Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(OCC)OCC
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 mmol), ethylene glycol (5 ml, 89 mmol), triethyl orthoformate (2.96 g, 20 mmol), and p-toluenesulfonic acid (0.086 g, 0.5 mmol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., (lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:5])[CH3:4].Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[CH2:22][CH2:21]1.C>CS(C)=O.C(O)(C)C>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[CH2:22][CH2:21]2)=[C:9]([O:14][CH3:15])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: COc1cc(NC(C)=O)ccc1O
Reactant: Fc1ccccc1N1CCN(CCCCl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: COc1cc(NC(C)=O)ccc1OCCCN1CCN(c2ccccc2F)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
1.13 g of powdery sodium hydroxide are added under nitrogen atmosphere to a solution of 5.08 g of 4-acetamido-2-methoxyphenol in 70 ml of anhydrous dimethylsulfoxide. The mixture is stirred at 50° C. for 2 hours. A solution of 6 g of 1-(3-chloro-n-propyl)-4-(2-fluorophenyl)-piperazine in 20 ml of anhydrous dimethylsulfoxide is added dropwise at 20° C. to the mixture, and said mixture is stirred at 100° C. for 1.5 hours. After cooling, the reaction mixture is poured into ice-water. The crystalline precipitates are collected by filtration, whereby a crude product is obtained. The mother liquor obtained after isolating the crude product is extracted with chloroform. The extract is washed with water, dried and then evaporated under reduced pressure to remove the solvent, whereby another crude product is obtained. Both crude products obtained above are dissolved in hot isopropyl alcohol and then treated with activated charcoal. 6.95 of 1-[3-(4-acetamido-2-methoxyphenoxy)-n-propyl]-4-(2-fluorophenyl)-piperazine are thereby obtained as colorless needles. Yield: 74%
Reaction SMILES: [CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]([CH:13]([NH:16][C:17](=O)[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH3:15])=[N:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>>[CH:1]1([C:6]2[NH:11][C:10](=[O:12])[C:9]3=[C:13]([CH2:14][CH3:15])[N:16]=[C:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(NC(=O)CC(C)C)c1nnc(C2CCCC2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(CC(C)C)n2nc(C3CCCC3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 200 mg (0.65 mmol) crude N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]-3-methylbutanamide, 165 mg (1.1 mmol) phosphoric trichloride are stirred at reflux for 4 hours, proportionate amounts of the solvents are used. The product is purified by chromatography (preparative HPLC).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:1][C:2]1[N:10]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[C:15]([F:14])([F:24])[F:25])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: FC(F)(F)c1ccccc1CBr
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1C(F)(F)F
Yield: 69 %

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-(trifluoromethyl)benzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 81A as white crystals in 69% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[NH:10][C:11]([C:13]2[C:18]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)=[CH:17][C:16](Br)=[CH:15][N:14]=2)=[O:12])=[CH:5][CH:4]=1.[NH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][C:11]([C:13]2[N:14]=[CH:15][C:16]([NH:37][CH2:38][CH2:39][CH2:40][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)=[O:12])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(=O)c2ncc(Br)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(C(NC(=O)c2ncc(NCCCNC(=O)OC(C)(C)C)cc2Nc2cc(C)cc(C)n2)c2ccc(OC)cc2)cc1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
N-[bis(4-methoxyphenyl)methyl]-5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide (PrepEx 1.11) (50 mg, 0.091 mmol), tert-butyl (3-aminopropyl)carbamate (32 mg, 0.18 mmol), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.01 mmol), Xantphos (11 mg, 0.018 mmol), and cesium carbonate (66 mg, 0.20 mmol) were combined in a dry flask and purged with argon for 5 minutes. To this mixture was added 1,4-dioxane (0.75 mL), and the reaction mixture was deoxygenated by flushing it with argon for 5 minutes. The reaction mixture was heated to 95° C. After 6 hours, the reaction mixture was cooled, diluted with ethyl acetate (50 mL), filtered through CELITE, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-60% ethyl acetate/hexanes, linear gradient) to afford tert-butyl {3-[(6-{[bis(4-methoxyphenyl)methyl]carbamoyl}-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl)amino}propyl]carbamate. MS ESI calc'd. for C36H45N6O5 [M+H]+ 641. found 641. 1H NMR (500 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.70 (d, J=8.5 Hz, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.5 Hz, 4H), 6.92-6.84 (m, 5H), 6.64-6.60 (m, 1H), 6.57 (s, 1H), 6.45 (s, 1H), 6.11 (d, J=8.5 Hz, 1H), 3.71 (s, 6H), 3.12-3.05 (m, 2H), 3.04-2.97 (m, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 1.74-1.66 (m, 2H), 1.32 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7]C(=O)[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:7][C:6]1[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:10]([NH2:9])(=[O:11])=[O:12]
Reactant: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(N)c(S(N)(=O)=O)c1
Yield: 61 %

