Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl.[NH2:30]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([C:27]#[N:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: NO
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.03 g), hydroxylamine hydrochloride (417 mg), sodium acetate (861.4 mg) in acetic acid (15 ml) was stirred at room temperature for 30 minutes. Acetic anhydride (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 90 minutes and further refluxed for an hour. The acetic acid was distilled off under reduced pressure, and to the resultant residue was added water, and the aqueous mixture was adjusted to pH 7 to 8 with sodium bicarbonate and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give an oil. This oil was subjected to column chromatography on silica gel with an eluent [a mixture of 4 parts of benzene and one part of ethyl acetate by volume]. The resultant oily substance (1.7 g) was crystallized by treating with a mixture of diethyl ether and n-hexane. g These crystals (1.5 g) were recrystallized from a mixture of diethyl ether and n-hexane to give pure crystals (1.23 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate, mp 126° to 127.5° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].P(=O)([O-])O[C:26](CC)(CC)[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[H-].[Na+].[N+](C1C=CC(C=CC=C)=CC=1)([O-])=O>CN(C)C=O.C(O)(=O)C.O.ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]([CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=CC=O)cc1
Agent: C=CC=Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCN(CCOC(C)=O)c1ccc(C=CC=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude reaction product of the previous step, viz. about 5 g of 4-di(2-acetoxyethyl)amino cinnamaldehyde in 125 ml of dimethyl formamide (DMF) were added 6 g of diethyl-4-nitro-benzyl phosphonate, prepared as prescribed by D. H. Wadsworth et al. in the Journal of Organic Chemistry, Vol. 30 (1965), p. 680 ff and, in small successive portions, 1.2 g of sodium hydride in the form of a 60%-dispersion in mineral oil, supplied by Jansses Chimica of Beerse, Belgium. The reaction mixture was stirred for 1 hour at room temperature and then poured, with vigorous stirring at 0° C., into a mixture of 400 ml of dichloromethane, 200 ml of water, and 20 ml of acetic acid. The organic layer was separated, washed twice with a saturated solution of sodium chloride, dried on magnesium sulphate, and concentrated by evaporation to a small volume. The residue was dissolved in 125 ml of dimethyl formamide (DMF), to which was added a solution of 8 g of sodium hydroxide in 25 ml of water. The resulting clear solution was boiled for 30 minutes with refluxing and then poured, with vigorous stirring, into 500 ml of water. The resulting precipitate was filtered off and after-washed with water until the filtrate had a pH of 7. The crude product after drying was crystallized from a mixture of 25 ml of dimethyl formamide (DMF) and 75 ml of dichloromethane. Obtained were 4.0 g of pure 1-(4-di-hydroxyethyl)aminophenyl)-4-(4-nitrophenyl)-1,3 butadiene having a melting point of 195°-198° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[Br:19])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:6]([O:5][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:20])=[CH:14][C:13]=1[Br:19])([F:11])[F:10])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CBr)cc1Br

Procedure:
A solution of [(2-bromo-4-methyl-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester (10.93 g, 30.6 mmol), N-bromosuccinimide (5.45 g, 30.6 mmol) and AIBN (100 mg) in benzene (300 mL) was refluxed for 18 h. The reaction mixture was concentrated in vacuo and redissolved in Ethyl acetate (200 mL). The solution was washed with H2O (50 mL), HCl (1 N, 50 mL), NaHCO3 (5%, 50 mL) and H2O (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (4:1) to provide a colorless oil (9.6 g, 80% purity with starting material as byproduct), which was taken on to the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])C.[CH3:18][O-:19].[Na+]>CO>[CH3:1][O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:19][CH3:18])=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5]
Reactant: CCOC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc2ccc(I)cc2c1OC
Temperature: 100 °C
Reaction time: 10 h
Yield: 89.7 %

