Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[Cl:17][C:8]1[CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](=[O:16])[N:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[CH3:10]
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A mixture of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 1(5) (3.0 g, 13.44 mmol) and N-chlorosuccinimide (1.79 g, 13.44 mmol) in N,N-dimethylformamide (27 mL) was stirred at room temperature for 16 h, and the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 3.19 g (92%) of the title compound as brown oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.C(N(CC)CC)C>C1COCC1>[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:8])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Clc1ncc2c(n1)CCNC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A solution of nicotinoyl chloride (0.230 g, 1.62 mmol) in anhydrous THF (1.5 mL) was treated with 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.250 g, 1.47 mmol) and triethylamine (0.3 g, 3.0 mmol) and subsequently allowed to stir at room temperature. After 4 hours the reaction was quenched with deionized H2O (10 mL). Following dilution with EtOAc (10 mL) the reaction mixture was washed twice with brine and once with saturated Na2HCO3(aq). The combined aqueous layers were then washed once with EtOAc. The combined organic layers were dried over anhydrous Na2SO4(s), filtered and then concentrated in vacuo. Purification over silica using a Methanol/CHCl3 gradient afforded the desired product in 87.9% yield (0.356 g, 1.3 mmol).
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[I:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[N:11]=[C:10]2[I:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
In a round-bottomed flask, 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1H-indazole (1.65 g, 4.41 mmol) was dissolved in THF (16 ml). The solution was cooled to 0° C. and potassium tert-butoxide (697 mg, 6.22 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then methyl iodide (0.38 ml, 6.08 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-10% EtOAc) to give 770 mg (45%) of 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1-methyl-1H-indazole as a light yellow solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCCCl)cc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Suspend anhydrous AlCl3 (156 g, 1.15 mol) in toluene (1500 mL) and cool to 2-4° C. Add, by slow addition, a solution of 4-chlorobutyryl chloride (165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutes and pour into stirring ice-water (2.5 L). Stir for 30 hours, decant the toluene and extract the aqueous phase with toluene (700 mL). Combine the organic layers and wash three times with water (1 L, 1 L, 500 mL). Evaporate the solvent in vacuo to give the title compound as a pale yellow oil (292.3 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4](Br)[N:3]=1.[CH3:22][NH2:23]>O1CCOCC1.C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH:23][CH3:22])[CH:5]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(Br)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(S(=O)(=O)c2cccc(C(F)(F)F)c2)cc(Br)n1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 81 %

Procedure:
0.222 g (0.0005 mol) of 2,6-dibromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridine was dissolved in 10 ml of dioxane and treated with 1.25 ml of 8M methylamine in ethanol. The mixture was stirred at room temperature for 18 mins., the solvents were then removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:19 and subsequently 1:9. There was obtained 0.16 g (81%) of [6-bromo-4-(3-trifluoromethylbenzenesulphonyl) -pyridin-2-yl]-methylamine as yellow crystals; m.p.: 115-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=O)[CH:6]=[CH:7][NH:8]2.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(=O)cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,7-dimethoxy-1H-quinolin-4-one (300 mg, 1.4 mmol) in POCl3 (5 mL) was heated to reflux for 15 h. The reaction mixture was cooled to rt and poured into ice-water. The mixture was then basified to pH 7 with NaHCO3 and stirred overnight. The solid was filtered and washed with water and dried to give 4-chloro-5,7-dimethoxyquinoline. LCMS m/z=224 (M+1); 1H NMR (CDCl3) δ: 8.56 (d, 1H, J=4.4 Hz), 7.23 (d, 1H, J=4.4 Hz), 7.05 (s, 1H), 6.58 (s, 1H), 3.93 (s, 6H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)=[O:20].Cl.[Cl-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3])=[O:20]
Reactant: OCc1ccccc1
Reactant: COC(=O)C1CCCCN1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCCN1S(=O)(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
To a stirred solution of 7.36 ml (85 mmol) of chlorosulfonyl isocyanate in 180 ml of methylene chloride was added phenylmethanol (8.82 ml, 85 mmol) at 0° C. over a period of 35 minutes. After stirring the above solution for 2 hours at this temperature, a solution of 16.65 g (93 mmol) of 2-piperidinecarboxylic acid methyl ester hydrochloride in methylene chloride (500 ml) containing triethylamine (35.3 ml) was added at 0°-5° C. and the resulting mixture was stirred overnight allowing the mixture to warm to room temperature. The reaction mixture was poured into 600 ml of 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride (2×200 ml) and the combined organic layer was washed with brine, dried and concentrated in vacuo to yield 31 g of N -(carbobenzyloxyaminosulfonyl)-2-piperidinecarboxylic acid methyl ester(Formula XIV: R=CH3 ; R1 =H; R2 and R3 together=--(CH2)4 --) as a solid.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[I:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([I:12])[C:5]2=[C:4]([Cl:11])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nc(Cl)c2ccnc-2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(Cl)c2c(I)cnc-2[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.66 mmol) was dissolved in anhydrous DMF (20 mL) and N-iodo succinimide (718 mg, 3.19 mmol) was added. After stirring for 45 minutes at rt, reaction mixture was poured into water (400 mL) and extracted with EtOAc (2×500 mL) Organics were combined and washed with brine (500 mL) and dried over sodium sulfate. Solvents were removed under reduced pressure and purified via column chromatography to afford 2,4-dichloro-5-iodo-1H-pyrrolo[2,3-d]pyrimidine (660 mg, 2.103 mmol) as a yellow solid. ESIMS (M+H)+=315
