Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH2:29]([N:37]=[C:38]=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:38]([NH:37][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CCCCCCCCN=C=O
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 125 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and n-octyl isocyanate (1.55 g; 10 mmole). Recrystallization from methanol/ethanol/water provided the title compound (3.1 g; 62% yield) as colorless crystals, m.p. 229°-230° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:13]([CH2:14][Cl:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][C@H:18]([NH:26][CH3:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.Cl>C1C=CC=CC=1>[ClH:15].[CH3:27][N:26]([CH2:14][C:13]1[O:16][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH:18]([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(CCl)o2)cc1
Reactant: CN[C@@H](C)Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: c1ccccc1
Product: CC(Cc1ccccc1)N(C)Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A solution of 11.9 g (0.05 mole) of 5-(4-nitrophenyl)furfuryl chloride and 14.9 g (0.10 mole) of d-N,a-dimethylphenethylamine in 60 ml of benzene was heated under reflux for 7 hrs. After standing overnight, the solid N,a-dimethylphenethylamine hydrochloride (9 g, 97%) was collected by filtration and washed with benzene. The benzene filtrate was washed with 10% Na2CO3 and water and dried over MgSO4. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in 100 ml of anhydrous ether and 35 ml of nhydrous MeOH. The solution was treated with 20 ml of ethereal HCl and diluted with ether to give an oil. The solvent was removed on a rotary evaporator, and the residual oil was dissolved in ethyl acetate with heating. Cooling gave an oil which was dissolved by the addition of MeOH and 10 ml of etheral HCl. After cooling and dilution with ether, the yellow solid which was deposited was collected by filtration to give 13 g (67%) of N-methyl-5-(4-nitrophenyl)-N-(a-methylphenethyl)furfurylamine hydrochloride; m.p. 168°-175°.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(CNCC2CCCCC2)CCCCC1.Br[C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1.N(C)(C1CCCCC1)C1CCCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:29][C:24]1[C:23](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Fc1ncccc1Br
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cccnc1F
Temperature: 110 °C
Yield: 94.7 %

Procedure:
To Pd[P(t-Bu)3]2 (0.210 g, 0.411 mmol) was added dioxane (6 mL), methyl acrylate (2.00 mL, 22.2 mmol), N,N-dicyclohexylmethylamine (3.60 mL, 17.0 mmol), and 3-bromo-2-fluoropyridine (1.02 g, 5.80 mmol). The reaction mixture was degassed and heated to 110° C. for 5 min. The reaction was cooled to room temperature and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 50% EtOAc in hexanes) gave the product which contained Cy2NMe. The Cy2NMe was removed by dissolving the mixture in DCM (5 mL) and diluting with hexanes (10 mL). The solution was concentrated to a volume of 5 mL and the solid precipitate was collected by filtration and dried under high vacuum to give (E)-methyl 3-(2-fluoropyridin-3-yl)acrylate (0.995 g, 5.49 mmol, 95% yield) as a white solid. MS (ESI, pos. ion) m/z: 182.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:20][C:21]#[C:22][CH3:23])([CH2:16][C:17]#[C:18][CH3:19])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26]>>[OH:26][NH:25][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:20][C:21]#[C:22][CH3:23])[CH2:16][C:17]#[C:18][CH3:19]
Reactant: NO
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 89 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in example 1. Starting from 2-(4-methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.27 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.23 g of the product was isolated. Yield 89%; white solid; mp 135-137° C.; MS: 349.9 (M+H)+1; 1H NMR (300 Mz, DMSO-d6) δ1.67 (s, 6H), 2.70-3.10 (mn, 4H), 3.88 (s, 3H), 7.15 (d, J=10.0 Hz, 2H), 7.71 (d, J=10.0 Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm−1): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:10]2)=[CH:5][CH:4]=1.[CH:23]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH:23]1([CH:14]([C:12]2[C:11]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:13]=2)[OH:15])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(-n2cc(C=O)c(CN3CCOCC3)n2)cc1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C(O)C3CCCCC3)c(CN3CCOCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution (15 mL) of 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazole-4-carbaldehyde (2.0 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (10 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.3 g, 51%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][CH:23]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:3]([CH:16]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]([O:26][CH3:27])=[O:25])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: C=C(c1cccc(C(=O)OC)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of methyl 3-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (2.5 g, 6.9 mmol) in ethyl acetate, in the presence of palladium-on-charcoal (700 mg) at a pressure of 6 bar of hydrogen, is stirred at room temperature for 4 h. The mixture is filtered through Celite and then concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:37][CH2:36][CH2:35][C@H:31]3[C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CCC[C@H]5C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), L-proline (28 mg) and acetic acid (0.1 mL) in DCM (10 mL) stirred at 20° C. was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-L-proline (E69) (12 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.71 (1H, m), 1.94 (2H, m), 2.16 (1H, m), 2.95 (1H, m), 3.05 (2H, m), 3.25 (2H, m), 3.60 (2H, m), 3.65 (3H, s), 4.88 (1H, m), 7.20 (1H, t), 7.31 (1H, s), 7.45 (2H, m), 7.86 (1H, dd), 8.13 (1H, dd), 8.20 (1H, d). MS (ES): C27H29ClN4O4 requires 508; found 509.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2[C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:25][CH3:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC)c2c(OS(=O)(=O)C(F)(F)F)c3ccccc3nc12
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c(C#C[Si](C)(C)C)c3ccccc3nc12
Yield: 96.2 %

Procedure:
To a solution of 1,4-dimethoxy-9-trifluoromethylsulfonyloxyacridine (prepared as described in Preparation 1 above) (1.2 g, 3.1 mmol) in dry tetrahydrofuran (10 ml) under N2 were successively added tetrakis(triphenylphosphine) palladium (0), (0.3 g, 0.3 mmol), N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) and trimethylsilylacetylene (1.3 ml, 9.3 mmol). The mixture was stirred at reflux for 5 h. After this time the solvent was evaporated and the residue was dissolved in CH2Cl2 and washed with water. The organic solution was dried an evaporated affording a residue which was purified by column chromatography. Elution with hexane/CH2Cl2 (1:1) gave the title compound (1.0 g, 98%) as a red solid; m.p. 110-111° C. (CH2Cl2). IR (film): ν/cm−1=2810 (w, C≡C), 1608 (s, Ar), 1527 (m, Ar), 1468 (s, Ar); 1H NMR (200 MHz, CDCl3): δH/ppm=0.41 (s, 9H, 3×CH3), 3.99 (s, 3H, OCH3), 4.11 (s, 3H, OCH3), 6.75 (d, J=8.4 Hz, 1H, H-2), 6.93 (d, J=8.4 Hz, 1H, H-3), 7.63 (dd, J=8.0 and 7.2 Hz, 1H, H-7), 7.78 (dd, J=8.4 and 7.2 Hz, 1H, H-6), 8.35 (d, J=8.4 Hz, 1H, H-5), 8.64 (d, J=8.0 Hz, 1H, H-8); 13C NMR (50.3 MHz, CDCl3): δC=0.0 (q, CH3), 55.8 (q, OCH3), 56.1 (q, OCH3), 101.5 (s, ≡C—Si), 103.9 (d, C-2), 105.7 (d, C-3), 111.8 (s, ≡C), 120.5 (s, C-9a), 126.4 (d, C-7), 126.9 (d, C-6), 127.5 (s, C-9), 129.9 (d, C-5), 130.0 (s, C-8a), 130.3 (d, C-8), 142.1 (s, C-4a), 147.0 (s, C-1), 149.4 (s, C-4 and C-10a); MS (EI); m/z (%)=336 [M+1] (10), 335 [M+] (36), 320 (100), 306 (13), 290 (10), 262 (14); HRMS: calcd. for C20H21NO2Si 335.1341; found 335.1336; Elemental analysis: C20H21NO2Si.0.125CH2Cl2 (346.10): calcd. C 69.84, H, 6.19, N, 4.05; found C 69.70, H 6.42, N 4.09.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:27])[N:19]2[CH3:28])=[CH:14][CH:13]=1.C(N(CC)CC)C>CO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:27])[N:19]2[CH3:28])=[CH:16][CH:17]=1
Reactant: Cn1c(=O)c2cccnc2n1-c1ccc(O)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1c(=O)c2cccnc2n1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (0.057 g), 1-(4-hydroxyphenyl)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (0.060 g) and triethylamine (3.5 ml) was stirred under a nitrogen atmosphere at 160° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with methanol, and silica gel was added. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.012 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30.0 g (155 mmol) of 2,3,4,5-tetrafluorobenzoic acid in 75 ml of dichloromethane was added 14.8 ml (1.1 equivalents) of oxalyl chloride. The mixture was then treated with three drops of dry N,N-dimethylformamide and the vigorous reaction was stirred at room temperature overnight. The mixture was then concentrated to an oil, taken up in toluene, and reconcentrated to afford 2,3,4,5-tetrafluorobenzoyl chloride which was used in the next step.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]([CH3:12])=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1)#[N:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:14]([O:13][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:12])[N:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CC(=O)c1cc(C#N)c(OCc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-cyano-5-acetyl-6-methyl-2(1H)-pyridinone (1.76 g, 0.01 mol) (L. Mosti et al, J. Het. Chem. 22, 1503 (1985)), benzyl bromide (2.12 g, 0.012 mol), silver carbonate (3.06 g, 0.011 mol) in benzene was stirred at room temperature under a nitrogen atmosphere overnight, while protected from light. The following day the mixture was filtered, and the solids washed well with benzene. Evaporation of the filtrate gave the desired intermediate, mp 94°-99° C.