Procedure:
To the suspension of 4-chloro-6-iodo-quinoline-3-carboxylic acid ethyl ester (14 g, 0.039 mol) in anhydrous methanol (180 mL) was added sodium methoxide (4.16 g, 0.07 mol). The mixture was heated to 100° C. under a pressure tube and stirred for 10 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (12 g, 92%) as a yellow solid. LC-MS m/e 344 (MH+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[F:9][C:4]1[CH:3]=[C:2]([C:24]2([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]2)[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a solution of 1-bromo-3,4-difluorobenzene (3.5 g, 18.13 mmol) in dry diethyl ether (25 mL) under nitrogen at −78° C., was added dropwise n-butyllithium (2.5 M in hexane, 7.25 mL, 18.13 mmol). The mixture was stirred for 30 min at −78° C. after which a solution of 1-N-boc-3-pyrrolidinone (3.35 g, 18.13 mmol) in dry diethyl ether (25 mL) was added drop wise. The mixture was stirred at −78° C. for 10 min and then brought to ambient temperature over a period of 2 h. Aqueous sodium carbonate (10%) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1) gave the title compound (2.6 g). MS m/z (rel. intensity, 70 eV) 243 (18), 198 (23), 141 (18), 127 (21), 57 (bp).
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([C:28]1[C:36]([NH:37][C@H:38]([CH3:41])[CH2:39][CH3:40])=[CH:35][C:31]([C:32](O)=[O:33])=[C:30]([CH3:42])[CH:29]=1)=[O:27].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C=O)C>[CH3:42][C:30]1[CH:29]=[C:28]([C:26]([NH2:25])=[O:27])[C:36]([NH:37][C@H:38]([CH3:41])[CH2:39][CH3:40])=[CH:35][C:31]=1[C:32]([NH2:2])=[O:33]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC[C@@H](C)Nc1cc(C(=O)O)c(C)cc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](C)Nc1cc(C(N)=O)c(C)cc1C(N)=O
Yield: 130.5 %

Procedure:
A solution of [6-(3-endo-amino-8-azabicyclo[3.2.1]oct-8-yl)pyridin-3-yl](cyclopropyl)methanone (100 mg, 0.37 mmol), HATU (210 mg, 0.55 mmol), 4-(aminocarbonyl)-2-methyl-5-{[(1R)-1-methylpropyl]amino}benzoic acid (synthesized in reagent preparation 41) (138 mg, 0.55 mmol), and diisopropylethyl-amine (256 μl, 1.47 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. Concentration and column chromatography on silica (dichloromethane:methanol 100:0 then 95:5) followed by trituration of the residue obtained on concentration of the combined pure fractions with ethyl acetate afforded N-{8-[5-(cyclopropyl-carbonyl)pyridin-2-yl]-8-azabicyclo[3.2.1]oct-3-endo-yl}-2-methyl-5-{[(1R)-1-methylpropyl]amino}benzene-1,4-dicarboxamide (179 mg, 96% yield) as a pale yellow powder. 1H NMR (400 MHz, methanol-d4): 8.84 (d, 1H), 8.11 (dd, 1H), 7.45 (s, 1H), 6.78 (d, 1H), 6.68 (s, 1H), 4.68 (br s, 2H), 4.02 (t, 2H), 3.77-3.67 (m, 1H), 3.25-3.19 (m, 2H), 2.76-2.70 (m, 1H), 2.32-2.25 (m, 7H), 2.18-2.14 (m, 2H), 1.97 (br s, 1H), 1.70-1.59 (m, 1H), 1.60-1.50 (m, 1H), 1.25-1.18 (m, 4H), 1.12-1.09 (m, 2H), 1.06-1.01 (m, 2H), 0.97 (t, 3H); MS (EI) for C29H37N5O3: 504 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][O:6][CH2:7][CH:8]=C.C(Cl)Cl.[CH3:22][OH:23]>>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][O:6][CH2:7][CH:8]([O:23][CH3:22])[N:10]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:18]
Reactant: C=CCOCC(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CO
Solvent: ClCCl
Product: COC(=O)C1COCC(OC)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A solution containing 3-allyloxy-2-tert-butoxycarbonylamino-propionic acid methyl ester (30.0 g, 116 mmol) in 550 mL of 10:1 CH2Cl2/MeOH is cooled to −78° C. and purged with ozone until a blue color persisted (45 min). The solution is then purged with N2 to remove excess ozone and treated with dimethylsulfide (35 mL). The solution is allowed to warm to room temperature overnight and the next morning concentrated in vacuo. The resulting solid is re-dissolved in 400 mL of MeOH and treated with 500 mg of p-toluenesulfonic acid. After stirring for 4 hours, the volume of solvent is reduced to about 100 mL and toluene (250 mL) is added. The solution is re-concentrate in vacuo and purified over silica gel (EtOAc/hexane) to afford 25 g (78%) of the desired product. 1H NMR (CDCl3) δ 5.21 (br s, 0.5H), 5.05 (br s, 0.5H), 4.65–4.45 (m, 2H), 3.98 (dd, J=12.8, 12.5 Hz, 1H), 3.79 (s, 3H), 3.66 (br d, J=11.3 Hz, 1H), 3.56 (dd, J=9.9, 9.9 Hz, 1H), 3.42 (s, 3H), 1.54 (s, 0.5×9H), 1.50 (s, 0.5×9H); MS 276 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:35](Cl)=[O:36]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:32]([O:31][CH3:30])[CH:33]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml of triethylamine and 241 mg of 3,4-dimethoxybenzoyl chloride are mixed together then the reaction medium is agitated at ambient temperature for approximately 5 hours. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. In this way 230 mg of expected product is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:17]=[CH:18][C:19]([C:27](OC)=[O:28])=[N:20][C:21]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25].O.[OH-].[Na+]>C(OCC)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:27][OH:28])=[N:20][C:21]=1[O:22][CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(OCC(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(F)c(-c2ccc(CO)nc2OCC(C)C)c1
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (250 mg) in diethyl ether (5.0 mL) was added a solution of methyl 5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypicolinate (594 mg) in diethyl ether (2.0 mL) at 0° C., and the mixture was stirred for 1 hr. Water and aqueous sodium hydroxide solution were added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:33][O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([NH2:43])[CH:37]=1>C1COCC1.N1C=CC=CC=1>[CH3:33][O:34][C:35](=[O:44])[C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[C:38]([NH:43][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:37]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Yield: 84.1 %

