Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.OS(O)(=O)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:29]([O-:31])=[O:30])=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2cc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Yield: 78 %

Procedure:
The title compound was prepared following the procedure described for step-3 of intermediate-55 using methyl 2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.380 g, 1.134 mmol), conc. H2SO4 (1.2 mL) and KNO3 (0.109 g, 1.077 mmol) to afford 0.320 g of the desired product. 1HNMR (DMSO-d6): δ 3.92 (s, 3H), 7.40-7.47 (m, 3H), 7.72 (s, 1H), 9.98 (m, 1H), 11.00-12.00 (s, 2H); MS [M+H]+: 381.03.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[N:2]1.C[C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1.N1C=CC=CC=1>CC#N>[C:22]([N:18]1[CH2:19][CH2:20][N:21]([C:11](=[O:12])[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:14])[CH2:16][CH2:17]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: O=C(Cl)C(=O)c1n[nH]c2ccccc12
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
The crude residue containing (1H-Indazol-3-yl)-2-oxo-acetyl chloride (50 mg) was dissolved in dry CH3CN (7 mL), and to the resulting solution was added 3-(R)-methyl-1-benzoyl piperazine (50 mg) and pyridine (1 mL). The reaction mixture was stirred for 1 hour at room temperature then was concentrated in vacuo. The resulting residue was purified using Shimadzu automated preparative HPLC System to give 1-(benzoyl)-4-[(1H-indazol-3-yl)-2-oxoacetyl]piperazine (2.5 mg). 1H NMR (500 MHz, MeOD) δ 8.42 (m, 2H), 7.90 (m, 1H), 7.69 (m, 1H), 7.46 (m, 5H), 5.00-3.00 (m, 8H), 1.30 (m, 3H). MS m/z: (M+H)+ calcd for C21H21N4O3:377.16; found 377.28. HPLC retention time: 1.49 minutes (column A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][CH:5]2O.[NH2:13][NH2:14]>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:14][N:13]=[CH:5]2
Reactant: O=C1OC(O)c2cc(Br)ccc21
Reactant: NN
Solvent: CC(C)O
Product: O=c1[nH]ncc2cc(Br)ccc12

Procedure:
5-Bromo-3-hydroxyphthalide (49 gm) was slurred in 200 ml isopropanol. Hydrazine (20 ml) was added and the mixture refluxed for 2 hours. The reaction mixture was allowed to cool and the product filtered off, washed with isopropanol and dried. The product weighed 46.8 gm and melted at 280°-283° C.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[CH:11]=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]2)=[O:19])[CH:11]=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cnc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cnc1C
Yield: 85 %

Procedure:
Phenyl-N-(5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].CC(C)([O-])C.[K+].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>O1CCOCC1>[C:1]([NH:6][C:14](=[O:15])[O:16][CH2:17][CH3:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=C(C)C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
In 200 g of dioxane, 4.26 g of methacrylamide and 6.37 g of potassium t-butoxide were dissolved and the solution was stirred for 60 minutes at 60° C. Then, 5.43 g of ethyl chloroformate was dissolved in 50 g of dioxane and the solution was added dropwise to the reaction mixture in 2 hours. After removing tetrahydrofurane in vacuo, 1000 g of water was added to the residue and the solution was extracted with 500 ml of ethyl acetate. The extract was evaporated in vacuo. The crude product was subjected to column chromatography, thereby obtaining 1.0 g of ethyl N-methacryloylcarbamate. Melting point of the product was 73°-74° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH2:13])[CH3:12])=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]2[C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[CH2:10][CH:11]([CH3:12])[NH:13]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1cccc(F)c1
Product: CC1Cc2c([nH]c3ccccc23)C(c2cccc(F)c2)N1

Procedure:
In addition, the compounds in Example 15(5) and Example 15(6) were prepared by separating diastereomer mixture which was obtained by reacting [2-(1H-indol-3-yl)-1-methylethyl]amine with 3-fluorobenzaldehyde, by column chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1>[C:19]([NH:27][C:28]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=S)NC(=O)c3ccccc3)nc12
Temperature: 100 °C
Yield: 54.8 %

Procedure:
To a suspension of 2-amino-4-methoxy-7-phenyl-benzothiazole (1.52 g, 6 mmol) in dioxane (60 ml) was added benzoylisothiocyanate (1.45 g, 8.9 mmol) and the mixture heated to 100° C. for 2 h, during which time the suspension dissolved. After cooling the solvent was removed and the solids suspended in hot acetonitrile (100 ml) and filtered while warm (50° C.). The solid collected was washed with acetonitrile (20 ml) then dried under vacuum (0.05 mmHg), at 60° C. to afford the title compound as a pale yellow amorphous solid (1.38 g, 55% yield), MS: m/e=419.0 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(Br)c2cc[nH]c2c1=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 108.4 %

