Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([NH2:28])=[CH:21]2>ClCCl>[N:28]([C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([CH3:17])=[CH:27][CH:26]=2)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ccc2cnc(N)cc2c1
Solvent: ClCCl
Product: Cc1ccc2cnc(N=C=S)cc2c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (220 mg, 0.948 mmol) in dichloromethane (10 mL) at ambient temperature was added 6-methylisoquinolin-3-amine (125 mg, 0.790 mmol). The reaction mixture was placed into a preheated oil-bath and stirred at 40° C. for 18 h, then removed from the oil-bath and cooled to ambient temperature. The mixture was concentrated and the crude material was purified by silica gel chromatography (5-30% ethyl acetate in hexanes) to afford 3-isothiocyanato-6-methylisoquinoline (75 mg, 0.375 mmol, 47.4% yield), as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (s, 1H), 7.88 (d, J=8.24 Hz, 1H), 7.56 (s, 1H), 7.46 (dd, J=8.24, 1.53 Hz, 1H), 7.39 (s, 1H) 2.57 (s, 3H). MS (LC/MS) R.T.=1.92; [M+H]+=201.13.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][N:11]([C:37](=[O:39])[CH3:38])[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29]CC[Si](C)(C)C)=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[C:37]([N:11]([CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([OH:29])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])[CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])(=[O:39])[CH3:38]
Reactant: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(C)=O)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COc1c(C)c2c(c(O)c1CC=C(C)CN(CCP(=O)(O)O)C(C)=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of [2-(acetyl-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}-amino)-ethyl]-phosphonic acid diethyl ester (14 mg, 0.024 mmol) in acetonitrile (0.5 mL) was added TMSBr (31 μL, 0.24 mmol) and 2,6-lutidine (28 μL, 0.24 mmol). The solution was stirred at room temperature for 1 hour. The reaction was quenched by addition of methanol and aqueous 1N HCl. The product was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 5.4 mg of the product (53%) as a white solid. The NMR data of this compound shows two rotamers. 1H NMR (300 MHz, CDCl3) δ 1.67 and 1.73 (s, 3H), 1.85-2.12 (m, 5H), 2.13 (s, 3H), 3.30-3.61 (m, 4H), 3.75 (s, 3H), 3.76 (br s, 2H), 5.17 (s, 2H), 5.31 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 27.5 and 28.8 ppm; MS (m/z) 428.2 [M+H]+, 450.2 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[OH-].[K+].CS(C)=O.[Cl:26][CH:27]=[CH:28][CH:29](Cl)C>O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([O:17][CH2:29][CH:28]=[CH:27][Cl:26])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CC(Cl)C=CCl
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Cl)c(OCC=CCl)cc1-n1nc2c(c1Cl)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3-Chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (1 g) was suspended in a solution of potassium hydroxide (0.84 g) in water (8 ml). Dimethylsulfoxide (21 ml) was added to the suspension to make a uniform solution. To the resultant solution, 1,3-dichloro-1-butene (1.26 g) was added, and the mixture was stirred at 100° C. for 4 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel thin chromatography using a mixture of ether and hexane (1:3) as an eluent to give 3-chloro-2-[4-chloro-2-fluoro-5-(3-chloro-2-propenyloxy)phenyl]-4,5,6,7-tetrahydro-2H-indazole (0.65 g) (Compound No. 2). M.P., 68.5°-70.5° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][CH:18]([CH2:20][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:21]([OH:26])([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][CH:18]([CH3:19])[CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccsc1-c1cccs1
Reactant: CC(C)CC(=O)CC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)CC(O)(CC(C)C)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 18.1 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (3.00 g, 12 mmol) in dry diethylether (100 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 7.50 mL, 12 mmol) in dry diethylether (100 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled 2,6-dimethyl-4-heptanone (2.17 mL, 12 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 50 mL) and water (50 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIb) as a green oil (0.67 g, 18%). 1H-NMR (CDCl3): δ=7.35 (dd, J=1.1 Hz, J=5.1 Hz, 1H), 7.22 (d, J=4.7 Hz, 1H), 7.08 (dd, J=1.1 Hz, J=3.6 Hz, 1H), 6.97 (d, J=4.7 Hz, 1H), 6.92 (dd, J=3.6 Hz, J=5.1 Hz, 1H), 1.85 (d, J=5.8 Hz, 4H), 1.08-0.78 (m, 2H), 0.50 (d, J=7.1 Hz, 12H). 13C-NMR (CDCl3): δ=146.24, 136.18, 130.09, 129.31, 128.92, 127.85, 127.35, 125.48, 79.83, 53.28, 25.10, 24.93.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: O=C(N1CCNCC1)C(F)(F)F
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
Ethyl trifluoroacetate (34.54 mL, 287.33 mmol) was added to a suspension of piperazine (25.0 g, 287.33 mmol) in THF (250 mL) at room temperature under nitrogen and stirred for 30 min and concentrated to remove solvent. The oily residue was taken up in ether and filtered and the filter cake was washed with ether. The filtrate was concentrated to give a clear oil (24.37 g, 47%). LC-MS [M+H]+=183.1, RT=1.07 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][C:4]#[CH:5].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:10]=1[C:11]#[N:12]>C(N(CC)CC)C.[Cu]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>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:5]#[C:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1Br
Reactant: C#CC[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CC#Cc1cccc(N)c1C#N
Yield: 125.2 %