Procedure:
A solution of 7-methoxy-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one (Example 2a, 15 g, 65.7 mmol) in a 50% aqueous sulfuric acid solution (140 mL) was heated at 130° C. for 6 h. The solution was then poured over ice and neutralized at 0° C. with the addition of saturated aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate. The organic phase was washed with brine, and dried over magnesium sulfate, filtered and dried in vacuo to afford the desired product, 2-amino-5-methoxy-benzenesulfonamide (8.1 g, 40.1 mmol, 61% yield) as a brown solid. See procedure described in Girard, Y., et al., J. Chem. Soc. Perkin Trans 1, 1043-1047 (1979). 1H NMR (400 MHz, DMSO -d6): δ 3.65 (s, 3H), 5.40 (s, 2H), 6.73 (d, 1H, J=8.8 Hz), 6.90 (dd, 1H, J1=8.8 Hz, J2=2.8 Hz), 7.07 (d, 1H, J=2.8 Hz), 7.19 (s, 2H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:39][CH2:38][CH2:37][C@H:31]1[C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:39][CH2:38][CH2:37][C@H:31]1[C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)(=[O:18])=[O:19])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Z-Leu-Arg(Tos)-Pro-NHEt 20.99 g produced as in Example 1 (1-2) was dissolved in 200 mL of methanol, then hydrogen was passed to the solution in the presence of 1.5 g of 10% palladium/carbon. The mixture was stirred at room temperature for 7 hours, the catalyst was removed, then the filtrate was concentrated under reduced pressure. The residue was solidified by treatment with ether. Thus, H-Leu-Arg(Tos)-Pro-NHEt was obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=[O:4])=[O:3].C(N=[C:20]=[O:21])CCC.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[N:1]([S:2]([C:5]1[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][S:8][C:9]=1[CH3:10])(=[O:4])=[O:3])=[C:20]=[O:21]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1csc(C)c1S(N)(=O)=O
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(C)c1S(=O)(=O)N=C=O
Temperature: 25 °C
Yield: 84.2 %

Procedure:
23.5 g of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate (1) (100 mmol) were initially charged in 250 ml of xylene. From this mixture, approx. 70 ml of xylene were distilled off on a water separator. After addition of 9.9 g of n-butyl isocyanate (100 mmol), the reaction mixture was heated to reflux. Subsequently, 24 g of phosgene were introduced over a period of 3 h at such a rate that the temperature remained at approx. 130° C. (excess phosgene was kept in the system by a phosgene condenser). For workup, the mixture was cooled to room temperature and excess phosgene was removed by passing an argon stream through. Subsequently, distillative purification was effected, in which the butyl isocyanate can be recovered. The methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate (2) can then be recovered as a colorless solid after a distillation under reduced pressure. 22 g of the methyl 4-(isocyanatosulfonyl)-5-methylthiophene-3-carboxylate (2) were obtained (83% of theory, content: 98%, b.p.: 120° C., 0.4 mbar). The identification and the determination of content were conducted by means of derivatization with methanol to the corresponding carbamate (1H NMR (400 MHz, d6DMSO): 2.72 (s), 3.61 (s), 3.79 (s), 8.00 (s), 11.96 (s)).
Reaction SMILES: [N:1]([C@@H:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@@H:4]([NH2:1])[CH3:21])[CH3:20]
Reactant: CCOC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: CCOC1=C2C=c3c(cnn3C[C@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
0.53 g (1.87 mmol) of (S)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 25 ml of anhydrous ethanol was hydrogenated on 55 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 50 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 217 mg (1.87 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 0.54 g (77%) of (S)-2-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 157° was obtained.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[C:1]1([N:7]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCN(C(=NNc2ccccc2)c2ccccc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a stirred solution, under nitrogen of 12.4 g of 1-[(phenylhydrazono)(2-fluorophenyl)methyl]-4-methylpiperazine in 100 ml of a solution of tetrahydrofuran was added dropwise, 5.3 g of potassium t-butoxide in 50 ml of tetrahydrofuran. Following the addition, the reaction mixture was stirred at ambient temperature for 1 hour, poured into water, and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was purified on a Water's Model 500 Preparative High Pressure Liquid Chromatograph utilizing two silica gel columns and dichloromethane/methanol (4%) as the eluent. Concentration of the appropriate fractions gave 7.0 g (61%) of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H indazole. Treatment of 3.1 g of the indazole with ethereal hydrogen chloride produced the hydrochloride salt. Recrystallization from ethanol gave 2.8 g of 1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole hydrochloride, mp 244°-246°.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:27](Cl)(Cl)=[S:28].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reaction time: 4 h