Procedure:
A solution of 4-bromo-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (5.81 g, 15.2 mmol) in ethanol (100 mL) was treated with 3.0 M sodium hydroxide in water (50.8 mL, 152 mmol) and stirred at 20° C. for 16 h. The reaction mixture was concentrated in vacuo to remove most of the ethanol. The remaining aqueous layer was neutralized with concentrated HCl to pH ˜7 and extracted with ethyl acetate (2×). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated to give the desired product (3.74 g, quantitative) which was used without further purification. LCMS calculated for C8H8BrN2O (M+H)+: m/z=227.0, 229.0. found: 227.0, 228.9.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:22]1[C:23]2[CH2:30][CH2:29][CH2:28][C:24]=2[N:25]=[CH:26][N:27]=1.Cl.C[O-].[Na+]>C(Cl)(Cl)Cl>[N:25]1[C:24]2[CH2:28][CH2:29][CH2:30][C:23]=2[C:22]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:15][CH:16]=2)=[N:27][CH:26]=1
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc(N)cc2)CC1
Reactant: Clc1ncnc2c1CCC2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(CCC(=O)c2ccc(Nc3ncnc4c3CCC4)cc2)CC1
Yield: 95.1 %

Procedure:
To 80 ml of chloroform were added 4.53 g of 4-[3-(1-acetylpiperidin-4-yl)propanoyl]aniline and 3.83 g of 4-chloro-5,6-dihydro-7H-cyclopenta[d]pyrimidine, and after adding 10 ml of a chloroform solution of hydrochloric acid (containing 0.9 g of hydrochloric acid), the mixture was refluxed under heating for 5 hours. After completion of the reaction, a 28% sodium methoxide was added to the mixture under ice cooling to make it alkaline and then the solvent was removed by distillation under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 6.16 g of the title compound as brown powder.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:11]=[C:10]([Br:12])[O:9][C:8]=1[CH3:13])=[O:6]>O.CO>[Br:12][C:10]1[O:9][C:8]([CH3:13])=[C:7]([C:5]([OH:6])=[O:4])[CH:11]=1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.4 %

Procedure:
A solution of sodium hydroxide (4.5 g) in water (10 ml) was added to a stirred solution of 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester (5 g, 233 mmoles) in methanol (70 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH2 with 1M aqueous hydrochloric acid. The precipitate was collected, washed with water, dried at 40° C. to afford 5-Bromo-2-methyl-furan-3-carboxylic acid (14)(4 g). LC/MS System A; Rt=2.86 min.
Reaction SMILES: [S:1]([O:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:14][CH:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[NH:39]([C:15]1[C:16]2[C:17](=[O:27])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:26])[C:25]=2[C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[CH:13][CH:14]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OS(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Yield: 79 %

Procedure:
1-(anilino)-4-tosyloxyanthraquinone was prepared by reaction of 1,4-ditosyloxyanthraquinone with aniline. The isolated and purified creaction product has the structure illustrated below (where "Ts" is ##STR11## The yield was 79% and the m.p. 185°-186° C. Mass spec m/e 469 (M+), 314 (M-C7H7SO2), 155 (C7H7SO2), 91 (C7H7); 1H-NMR (CD2Cl2)δ11.50 (br s, 1H), 8.26-8.12 (m, 2H), 8.02-7.84 (m, 2H), 7.79-7.62 (m, 4H), 7.54-7.13 (m, 7H), 2.31 (s, 3H); IR (Nujol) 1355 cm-1 (asymmetric SO2 stretch), 1184 cm-1 (symmetrical SO2 stretch), 945 cm-1, 872, 840, 822, 810, 800, 788, 755 (S--O--C stretch); UV/VIS max (Xylenes) 500 nm (ε7000).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:6]=1[F:24])(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:6]=1[F:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(OCc2ccccc2)ccc(OC(C)=O)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(O)ccc(OC(C)=O)c1F