Procedure:
To a stirred solution of trimethyl(prop-2-ynyl)silane (1.12 g, 10 mmol), 2-amino-6-bromobenzonitrile (Klaubert, D. H.; Sellstedt, J. H.; Guinosso, C. J.; Capetola, R. J.; Bell, S. C. J. Med. Chem. 1981, 24, 742) (1.0 g, 5 mmol), CuI (0.01 equiv.) in triethylamine (50 mL) was added Pd(PPh3)4 (0.1 equiv.) at room temperature under nitrogen. The reaction mixture was then refluxed under nitrogen overnight. The solvent was evaporated, and the residue was titrated with EtOAc/water. The organic layer was separated, were washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 15% EtOAc in hexanes to give the title compound (1.43 g, 63%) as a as a liquid. MS 229 (MH+).
Reaction SMILES: [N:1]1([C:8]2[C:13]([CH2:14][NH:15][C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])[CH:19]=[N:18][N:17]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C)C=O>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:19]=[N:18][N:17]=[C:16]1[NH:15][CH2:14][C:13]1[C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=O)CBr
Reactant: Clc1cccc(-n2cnnc2NCc2cccnc2N2CCCNCC2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN1CCCN(c2ncccc2CNc2nncn2-c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a solution of Example 113A (250 mg, 0.597 mmol) in dimethylformamide (7 ml) was added potassium carbonate (165 mg, 1.194 mmol) and bromoacetamide (124 mg, 0.896 mmol). The reaction mixture was stirred at room temperature for 16 hours then poured onto ice water. The aqueous mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) to give the title compound (109 mg). MS (ESI+) m/z 475.6 (M+H)+; Rt=1.41. 1H NMR (DMSO-d6) δ 8,170 (s, 1H); 8,054 (d,1H); 7,832 (d,1H); 7,579(m,3H); 7,251 (s,1H); 7,112 (s,1H); 6,832 (dd,1H); 6,545 (t,1H); 4,338 (d, 2H); 3,423 (m,4H); 3,011 (s,2H); 2,772 (m,2H); 2,710 (m,2H); 1,856(m,2H).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:16](=O)[CH2:17]Br)=[C:13]([CH3:15])[N:14]=2)=[N:5]1)(=O)C.Br.C(N1C=CC(NC2SC(C(=O)CBr)=C(C)N=2)=N1)(=O)C.[C:40]([CH2:42][C:43]([NH2:45])=[S:44])#[N:41].CCOCC>CCO>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:6]2[CH:7]=[CH:8][NH:4][N:5]=2)[S:11][C:12]=1[C:16]1[N:45]=[C:43]([CH2:42][C:40]#[N:41])[S:44][CH:17]=1
Reactant: CC(=O)n1ccc(Nc2nc(C)c(C(=O)CBr)s2)n1
Reactant: N#CCC(N)=S
Agent: Br
Solvent: CCOCC
Solvent: CCO
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1csc(CC#N)n1
Temperature: 80 °C
Yield: 62 %

