-(4-nitrophenyl)isothiazol-5-yl)-3-(3-morpholinopropyl)urea (113 mg, 0.27 mmol) in 3.5 mL conc. H2SO4 was heated at 45° C. After 1.5 hours the reaction was quenched into 100 mL ice water giving a white gel-like solid. The aqueous solution was made basic using Na2CO3 and then extracted with EtOAc, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated giving the title compound as a light beige solid (118 mg, 100%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7](=[O:8])[C:2]=1[C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)[CH3:28]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(CC)c(-c2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
To a solution of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 4-methoxyphenylboronic acid (0.26 g) in 1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.48 g, 91%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7](OS(C)(=O)=O)[NH:6][C:5]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[N:22][C:4]1=2)[CH3:2].Cl.[O:26]([NH2:28])[CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[N:28][O:26][CH3:27])[NH:6][C:5]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[N:22][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncccc2C(OS(C)(=O)=O)Nc2c(C)cc(C)nc21
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1c2ncccc2C(=NOC)Nc2c(C)cc(C)nc21
Yield: 31.4 %

Procedure:
A solution of 5,11-dihydro-11-ethyl-6-methanesulfonyloxy-2,4-dimethyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.3 g, 0.75 mmol), methoxylamine hydrochloride (0.15 g, 1.8 mmol) and diisopropylethylamine (0.3 g, 2 mmol) in methylene chloride was stirred at room temperature for 4 days. The organic phase was washed with water, dried, and filtered. The solution was concentrated in vacuo and the residue was chromatographed over silica with 20% ethyl acetate/hexane to give 0.07 g of the title compound, m.p. 164°-166° C.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20]>CN(C)C=O.O>[I:1][C:2]1[N:3]([CH:19]([CH3:21])[CH3:20])[N:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c[nH]nc1I
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C(C)C)c1I
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a solution of ethyl 3-iodopyrazole-4-carboxylate (1.58 g, 5.94 mmol, Truong; et al. Bioorg. Med. Chem. Lett., 19, 4920 (2009)) in 20 mL N,N-dimethylformamide was added cesium carbonate (3.87 g, 11.9 mmol) and 2-iodopropane (0.89 mL, 8.90 mmol). The mixture was stirred 2 hours at 60° C. and then cooled to ambient temperature. The reaction mixture was diluted with 150 mL water and extracted with 2×100 mL diethyl ether. The combined organics were washed with 50 mL brine, dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by flash chromatography (7-60% ethyl acetate/heptane gradient, 50 g silica) to yield 340 mg of ethyl 5-iodo-1-isopropyl-1H-pyrazole-4-carboxylate as a clear oil which crystallized on standing and 740 mg of ethyl 3-iodo-1-isopropyl-1H-pyrazole-4-carboxylate as a clear oil. Ethyl 5-iodo-1-isopropyl-1H-pyrazole-4-carboxylate: +APCI (M+H) 309.0; 1H NMR (400 MHz, CDCl3, δ): 8.05 (s, 1H) 4.82 (spt, J=6.6 Hz, 1H) 4.33 (q, J=7.2 Hz, 2H) 1.50 (d, J=6.6 Hz, 6H) 1.37 (t, J=7.1 Hz, 3H). Ethyl 3-iodo-1-isopropyl-1H-pyrazole-4-carboxylate: +APCI (M+H) 309.0; 1H NMR (400 MHz, CDCl3, δ): 7.84 (s, 1H) 4.52 (spt, J=6.7 Hz, 1H) 4.32 (q, J=7.1 Hz, 2H) 1.52 (d, J=6.6 Hz, 6H) 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:50]I)[CH2:48]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1.CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH3:48])[CH3:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(CI)(CI)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3OC(C)(C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 120 °C
Yield: 147.7 %