Procedure:
Following General Procedure G and using acetoxymethyl-4-benzyloxy-2-fluoro-phenyl acetate (Compound 20, 0.75 g, 2.26 mmol), ethyl acetate (15 mL) and 10% palladium on carbon (0.08 g), the title compound was obtained as an oil (0.48 g, 88%). 1H-NMR (300 MHz, CDCl3): δ2.09 (s, 3H), 3.62 (s, 2H), 5.75 (s, 2H), 6.48-6.54 (m, 2H), 7.02 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([NH2:18])[C:10]=2[N:9]=[C:8]1[CH2:19][CH3:20].[C:21]([N:29]=[C:30]=[O:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:18][C:11]1[C:10]2[N:9]=[C:8]([CH2:19][CH3:20])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:31])[C:15]=2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: CCc1nc2c(N)nc(C)c(C)c2n1CCOCCN
Reactant: O=C=NC(=O)c1ccccc1
Product: CCc1nc2c(N)nc(C)c(C)c2n1CCOCCNC(=O)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.60 g, 5.77 mmol) was treated with benzoyl isocyanate (0.98 g, 6.6 mmol) using the method described in Example 105. The crude product was purified by column chromatography on silica gel (150 mL, eluting with 90:10 dichloromethane:methanol) and recrystallized from acetonitrile (75 mL/g). The crystals were subsequently recrystallized twice from 2-propanol (40–44 mL/g) and then stirred in water for 30 minutes and isolated by filtration. The solid was dried for three days under high vacuum to provide 0.54 g of N-{2-[2-(4-amino-2-ethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-N′-benzoylurea as a white solid, mp 185–187° C. 1H NMR (300 MHz, CDCl3) δ 8.98 (br s, 1H), 8.87 (br t, 1H), 7.93–7.87 (m, 2H), 7.63–7.56 (m, 1H), 7.52–7.44 (m, 2H), 4.84 (s, 2H), 4.45 (t, J=5.8 Hz, 2H), 3.76 (t, J=5.8, 2H), 3.57–3.46 (m, 4H), 2.91 (q, J=7.5, 2H), 2.42 (s, 6H), 1.41 (t, J=7.5, 3H); MS (APCI) m/z 425 (M+H)+; Anal. Calcd for C22H28N6O3.0.25 H2O: C, 61.59; H, 6.70; N, 19.59. Found: C, 61.25; H, 6.90; N, 19.72.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1.Cl.[CH3:20][CH2:21]O>>[CH2:20]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([NH2:6])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CCO
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H).
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][C:19]=2[O:29][CH3:30])[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][C:19]=2[O:29][CH3:30])[N:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(C)=O)n1
Reaction time: 1 h
Yield: 27.4 %

Procedure:
MeMgBr (1 M solution in THF, 50 mL, 50 mmol) was added dropwise at −78° C. to a solution of N,5-dimethoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (6.32 g, 16.4 mmol) in THF (100 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with AcOEt and recrystallized from MeOH to give the title compound (1.53 g, 27% yield) as pale yellow prisms: mp 193-196° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.90 (3H, s), 4.00 (3H, s), 6.54 (1H, dd, J=1.9, 2.3 Hz), 7.30 (1H, dd, J=2.3, 8.7 Hz), 7.57 (1H, d, J=8.7 Hz), 7.63 (1H, d, J=2.3 Hz), 7.77-7.78 (2H, m), 8.00 (1H, d, J=2.3 Hz). Anal. Calcd for C12H16N4O4: C, 59.99; H, 4.74; N, 16.46. Found: C, 59.68; H, 5.00; N, 16.26.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][C@H:17](O)[CH3:18])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14](=[O:20])[NH:15][CH2:16][C@@H:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:18])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](CNC(=O)OC(C)(C)C)Oc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.33 g, 1.88 mmol), ((R)-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.33 g, 1.88 mmol) and triphenylphosphine (0.74 g, 2.82 mmol) were dissolved in anhydrous toluene. A solution of di-tert-butyl azodicarboxylate (0.65 g, 2.82 mmol) in toluene (5 ml) was added slowly ensuring that the temperature did not exceed 35° C. The reaction mixture was heated to 80° C. and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and subsequently washed with 1M HCl, water, then brine and dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield: 0.62 g, 100. LCMS method: 2, RT: 6.18 min; MI: 330-332 [M+1].
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:10]([OH:12])=[CH:9][CH:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:20]1[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:20]2[N:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1CCOc2cccc(O)c21
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCOc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
4-methyl-3,4-dihydro-2Hchromen-5-ol (Intermediate 211, 111 mg, 0.676 mmol) was dissolved in 5.0 mL of DMF. K2CO3 (140 mg, 1.01 mmol) and 2-chloro-5-nitropyrimidine (162 mg, 1.01 mmol) were added and the reaction mixture was stirred for 1 hour at room temperature. DMF was then evaporated under high vacuum and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 1:0 to 7:3 as eluents affording the title compound (192 mg).
Reaction SMILES: CN(CC[C:6]1[C:10]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])([CH:11]([CH2:13][CH2:14][CH3:15])[CH3:12])[CH:9]=[CH:8][CH:7]=1)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:32]([N:36]([CH:41](O)[CH3:42])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([N:36]([CH2:41][CH2:42][C:9]1[C:10]([CH:16]([CH2:18][CH2:19][CH3:20])[CH3:17])([CH:11]([CH2:13][CH2:14][CH3:15])[CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN(CCCC)C(C)O
Reactant: CCCC(C)C1(C(C)CCC)C=CC=C1CCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCCCN(CCCC)CCC1=CC=CC1(C(C)CCC)C(C)CCC