Procedure:
To a solution of 1-{2-[(1-acetyl-1H-pyrazol-3-yl)amino]-4-methyl-1,3-thiazol-5-yl}-2-bromoethanone, (Intermediate 4) (150 mg; 0.35 mmol; 1 eq.) in EtOH (5 ml) is added 2-cyanothioacetamide (35.4 mg; 0.35 mmol; 1 eq.). The resulting mixture is heated 10 min at 60° C., 10 min at 70° C. and 10 min at 80° C. under microwave action. As the reaction is complete, Et2O is added. The resulting precipitate is filtered and washed with Et2O, affording Compound (55) as beige solid (84.1 mg; 62%). 1H NMR (DMSO-d6) δ 2.46 (s, 3H), 4.61 (s, 2H), 6.01 (d, J=2 Hz, 1H), 7.65 (s, 1H), 7.72 (d, J=2 Hz, 1H), 11.26 (br s, 1H). M− (ESI): 301.13; M+ (ESI): 303.14. HPLC (method A), Rt: 1.84 min (purity: 92.7%).
Reaction SMILES: CN(C)[CH:3]=[O:4].Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:8]=1.C([O-])=O.[Na+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:19][C:18]1[O:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:4]
Reactant: Cc1ccc(-c2nc(Cc3cccc(Br)c3)c(C)o2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc(Cc3cccc(C=O)c3)c(C)o2)cc1
Temperature: 110 °C
Reaction time: 9 h

Procedure:
N,N-Dimethylformamide (30 ml) was added to 9.48 g of 1-bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene, 2.83 g of sodium formate and 0.97 g of bis(triphenylphosphine)palladium (II) dichloride, and the mixture was stirred for 9 hours at 110° C. under bubbling carbon monoxide. To the reaction solution was added water, and extracted with ethyl acetate, filtered to remove insolubles, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 3.58 g of the objective compound as colorless crystals. M.p. 98–99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH2:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18](=[O:19])[C:17]3[C:12](=[C:13]([C:20]([NH:22][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:23])[CH:10]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(COc2cn(C)c3c(C(N)=O)cccc3c2=O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c3c(C(=O)NCCN4CCCC4)cccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.4 %

Procedure:
To a solution of 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-8-carboxamide (1.09 g, 3.22 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (0.193 g, 4.83 mmol) and the mixture was stirred at room temperature for 1 h. Then the mixture of 1-(2-chloroethyl)pyrrolidine, Hydrochloride (0.548 g, 3.22 mmol) and triethylamine (0.494 mL, 3.54 mmol) in N,N-dimethylformamide (30.0 mL) was added in one portion. The resulting mixture was stirred at 50° C. for 3.5 h. Extra NaH (0.15 eq) was added, the mixture was stirred at 50° C. for another 0.5 h. The solvent was removed in vacuo, and the residue was partitioned between water (50 mL) and dichloromethane (50 mL), and extracted with DCM for three times. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The light yellow residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with [CH2Cl2/MeOH/NH4OH (80:20:2)]/CH2Cl2 (0-50%) to afford 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-8-carboxamide (0.3 g, 0.689 mmol, 21.38% yield) as a light brown oil. LCMS: (M+H)+: 436.3.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([OH:14])=O)=[CH:8][NH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:14])=[CH:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)c[nH]c2n1
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)c[nH]c2n1

Procedure:
1,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (4 g) and N,N'-carbonyldiimidazole (3.5 g) in dimethylformamide (40 ml) were heated at 80° for 6 hours. 5-Amino-1H-tetrazole (2.5 g) was added and the mixture was stirred and heated at 80° for 1.5 hours. The solid was collected and dissolved in aqueous sodium hydroxide. The solution was acidified with glacial acetic acid and the solid was collected and dried. It had m.p. 344°-345.5°, (47%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#CCCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 7.2 mmol (1.85 g) of 3', 4'-dichloro-5-cyanovalerophenone (melting point 49°-51° C), 7.2 mmol (1.08 g) of 2-aminooxyethylamine dihydrochloride, 1.0 ml of pyridine and 7 ml of absolute ethanol was refluxed for 3 hours. The reaction mixture was then further processed in a manner identical to that described in Example 1. After crystallization from an ethanol-ether mixture the above entitled compound was obtained with a melting point of 134°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(O)(=O)C.[N:17]([O-])=[O:18].[Na+]>O>[N:17]([C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12])=[O:18]
Reactant: O=N[O-]
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Nc1c(O)ccc2cc(Br)ccc12
Reaction time: 23 h