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:12]=C)=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.C[OH:15]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH:12]=[O:15])=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: C=Cc1nc([N+](=O)[O-])ccc1OC
Reactant: CO
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])nc1C=O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 0.63 g (3.5 mmol) 3-methoxy-6-nitro-2-vinyl-pyridine in 50 ml of CH2Cl2 and 10 ml of methanol was cooled to −70° C. Ozone was bubbled into the solution until a blue color persisted. The mixture was stirred for 60 minutes at −70° C. and then quenched with excess dimethyl sulfide. The reaction was warmed to room temperature and the solvent evaporated. The residue was dissolved in ethyl acetate and water. The pH of the solution was adjusted to 2.0 with 1N HCl and the mixture stirred for 30 minutes. The pH of the solution was then adjusted to 8.0 with 1N NaOH. The mixture was extracted with excess ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4) and evaporated to yield 0.6 g of 3-methoxy-6-nitro-pyridine-2-carbaldehyde as a tan solid. TLC. Rf=0.2 (1.1 ethyl acetate/hexane). 1H NMR (CDCl3) δ 10.1 (s, 1H), 8.5 (d, 1H), 7.85 (d, 1H), 4.15 (s, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])=[N:7][N:6]=1>C(O)C>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH2:17][C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH:2][NH2:3])=[N:6][N:7]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(NN)c2c1
Yield: 109.1 %

Procedure:
Hydrazine hydrate (0.81 ml, 0.84 g, 16.8 mmoles) was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (2 g, 5.6 mmoles), obtained as described in example 13, in ethanol (30 ml), and the mixture was kept under reflux for 24 hours, then cooled in ice and the resultant precipitate was filtered, washed with ethanol and ethyl ether and dried under vacuum at 50° C. to give 2.14 g of the title compound (stoichiometric yield). m.p.: 297-299° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetylchloride (52.11 grams) is added dropwise into a stirred solution of 89.27 grams of octadecanol and 50 ml of triethylamine in 400 ml of methylene chloride at 25°-30° C. After stirring the reaction mixture at room temperature overnight under N2, the mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by liquid chromatography affords octadecyl bromoacetate as a white solid, mp 37°-40° C.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[C:15](SC)[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=2[N+:23]([O-:25])=[O:24])[CH2:7][CH2:6][N:5]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:3])[CH3:2].[CH:33]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:44][S:45]([O-:48])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]([C@@H:4]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[C:15]([S:45]([CH3:33])(=[O:48])=[O:44])[C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=2[N+:23]([O-:25])=[O:24])[CH2:7][CH2:6][N:5]1[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])([CH3:3])[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1SC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a 2 L round-bottom flask containing (R)-tert-butyl 2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylthio)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (crude 91.7 g, 0.196 mol) in CH2Cl2 (1 L) was added m-CPBA (84.6 g, 0.49 mmol, 2.5 eq). The mixture was stirred at rt overnight. Sat. Na2S2O3 solution was added slowly to quench the reaction. The mixture was extracted with CH2Cl2 (4×3 L). The combined organic layers were washed successively with Na2S2O3 solution (500 mL), NaHCO3 solution (500 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with dichloromethane to give (R)-tert-butyl 2-isopropyl-4-(4-(methoxycarbonyl)-5-(methylsulfonyl)-2-nitrophenyl)-3-oxopiperazine-1-carboxylate (83.7 g, 85.4% yield) as a yellow solid. LC-MS MS (ESI) m/z 444.0 [M−56+H]+, 522.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.29 (s, 1H), 8.12 (s, 1H), 4.61-4.17 (m, 2H), 4.00-3.94 (m, 4H), 3.70-3.60 (m, 1H), 3.51-3.43 (m, 4H), 2.39-2.32 (m, 1H), 1.50 (s, 9H), 1.07 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl>[C:19]([O:16][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([S:9][CH2:8][C:7]2[C:6]([CH3:18])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[N:15]=1)(=[O:21])[CH3:20]
Reactant: Cc1cc(O)nc(SCc2c(C)cncc2Cl)n1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)nc(SCc2c(C)cncc2Cl)n1
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
In a 250 mL round bottom flask, 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (565 mg, 2.0 mmol) was dissolved in dichloromethane (25 mL). Acetyl chloride (0.21 mL, 3.0 mmol) was added, followed by triethylamine (0.42 mL, 3.0 mmol). After 30 minutes, the reaction mixture was evaporated. The crude product was purified by column chromatography (0˜35% ethyl acetate/hexane) to provide 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-yl acetate as a white solid (500 mg, 77% yield); 1H NMR (500 MHz, CDCl3): δ 2.35 (s, 3H), 2.45 (s, 3H), 2.52 (s, 3H), 4.57 (s, 2H), 6.73 (s, 1H), 8.29 (s, 1H), 8.44 (s, 1H); M+ 324.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH2:11][C@@H:10]([OH:17])[CH2:9][OH:8]