Procedure:
The reaction is carried out in a manner identical to that for (dimethylaminoethyl)-di-(2-pentyl)cyclopentadiene, the tosylate of N,N-di-n-butylaminoethanol being prepared in situ. The conversion was 88%. The (di-n-butylaminoethyl)-di-(2-pentyl)cyclopentadiene was obtained after preparative column purification on silica gel using, successively, petroleum ether (40-60° C.) and THF, followed by distillation under reduced pressure, the yield being 51%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:20])[CH:3]=1.[CH2:21]([CH:23]([NH2:26])[CH2:24][CH3:25])[CH3:22]>CN1CCCC1=O>[CH2:21]([CH:23]([NH:26][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:20])[CH:3]=1)[CH2:24][CH3:25])[CH3:22]
Reactant: CCC(N)CC
Reactant: Cc1cc(C)c(-c2cnn3c(Cl)cc(C)nc23)c(C)c1
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc2c(-c3c(C)cc(C)cc3C)cnn12
Temperature: 125 °C
Yield: 87 %

Procedure:
A mixture of 7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (190 mg, 0.63 mmol) and 1-ethylpropylamine (4 ml) in 1 ml of N-methylpyrrolidinone was heated at 125° C. oil bath for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated and purified through silica gel column chromatography using chloroform to 2% methanol in chloroform as eluent to give 195 mg (87%) of the title compound as a green solid. 1H NMR (CDCl3) ä 7.87(s, 1H), 6.97(s, 2H), 6.12(d, 1H), 5.85(s, 1H), 3.52(m, 1H), 2.48(s, 3H), 2.09(s, 3H), 2.16(s, 6H), 1.6-1.9(m, 4H), 1.05(t, 6H)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[I:11].CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Cl)c(I)c1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Borane-THF complex (10 ml) was added dropwise over 20 minutes to a solution of 4-chloro-3-iodobenzoic acid (1.4 g) in THF (25 ml). The reaction mixture was stirred for 2 hours and then cooled (ice bath) and methanol (20 ml) was added cautiously. The solvent was removed and the residue was dissolved in methanol (10 ml) and stirred with aq. 2M sodium hydroxide (10 ml) for 2 hours. Ethyl acetate (50 ml) was added and the mixture was washed with saturated aq. sodium bicarbonate solution (50 ml). The aqueous extracts were washed with ethyl acetate (2×50 ml) and the combined ethyl acetate extracts were washed with water (50 ml) and brine (50 ml) and died. Removal of the solvent gave 4-chloro-3-iodobenzyl alcohol (1.15 g). NMR (CD3SOCD3): d 4.45 (d, 2H), 5.3 (t, 1H), 7.3 (m, 1H), 7.5 (m, 1H), 7.8 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11].Cl.Cl[CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][C:6]1[C:10]([CH3:11])=[N:9][N:8]([CH2:19][CH2:20][NH2:21])[C:7]=1[CH3:12]
Reactant: Cc1n[nH]c(C)c1Cc1cc(Cl)cc(Cl)c1
Reactant: NCCCl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1nn(CCN)c(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 120 °C
Yield: 19.3 %

Procedure:
A stirred suspension of the pyrazole (200 mg, 0.78 mmol) of Example 23 and 2-chloroethylamine hydrochloride (136 mg, 1.18 mmol) in toluene (1 ml) was heated at 120° C. in a sealed Reacti-vial (Trade Mark) for 18 hours. After cooling, the mixture was diluted with dichloromethane (30 ml), washed with 2M aqueous sodium hydroxide solution (20 ml), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with methanol:dichloromethane:ammonia (5:95:0.5, by volume) to afford the title compound (45 mg) as white crystals, m.p. 70–72° C.