Procedure:
76.2 g (0.342 mol) of 6-bromo-β-naphthol were suspended in 385 ml of 90%-strength acetic acid and nitrosated for two hours at 4° C. with 28.5 g (0.413 mol) of sodium nitrite in 230 ml of water, and stirring was then continued for 23 h at room temperature. The suspension was then made up to twice its volume by filling up with water and the product formed was filtered off by suction. After drying, 83.8 g (97.3%) of crude 1-nitroso-6-bromo-β-naphthol whose purity is adequate for the further reaction was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[CH2:19](C1C=CC(F)=C(B(O)O)C=1)[CH3:20]>>[CH2:19]([C:7]1[CH:6]=[CH:5][C:4]([F:10])=[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[CH:2]=1)[CH3:20]
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: CCc1ccc(F)c(B(O)O)c1
Product: CCc1ccc(F)c(-c2nc(C(=O)O)cs2)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (5-ethyl-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1.[NH2:19][CH2:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:19][CH2:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)[N:3]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: Cc1coc(-c2nc(N)nc(S(C)=O)c2C#N)c1
Solvent: COCCOC
Product: Cc1coc(-c2nc(N)nc(NCc3ncc(C(F)(F)F)cc3Cl)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-furan-2-yl)-pyrimidine-5-carbonitrile and 2-aminomethyl-3-chloro-5-(trifluoromethyl)pyridine in DME. ES-MS m/e (%): 411 (M{37Cl}+H+, 35), 409 (M{35Cl}+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=O)=[CH:16][CH:15]=1)#[N:13].N>P(Cl)(Cl)(Cl)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1

Procedure:
3.1 g (0.02 mol) of 4-nitro-o-phenylenediamine and 3.7 g (0.023 mol) of 4-cyanophenylacetic acid are refluxed for 2 hours in 30 ml of phosphorus oxychloride. After cooling the mixture is neutralised with concentrated ammonia and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with methylene chloride/methanol (50:1). The desired fractions are concentrated by evaporation, the residue is triturated with ethyl acetate/ether, suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][OH:13]>>[OH:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([O:13][CH3:12])=[O:5]
Reactant: O=C(Cl)c1c(I)ccnc1O
Reactant: CO
Product: COC(=O)c1c(I)ccnc1O

Procedure:
Thionyl chloride (3.81 ml, 52.2 mmol) was added to a suspension of 2-hydroxy-4-iodonicotinic acid (3.46 g, 13.1 mmol) in dichloromethane (12 mL) in a pressure vessel at room temperature. The reaction mixture was then heated at 75° C. for 3 h. An aliquot was taken and hydrolyzed with methanol. LCMS analysis showed the derived methyl ester seen as major compound. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give 2-hydroxy-4-iodonicotinoyl chloride. 2-hydroxy-4-iodonicotinoyl chloride in MeOH (100 mL) was stirred at room temperature for 2 h. Concentration in vacuo of the reaction mixture afforded methyl 2-hydroxy-4-iodonicotinate (3.64 g, 13.1 mmol, quantitative yield). MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C7H61NO3: 279.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12

Procedure:
6-hydroxy-1-napthoic acid (3.2 g, 17 mmol) was reacted with 2,4-dichloropyridine (2.5 g, 17 mmol) and Cs2CO3 (16.6 g, 51 mmol) under the conditions of Example 421 step a to furnish the title compound as a brown solid. MS (ESI, pos. ion) m/z: 300.4 (M+1). Mass Calc'd for C16H10ClNO3: 299.708.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18]CC2C=CC=CC=2)=[C:13]([Cl:26])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[H][H]>[Ni].CO>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([Cl:26])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1cc(C)c(OCc2ccccc2)c(Cl)c1)NC(C)=O
Agent: [Ni]
Solvent: CO
Product: COC(=O)C(Cc1cc(C)c(O)c(Cl)c1)NC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 7.40 g (19.8 mmol) methyl 2-acetylamino-3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-acrylate, 300 mL MeOH and 800 mg Raney nickel was shaken at RT and 3000 hPa hydrogen pressure for 7 h. After the reaction had ended the catalyst was filtered off and the remainder was evaporated down i.vac.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH2:18])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.C(N(CC)CC)C.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: O=C(O)c1ccccc1
Reactant: NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.7 %

Procedure:
A mixture of 8-bromo-5-aminomethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione hydrochloride (134 mg, 0.405 mmol), triethyl amine (124 μL, 0.892 mmol), benzoic acid (54 mg, 0.446 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (69 mg, 0.446 mmol) and N-hydroxybenzotriazole (68 mg, 0.446 mmol) in DMF (6 mL) was stirred for 20 h at room temperature and 0.1N hydrochloric acid (20 mL) was added. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 87 mg of the title compound (52%): mp 180.5°~182° C.; 1H NMR (270 MHz, DMSO-d6) δ11.86 (s, 1H), 8.56 (t, 1H, J=6 Hz), 7.34~7.54 (m, 5H), 7.12 (s, 1H), 7.17 (s, 2H), 4.96~5.06 (m, 1H), 3.90~4.00 (m, 1H), 3.72~3.82 (m, 1H), 3.43 (dd, 1H, J=17, 10 Hz), 3.19 (dd, 1H, J=17, 3 Hz).