Procedure:
To a solution of (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-bis-iodomethyl-tetrahydro-pyran (100 mg, 0.10 mmole) in toluene (2 mL), tristrimethylsilllylsilane (0.1 mL), AIBN (12 mg) was added and heated at 120° C. for 24 hour in a sealed tube. The reaction mixture was diluted with methanol and evaporated, washed with water (10 mL) and extracted with Ethyl acetate (3×15 mL). The crude product obtained after the removal of solvent to furnish 100 mg of crude (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2,2-dimethyl-tetrahydro-pyran.
Reaction SMILES: [F:1][C:2]1[C:3]([O:8][CH2:9][C@@H:10]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH3:11])=[N:4][O:5][C:6]=1[CH3:7].BrN1C(=[O:29])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.FC(C1C=CC=CC=1)(F)F>O>[F:1][C:2]1[C:3]([O:8][CH2:9][C@@H:10]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH3:11])=[N:4][O:5][C:6]=1[CH2:7][OH:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1onc(OC[C@H](C)N2C(=O)c3ccccc3C2=O)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: FC(F)(F)c1ccccc1
Product: C[C@@H](COc1noc(CO)c1F)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 2-{(1S)-2-[(4-fluoro-5-methylisoxazol-3-yl)oxy]-1-methylethyl}-1H-isoindole-1,3(2H)-dione (383 mg), N-bromosuccinimide (269 mg), 2,2′-azobis(2-methylpropionitrile) (20.7 mg) and (trifluoromethyl)benzene (5 mL) was stirred at 100° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). The obtained residue was mixed with 1-methylpyrrolidin-2-one (5 mL) and water (10 mL), and the mixture was stirred at 105° C. overnight. The reaction mixture was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (118 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[C:7]([CH3:25])=[C:8]([CH3:24])[C:9]([CH:12]3[CH2:17][C:16](=[O:18])[C:15]([C:19](=O)[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]3)=[C:10]([CH3:11])[C:4]=2[O:3]1.C([O-])(=O)C.[Na+].Cl.[CH2:33]([O:35][NH2:36])[CH3:34]>C(O)C>[CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[C:7]([CH3:25])=[C:8]([CH3:24])[C:9]([CH:12]3[CH2:17][C:16](=[O:18])[C:15]([C:19](=[N:36][O:35][CH2:33][CH3:34])[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]3)=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(C)c3c(c2C)OC(C)(C)C3)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c(C)c3c(c2C)OC(C)(C)C3)CC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
To a solution 0.3 g of the 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-2-propionyl-3-hydroxycyclohex-2-en-1-one in 10 ml of ethanol was added 0.14 g of sodium acetate and 0.09 g of ethoxyamine hydrochloric acid. After stirring at room temperature for 20 hours, the reaction mixture was quenched with 20 ml water and extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 0.28 g of 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-2-[1-(ethoxyimino)propyl]-3-hydroxycyclohex-2-en-1-one as yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:8][CH2:7]1)C.[ClH:31].O>C(O)C>[ClH:31].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:30])=[O:3])[CH2:11][CH2:10]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)CC1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of the above ester (0.6 g, 0.0015 mol) in ethanol (5 ml) 4 N sodium hydroxide (0.8 ml) was added and the mixture was stirred at room temperature for 2.5 h and then left in a freezer overnight. The cold reaction mixture was allowed to warm to room temperature during 1 h, and 4 N hydrochloric acid (1.2 ml) and water (10 ml) were added. The mixture was extracted with dichloromethane (2×100 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The residue was reevaporated with a mixture of acetone and isopropyl acetate and then treated with a mixture of acetone and isopropyl acetate to give a solid which was isolated and dried in vacuo. This afforded 0.33 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH:5]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O1CCCC1>[F:29][C:2]([F:1])([F:28])[CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Reaction time: 17 h

Procedure:
To a solution of ethyl(+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate (95 mg, 0.24 mmol) in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) was added 1 N aq sodium hydroxide (1.2 mL, 1.2 mmol). After 17 hours, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH 5 with 1 N aq hydrochloric acid and diluted with sat. aq sodium chloride (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoic acid. 1HNMR (400 MHz, CD3OD) δ 8.50 (br. s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.80-7.73 (m, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.40-7.32 (m, 2H), 6.95 (d, J=2.5 Hz, 1H), 4.73-4.64 (m, 1H), 2.55-2.39 (m, 1H), 2.39-2.22 (m, 1H), 2.22-2.04 (m, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:23])=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:26]#[C:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[CH3:23][C:4]1[S:3][C:2]([C:26]#[C:27][CH2:28][CH2:29][CH3:30])=[N:6][C:5]=1[CH2:7][O:8][N:9]=[C:10]([C:17]1[N:21]([CH3:22])[N:20]=[N:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1sc(Br)nc1CON=C(c1ccccc1)c1nnnn1C
Reactant: C#CCCC
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCC#Cc1nc(CON=C(c2ccccc2)c2nnnn2C)c(C)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a stirred solution of N-[(2-bromo-5-methyl-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.509 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added pentyne (0.069 g, 1.01 mmol, 2 eq.) followed by triethylamine (0.205 g, 2.03 mmol, 4 eq.), Copper Iodide (0.014 g, 0.076 mmol, 0.15 eq.) and Tetrakis(triphenylphosphine)palladium (0.029 g, 0.025 mmol, 0.05 eq.). The reaction was stirred for 20 hrs at room temperature for complete conversion. The reaction was diluted with EtOAc (50 ml), filtered through “Chem Elut” cartridge, washed with fresh EtOAc (2×20 ml) and the filtrate was evaporated. The residue was chromatographed on silica gel to give N-{[5-methyl-2-(pent-1-yn-1-yl)-1,3-thiazol-4-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.141 g, 69% yield) as a brown gum.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH2:17][OH:18])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:2]1([C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH2:17][O:18]1
Reactant: N#Cc1cccc(C(O)c2ccncc2CO)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1cccc(C2OCc3cnccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[Hydroxy-(3-hydroxymethyl-pyridin-4-yl)-methyl]-benzonitrile (100 mg, 0.42 mmol) and tosyl chloride (96 mg, 0.50 mmol) were dissolved in dichloromethane (5 mL) and then the reaction mixture was treated with triethylamine (0.09 mL, 0.65 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with ethyl acetate and washed with 5% sodium bicarbonate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by chromatography of silica gel with 30% ethyl acetate in hexane to yield 3-(1,3-dihydro-furo[3,4-c]pyridin-1-yl)-benzonitrile as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1.[CH3:25][O:26][N:27]=[C:28]1[C:32]2([CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)[CH2:31][NH:30][CH2:29]1.C(#N)C>C(N(CC)CC)C>[C:39]([O:38][C:36]([N:34]1[CH2:35][C:32]2([C:28](=[N:27][O:26][CH3:25])[CH2:29][N:30]([C:16]3[CH:17]=[C:18]4[C:13]([C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:20])[CH2:31]2)[CH2:33]1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)CC12CN(C(=O)OC(C)(C)C)C2
Reaction time: 4 h
Yield: 67.8 %