Procedure:
To a stirred mixture of 75 g of 6-Amino-2-tert-butyl-5-(4-methylpiperazin-1-yl)benzothiazole and 29 g of sodium bicarbonate in 1100 ml of chloroform at 0° is added 41 g of thiophosgene and the mixture stirred at 10° for 4 hours. After filtering off the solid, the solution is evaporated to get a yellow solid which is dissolved in water and the pH of the solution is brought to 7 by the addition of dilute sodium hydroxide. The solid separated is extracted with hexane and filtered through 150 g of neutral alumina to give 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole, melting at 124°-126°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC.CO>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)([O-:3])=[O:2]
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a cooled solution (−5° C.) of (3,4-dinitrophenyl)-(4-methylpiperazin-1-yl)methanone (5.88 g, 20 mmol) in THF, was added powdered NaBH4 (1.89 g, 50 mmol), followed by the dropwise addition of BF3.OEt2 (6.4 mL, 50 mmol), while keeping the temperature below 5° C. The mixture was allowed to come to room temperature over 2 hrs, and then stirred for a further 3 hrs at room temperature. MeOH was then added cautiously to the mixture, the stirring was continued for 10 minutes and then the mixture was concentrated. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL). The organic layer was washed with water (100 mL), brine (100 mL) and then dried by Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluent: 2% MeOH in CH2Cl2) to give a yellow solid (4.5 g, 80.3%). 1H NMR (300 MHz, CDCl3) δ: 7.90-7.92 (1 H, d, J=6.0 Hz), 7.90 (1 H, s), 7.69-7.71 (1 H, d, J=6.0 Hz), 3.73 (2 H, s), 3.07-3.10 (2 H, m), 2.94-2.99 (2 H, m), 2.76-2.81 (2 H, m), 2.67 (3 H, s), 2.53-2.56 (2 H, m).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[Cl:18][C:19]1[N:20]=[C:21]([C:25](O)=[O:26])[NH:22][C:23]=1[CH3:24].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[N:20]=[C:21]([C:25]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:26])[NH:22][C:23]=1[CH3:24]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: Cc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Yield: 43 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (18a) (0.34 g, 1.37 mmol), 4-chloro-5-methyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (5c) (0.16 g, 0.91 mmol), WSC hydrochloride (1.18 g, 6.15 mmol) and DMAP (0.12 g, 0.94 mmol), to obtain 0.23 g of the title compound as a pale yellow solid (43%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(NCC)C>CN(C=O)C.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.[Cu]I>[C:13]1([C:19]#[C:20][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 173.2 %

Procedure:
To a solution of ethyl 4-iodobenzoate (5.0 g, 18.2 mmol) in DMF (8 mL) was added phenylacetylene (2.25 g, 22.1 mmol), Pd(Ph3P)4 (502 mg, 0.45 mmol), CuI (172 mg, 0.91 mmol) and diethylamine (2 mL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc:hexanes (2:1, 150 mL) and washed with water (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (silica gel) using 0 to 10% EtOAc/hexanes to afford ethyl 4-(phenylethynyl)benzoate (7.89 g, 86%) as a pale yellow solid; 1H-nmr (400 MHz, CDCl3) δ 8.05 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.56 (dd, J=8.0, 2.0 Hz, 2H), 7.41-7.37 (m, 3H), 4.41 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H); LC (275 nM) 5.79 min (>98%); MS (ESI) m/z=250.9.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C(N(CC)CC)C>[C:1]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.28 mL of benzoyl chloride was added to 10 mL of methylene chloride solution containing 0.50 g of methyl 2-amino-4-phenylbenzoate and 0.36 mL of triethylamine and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.52 g of methyl 2-(benzamido)-4-phenylbenzoate as white solid.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[NH:11][C:12]([CH2:21][CH3:22])=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:14]=1>O1CCCC1.[O-2].[Mn+2]>[CH:4]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[NH:11][C:12]([CH2:21][CH3:22])=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:14]=1)=[O:3]
Reactant: CCc1[nH]c(-c2ccsc2CO)nc1-c1cccnc1
Agent: [Mn+2]
Agent: Cl
Agent: [O-2]
Solvent: C1CCOC1
Product: CCc1[nH]c(-c2ccsc2C=O)nc1-c1cccnc1
Yield: 55.5 %

Procedure:
A mixture of 2-(2-hydroxymethylthiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole dihydrochloride (212 mg) and manganese oxide (2 g) in tetrahydrofuran (15 ml) was refluxed for one hour. The reaction mixture was filtered and washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: chloroform:methanol=30:1→20:1) to obtain 2-(2-formylthiophen-3-yl)-5-ethyl-4-(3-pyridyl)imidazole (93 mg) as orange crystal.
Reaction SMILES: [C:1]([C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([OH:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Cl[C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28].O1CCCC1>C(Cl)Cl.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([O:22][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(C#N)nc3n2)CC1
Yield: 39 %

Procedure:
Following the procedure of Example 4 but starting with 2-(7-cyano-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (4.7 g.), sodium hydride (50% dispersion in mineral oil) (1.5 g.), 1-chlorocarbonyl-4-methylpiperazine (5.04 g.), anhydrous tetrahydrofuran (97 cc.) and anhydrous hexamethylphosphotriamide (25 cc.), a crude product (5.7 g.) is obtained which is then dissolved in methylene chloride (100 cc.). The resulting solution is passed through a column of silica gel (57 g.). Elution is carried out successively with methylene chloride (2,400 cc.), ethyl acetate (1,400 cc.) and then a mixture (200 cc.) of ethyl acetate And methanol (50--50 by volume), collecting 200 cc. fractions. The last eight fractions are combined and concentrated to dryness. The residue, weighing 3.4 g., is recrystallised from acetonitrile (250 cc.) to yield 2-(7-cyano-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-isoindolin-1-one (2.6 g.) melting at 266°-268° C.