Procedure:
4-Adamantan-1-yl-phenoxy acetic acid (143.2 mg, 0.5 mmol) was dissolved in 5 ml of THF and oxalyl chloride (178.5 mg, 0.11 ml, 1.5 mmol), to which DMF was added. After reacting the mixture at room temperature for 1 hour, 3-amino-4-hydroxy-benzoic acid methyl ester (125.4 mg, 0.75 mmol) and pyridine (0.05 ml) were added thereto. The reaction mixture was reacted at room temperature. Upon completion of the reaction, the reaction mixture was extracted with ethylacetate and NaCl solution, thereafter the organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silicagel column chromatography (N-Hexane: EtOAc:MeOH=6:3:1) to give the target compound as a white solid (183.2 mg, yield: 84.1%).
Reaction SMILES: OS([O-])=O.[Na+].[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[C:18]1([NH2:25])[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(O)C>[NH:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:25]=[C:6]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
An aqueous solution of NaHSO3 (20.0 mL, 40% in water) was treated with a solution of methyl 4-formylbenzoate (2.20 g, 13.4 mmol) in ethanol (15.0 mL) and stirred at ambient temperature for 1 h. 1,2-benzenediamine (1.45 g, 13.4 mmol) was added and the solution was heated to reflux overnight. Upon cooling, the solution was poured into ice water and the resultant precipitate was collected by filtration, washed with water, and dried in vacuo to provide the title compound as a grey solid (3.40 g; 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.19 (d, J=7.8 Hz, 2H) 8.15 (d, J=7.8 Hz, 2H) 7.70 (s, 2H) 7.34 (dd, J=6.1, 3.3 Hz, 2H) 3.98 (s, 3H). MS (ES+) m/e 253 [M+H]+.
Reaction SMILES: [I-].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br-:20].[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][C:29]=1[CH3:37])([OH:23])=[O:22].[Br-].CC1SC2C=CC=CC=2[NH+]=1>C(Cl)Cl>[Br-:20].[CH3:2][N+:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:37]=[C:29]2[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]([OH:23])=[O:22])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30]2)=[CH:5][CH:4]=1
Reactant: Cc1sc2ccccc2[n+]1CCCCC(=O)O
Reactant: C[n+]1cccc2ccccc21
Agent: Cc1[nH+]c2ccccc2s1
Agent: [Br-]
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[n+]1ccc(C=C2Sc3ccccc3N2CCCCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Next, 1.36 g (5.0 mmol) of N-methylquinolinium iodide (Compound III) (FW 271.10), 7.0 mL (50 mmol) of triethylamine (FW 101.19, d=0.726), and 100 mL of methylene chloride were added to 3.24 g of mixture (crude product) containing Compound 112 (3-(4-carboxybutyl)-2-methylbenzothiazolium bromide) and 2-methylbenzothiazolium bromide. As a result, a transparent solution was obtained. This solution was stirred at 25° C. for 16 hours. Thereafter, the solvent was evaporated under reduced pressure. Acetone (200 mL) then was added to the residue and the precipitate obtained thereby was filtered, which then was washed with acetone. The residue thus obtained was dried under reduced pressure, and the red residue obtained after drying was washed with distilled water (50 mL). This further was filtered, which was washed with distilled water and then dried under reduced pressure. Thus a target substance (Compound 107) was obtained as red powder (654 mg, 1.39 mmol, 28%). This red powder was confirmed to be the target substance (Compound 107) through a comparison in 1HNMR spectrum with the reference value. Peak values from 1HNMR and 13CNMR (DMSO-d6) and the measured values of HRMS (ESI) are indicated below. Furthermore, FIG. 6 shows the 1HNMR spectrum (DMSO-d6) of Compound 107.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33]3)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C.O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:13][CH2:14][N:15]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]6[C:36](=[CH:37][CH:38]=5)[NH:35][C:34](=[O:39])[CH2:33]6)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:17]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C1Cc2cc(C(=O)c3cc(Cl)ncn3)ccc2N1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4ccc5c(c4)CC(=O)N5)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
99 mg (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 98 mg (0.40 mmol) 5-(6-chloro-pyrimidine-4-carbonyl)-1,3-dihydro-indol-2-one and 0.070 mL (0.40 mmol) DIPEA were combined in 2 mL DMF and shaken overnight at RT. The mixture was diluted with acetonitrile/water and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:13]([C:14]([NH:16][OH:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>CN(C)C=O>[CH3:20][N:21]([CH3:25])[C:22](=[O:15])[OH:23].[Br:8][C:9]1[CH:18]=[C:13]([C:14]([NH:16][OH:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)Cl
Agent: O=C(NO)c1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
81 ml of triethylamine was gradually added to a dimethylformamide solution containing 136 g of 5-bromosalicylhydroxamic acid prepared as in (2-2) above and 54 ml of N,N-dimethylcarbamyl chloride at room temperature (about 20°-30° C.), then stirred for 10 hours. This solution was poured into ice-water to collect the precipitate by filtration followed by drying. Yield: 102 g; mp. 118°-119° C. (dec.)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:12]1[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][N:21]=[CH:22][C:15]=2[N:14]=[C:13]1[CH:23](Br)[CH:24]([CH3:26])[CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>CN(C=O)C>[N:1]([CH:23]([C:13]1[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:17](=[O:18])[C:16]2[CH:19]=[CH:20][N:21]=[CH:22][C:15]=2[N:14]=1)[CH:24]([CH3:26])[CH3:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)C(Br)c1nc2cnccc2c(=O)n1Cc1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C(N=[N+]=[N-])c1nc2cnccc2c(=O)n1Cc1ccccc1
Temperature: 65 °C