Procedure:
1-(2,4-difluorophenyl)-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 120 mg of t-butyl 8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate and 400 mg of AmberliteR IRA-420 were added to 10 ml of acetonitrile and thereto 0.5 ml of triethylamine was added by dropping. The resulting mixture was refluxed for 48 hours and thus precipitated solid was filtered off. To the filtrate 5 ml of ethylether was added and the resulting mixture was stirred for 4 hours. The precipitated solid was filtered and dried to give 110 mg of the titled compound (yield: 67.8%).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([NH2:16])[C:4]=2[N:3]=1.[CH3:17][O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[CH2:21][C@H:22]1[CH2:27]N[CH2:25][CH2:24][NH:23]1>>[CH3:17][O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[CH2:21][C@@H:22]1[NH:23][CH2:24][CH2:25][N:16]([C:5]2[C:4]3[N:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:27]1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: COc1ccccc1C[C@H]1CNCCN1
Product: COc1ccccc1C[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)nc32)CCN1
Yield: 35 %

Procedure:
By a similar method to the method of Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.687 g, 2.98 mmol) and (S)-2-(2-methoxy-benzyl)-piperazine (0.615 g, 2.98 mmol) gives 0.437 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=420 (M+1); Analysis for C23H25N5OS(0.5 H2O): calcd: C, 64.46; H, 6.12; N, 16.34; found: C, 64.20; H, 5.77; N, 16.14.
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([CH2:43][O:44][C:45]2[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=[CH:49][C:50]=2[O:51][CH3:52])[CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:47]1[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:46]=1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC1CC1
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OCC1CC1
Yield: 64.9 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 0.40 g (1.1 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 0.57 g (1.9 mmol) of 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 2-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 0.34 g of the title compound was obtained as a pale yellowish solid. (Yield: 67%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[OH:17])=[O:9])=[CH:4][CH:3]=1.[Br:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22]Br.C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[Br:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[O:9])=[C:11]([OH:17])[CH:12]=1
Reactant: BrC/C=C/CBr
Reactant: O=C(c1ccc(Br)cc1)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)c1ccc(OC/C=C/CBr)cc1O

Procedure:
A solution of 0.88 g of (4-bromo-phenyl)-(2,4-dihydroxy-phenyl)-methanone and (E)-1,4-dibromo-2-butene in 7.5 ml of DMF and 0.56 g of lithium carbonate is stirred at 40° C. for 48 hrs. After working up with methylene chloride/0.5M hydrochloric acid and purification over silica gel with hexane/ethyl acetate (9:1) there is obtained 0.14 g of (E)-[4-(4-bromo-but-2-enyloxy)-2-hydroxy-phenyl]-(4-bromo-phenyl)-methanone which, with N-allyl-methyl-amine analogously to Example 3c), gives (E)-[4-(4-allyl-methyl-amino-but-2-enyloxy)-2-hydroxy-phenyl]-(4-bromo-phenyl)-methanone which is converted into the hydrochloride, MS: m/e 416 (M+H+, 1Br).