Reactant: [H][H]
Reactant: O[C@@H](COCc1ccccc1)Cc1ncc[nH]1
Agent: [Pd]
Solvent: CO
Product: OC[C@H](O)Cc1ncc[nH]1
Yield: 97.9 %

Procedure:
To a solution of (2R)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol (424 mg) in methanol (10 ml), 10% palladium carbon (50% hydrated, 85 mg) was added, followed by stirring at 50-60° C. in a hydrogen atmosphere for 2 days. The catalyst was filtered off; the filtrate was concentrated to yield the titled compound (254 mg) as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:19](=O)[CH2:20][CH2:21][CH3:22].N1CCCCC1>C(O)C>[CH:19](=[C:15]1[S:14][C:13](=[O:18])[N:12]([CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CSC(=O)N1CCc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.18 g (4.5 mmol) of 3-[2-(imidazo[1,2-a]pyridin-5-yl)ethyl]thiazolidine-2,4-dione and 0.41 ml (4.5 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 1.15 g (81.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[C:15]([Cl:26])[C:14]=2[N+:27]([O-:29])=[O:28])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([N:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=1)[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[C:15]([Cl:26])[C:14]=1[N+:27]([O-:29])=[O:28])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Nc1ncc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)N(c1ncc(C(F)(F)F)cc1Cl)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
In 20 ml. of pyridine, 2.3 g. of N-(3-chloro-5-trifluoromethyl-2-pyridyl)-2,6-dinitro-3-chloro-4-trifluoromethylaniline (obtained in Preparation 4) was dissolved and a solution of 0.34 g. of acetylchloride in 10 ml. of pyridine was added dropwise to react them at 60° to 70° C. for 2 hours. Pyridine was distilled off from the reaction mixture and the product was separated by a silica gel column with an eluent of n-hexane and ethyl acetate (4:1) and the solvent was distilled off to obtain 0.8 g. of the object compound having the melting point of 75° to 77° C.
Reaction SMILES: [NH2:1][CH:2]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:3][CH2:4][C:5]([N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][OH:10])=[O:6].[N+:23]([C:26]1[C:27]([CH:39]=O)=[CH:28][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][CH:31]=1)([O-:25])=[O:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH:17]1([CH:2]([NH:1][CH2:39][C:27]2[C:26]([N+:23]([O-:25])=[O:24])=[CH:31][N:30]=[C:29]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:28]=2)[CH2:3][CH2:4][C:5]([N:7]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:8][CH2:9][OH:10])=[O:6])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: NC(CCC(=O)N(CCO)C1CCCCC1)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(CCC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)N(CCO)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-butyramide (2.0 g, 6.5 mmol) and 5-nitro-2-phenoxypyridine-4-carbaldehyde (1.6 g, 6.5 mmol) in 1,2 dichloroethane (50 mL), NaBH(OAc)3 (2.0 g, 9.4 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After the addition of 1N NaOH solution, the reaction mixture was then extracted with EtOAc (200 mL×2). The organic layer was dried with Mg2SO4 and then evaporated to a residue which was purified by column chromatography to yield 4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyramide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[CH2:37]([O:39][C:40](=[O:48])[C:41]1[CH:46]=[C:45](Br)[CH:44]=[N:43][CH:42]=1)[CH3:38].C([O-])(O)=O.[Na+]>C(#N)C>[CH2:37]([O:39][C:40](=[O:48])[C:41]1[CH:46]=[C:45]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)[CH:44]=[N:43][CH:42]=1)[CH3:38]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cncc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1
Yield: 69 %

Procedure:
Into a 20 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.995 g, 2.18 mmol), 5-Bromo-nicotinic acid ethyl ester (0.645 g, 2.33 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (95.5 mg, 0.117 mmol), acetonitrile (10 mL) and saturated aqueous NaHCO3 (10 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 5-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-nicotinic acid ethyl ester as a white powder (0.794 g, 69%). MS: m/z 528.1 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:16]([C:31]([NH2:33])=[O:32])=[N:17][CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[N:20]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:34](O)C.N1(CO)C2C=CC=CC=2N=N1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:16]([C:31]([NH2:33])=[O:32])=[N:17][CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[N:20]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:34])[CH2:10][CH2:9]1
Reactant: NC(=O)c1ncc(Oc2cccc([N+](=O)[O-])c2)nc1Nc1ccc(N2CCNCC2)c(Br)c1
Reactant: CCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCn1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-{[3-bromo-4-(piperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (523 mg) and ethanol (5 mL)-tetrahydrofuran (15 mL) were added 1H-benzotriazole-1-methanol (159 mg) and sodium triacetoxyborohydride (323 mg), followed by stirring at room temperature for 6 hours, then diluting with chloroform, and washing with a saturated aqueous sodium hydrogen carbonate solution. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-50:1:0.1) to obtain 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (447 mg) as a pale yellow solid.