Procedure:
To a solution of sodium azide (1.41 g, 21.7 mmol) in DMF (12 mL) was added 3-benzyl-2-(1-bromo-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (5.4 g, 14.50 mmol) in DMF (12 mL). The reaction was heated to 65° C. for 1.5 h, and then the solution was cooled to room temperature. The reaction contents were poured into a separatory funnel filled with ether and ice water. The organic solution was washed with brine and dried over sodium sulfate. Filtration and concentration afforded the title compound as a brown oil. 1H NMR (500 MHz, CDCl3) δ 0.61 (d, J=6.5 Hz, 3H), 1.09 (d, J=6.5 Hz, 3H), 2.67-2.73 (m, 1H), 3.71 (d, J=10 Hz, 1H), 5.10 (d, J=16.5 Hz, 1H), 5.83 (d, J=16 Hz, 1H), 7.16 (d, J=8 Hz, 2H), 7.32-7.38 (m, 3H), 8.12 (d, J=6.5 Hz, 1H), 8.75 (d, J=5.5 Hz, 1H), 9.13 (s, 1H). MS [M+H] C18H18N6O=335.1.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([CH:26]=[N:27][OH:28])[C:10]=1[S:29]([CH3:31])=[O:30]>O1CCCC1>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:19]([Cl:20])[C:14]=1[N:13]1[CH:9]=[C:10]([S:29]([CH3:31])=[O:30])[C:11]([CH:26]=[N:27][OH:28])=[N:12]1
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CS(=O)c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C=NO
Reaction time: 4.5 h
Yield: 12.5 %

Procedure:
Tert-butyl nitrite (1.25 g) was added to 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (2.0 g) in tetrahydrofuran and stirred for 4.5 hours. After evaporation the resulting orange solid was triturated with carbon tetrachloride to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (0.24 g) m.p. 239-240° C. Compound 20.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][C:22]#[C:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].FC(F)(F)C(O)=O>ClCCl>[NH2:26][CH2:25][CH2:24][C:23]#[C:22][CH2:21][O:20][C:19]1[CH:34]=[CH:35][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([NH:2][OH:1])=[O:4])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)NO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCN)cc2)C1C(=O)NO
Yield: 100.5 %

Procedure:
A solution of 0.071 g (0.135 mmol) of tert-butyl 5-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholinyl}sulfonyl)phenoxy]-3-pentynylcarbamate from Example 245, 1 mL of trifluoroacetic acid and 3 mL of dichloromethane was stirred for 1.5 h. The solution was concentrated in vacuo and the residue was triturated with ether to provide 0.058 g (79%) of 4-({4-[(5-amino-2-pentynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide as a pale orange solid. Electrospray Mass Spec: 428.3 (M+H)+.