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:11]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of methyl 3-amino-2,6-dibromoisonicotinate (5.00 g, 16.1 mmol), 4-methoxycarbonylphenylboronic acid (2.90 gm, 16.1 mmol), and tetrakis-(triphenylphosphine)palladium(0) (0.932 g, 0.807 mmol) in a flask was flushed with nitrogen. Toluene (70 mL), MeOH (14 mL), and a 2 N aqueous solution of sodium carbonate (18 mL, 37 mmol) were added and the reaction was heated in a 120° C. oil bath for 4 hr. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)isonicotinate (2.0 gm). MS (ESI) m/z 365.0 and 367.0 (M+H). 1H NMR (CDCl3) δ ppm 8.15 (2H, d, J=8.24 Hz), 7.84 (1H, s), 7.71 (2H, d, J=8.24 Hz), 5.94 (2H, br. s.), 3.94 (6H, d, J=5.19 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.CC(O[Na])=O.[Br:18]Br.Cl>C(O)(=O)C.C(OCC)(=O)C>[Br:18][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]=1[OH:9]
Reactant: BrBr
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-Methoxy-2-nitro-phenol (10 g) was dissolved in glacial acetic acid (60 mL) and CH3CO2Na (8.2 g) was added. Next, bromine (3 mL) dissolved in glacial acetic acid (12 mL) was added drop wise to the stirring solution at room temperature. After complete addition of bromine, the mixture was stirred for 30 min at room temperature and then placed in an oil bath at 75° C. for 2 h. After reaction mixture cooled to room temperature, concentrated HCl (500 mL) was slowly added to the mixture followed by addition of ethyl acetate (500 mL). The layers were separated and the organic layer was washed with water, brine, dried (Na2SO4). Flash chromatography on silica gel eluting with 5% ethyl acetate-hexane afforded 8.8 g (60%) of the title compound as a solid. MS: 218 (MH+−30), HPLC tR: 2.40 min.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CN.Cl.[BH3-][C:19]#[N:20].[Na+]>CO.CC(O)=O>[CH3:19][NH:20][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 55 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.126 mmol, 1.0 eq.) was dissolved in MeOH (50 ml); AcOH (2 drops) and CH3NH2.HCl (2.2 g, 32.663 mmol, 1.3 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.11 g, 50.25 mmol, 2.0 eq.) was added in portions at 0° C. and the mixture was stirred for 14 hours at RT. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 55% (3.0 g, 14.019 mmol)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: OCCc1ccccc1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1

Procedure:
2-Phenylethanol (3.1 g) was reacted with p-styrene sulfonyl chloride (5.3 g) and triethylamine (2.7 g) in 20 ml of dichloromethane for 3 hours to give the desired product as a light yellow viscous oil that was purified by passing through basic aluminum oxide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C[Si]([N:12]=[C:13]=[O:14])(C)C>C(O)(C)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:13]([NH2:12])=[O:14])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: CN1CCN(C(N)=O)CC1
Reaction time: 8 h
Yield: 121.1 %

Procedure:
To a stirred solution of 1-methylpiperazine (1.66 mL, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution stirred overnight. The volatiles were removed in vacuo to give 4-methyl-piperazine-1-carboxylic acid amide (2.6 g, quant.) as an oil which slowly crystallised on standing; 1H-NMR (300 MHz, CDCl3) 4.62 (2H, s), 3.40 (4H, t), 2.39 (4H, t), 2.29 (3H, s); m/z (ES+) 143 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:27][CH:28]([CH3:32])[CH2:29][NH:30][NH2:31]>CO>[CH3:27][CH:28]([CH3:32])[CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: CC(C)CNN
Solvent: CO
Product: CC(C)Cn1nccc1-c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Yield: 14.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.: 379, MS Found: 380 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10](OCC)=[O:11])[C:3]1=[O:15].[NH2:16][C:17]1[N:21]=[CH:20][NH:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[N:21]=[CH:20][NH:19][N:18]=2)=[O:11])[C:3]1=[O:15]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2nc[nH]n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 81.3 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 78 mg of 3-amino-1,2,4-triazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 7.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 188 mg of 1,6-dimethyl-4-hydroxy-2-oxo-N-(1,2,4-triazol-3-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 23) represented by the formula: