Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(O)C>[OH-].[Na+]>[C:16]([NH:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
Compound 6 (6.20 g) was acetylated with acetic anhydride (9 ml) in aqueous sodium hydroxide at pH 9 and 4° C. according to the procedure of Yoshida and Ishii [J. Biochem., 71, 185-191 (1972)]. Obtained 5.32 g (71.4%), mp 165°-166° C., [α]D25 =-46.2 °(c =2.8, ethanol)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]C(OC)=O)=[CH:26][C:25]=1[OH:36]>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:36][C:25]3[CH:26]=[C:27]([OH:31])[C:28]([CH3:30])=[CH:29][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Oc1cc(O)c(F)cc1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Yield: 73.8 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (132 mg, 0.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylphenol (96 mg, 0.48 mmol) in pyridine (2 ml) was heated at reflux for 3 hours. The mixture was allowed to cool, the solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ether (70/30). The resulting solid was crystallised from methylene chloride and-methanol to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxyquinazoline (120 mg, 64%).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:14])/[CH:7]=[C:8](\[NH2:13])/[C:9]([F:12])([F:11])[F:10])C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:6](=[O:14])[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:13][C:23]2=[O:24])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: O=C=Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
To a suspension of sodium hydride (60% dispersion in oil, 2.5 g) in anhydrous N,N-dimethylformamide (100 ml) was added dropwise a solution of ethyl-3-amino-4,4,4-trifluorocrotonate in toluene (50 ml) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred for 20 min at same temperature, then cooled to −30° C. A solution of (4-chloro-2-nitrophenyl)isocyanate in toluene (50 ml) was added dropwise. After stirring for 20 min, the cold bath was removed and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate and 1N-hydrochloric acid. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluted with ethyl acetate and hexane (1:1) to afford 3-(4-chloro-2-nitrophenyl)-6-trifluoromethyl-2,4 (1H, 3H)-pyrimidinedione (10.2 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[C:10]([C:11]#[C:12][CH2:13][OH:14])=[CH:9][N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C1(C)C=CC=CC=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[C:10]([C:11]#[C:12][CH2:13][O:14][C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])=[CH:9][N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1
Reactant: CN(C)CC(=O)Cl
Reactant: COc1c(C)cnc(Cn2cc(C#CCO)c3c(Cl)nc(N)nc32)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1c(C)cnc(Cn2cc(C#CCOC(=O)CN(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 3-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-prop-2-yn-1-ol (see example 1, 177 mg, 0.48 mmol) in anhydrous pyridine (3 mL) was treated with N,N-dimethylamino-acetyl chloride hydrochloride (113 mg, 0.72 mmol) at rt for 30 min. Addition of toluene (10 mL) caused the formation of a sticky pellet. The toluene solution was discarded, and the pellet was partitioned between water and DCM. The DCM layer was concentrated, and purifed by flash chromatography (EtOAc/DCM/Et3N 33:66:1, gradually adding MeOH (0-2%)) to afford the title compound. tR=4.51 min. 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.14 (s, 1H), 5.31 (s, 2H), 5.00 (s, 2H), 4.98 (s, 2H), 3.76 (s, 3H), 3.25 (s, 2H), 2.38 (s, 6H), 2.28 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1noc2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
To a stirred solution of 100 mg (0.65 mmol) of 3-chloro-1,2-benzisoxazole in pyridine (1 mL) was added 145 mg of piperazine-1-carboxylic acid tert-butyl ester (0.78 mmol) and 0.18 mL of DBU (0.78 mmol). The mixture was stirred at 100° C. overnight and then partitioned between EtOAC (50 mL) and water (20 mL) and separated. The aqueous layer was extracted with EtOAC (2×30 mL). The combined organic layers were then washed with water (25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give crude product. Purification by column chromatography (silica, 60-100% CH2Cl2/hexanes) gave 82 mg (42%) of the desired product as a light yellow solid. MS (electrospray): exact mass calculated for C16H21N3O3, 303.16; m/z found, 326.1 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 7.68 (dt, J=8.02, 0.98 Hz, 1H), 7.52-7.44 (m, 2H), 7.24 (ddd, J=8.42, 6.46, 1.57 Hz, 1H), 3.66-3.61 (m, 4H), 3.56-3.49 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: O1CCCC1.[CH2:6]([OH:9])[CH2:7][OH:8].[H-].[Na+].[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:17](Cl)[N:16]=[CH:15][N:14]=1>C(O)(=O)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([O:8][CH2:7][CH2:6][OH:9])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: OCCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1

Procedure:
To a mixture of tetrahydrofuran (400 ml) and ethylene glycol (60 ml) is added with stirring sodium hydride (60% dispersion, 3.38 g) under ice-cooling, and thereto is added 4,6-dichloro-5-(4-methylphenyl)pyrimidine (20.0 g). The mixture is stirred under ice-cooling for 30 minutes, and then stirred at room temperature for two hours. The mixture is weakly acidified with acetic acid, and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and washed, dried, and concentrated to dryness under reduced pressure. The residue is crystallized from hexane to give 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g).
Reaction SMILES: C1(=O)OC(=O)C=C1.[CH2:8]([C:10]1([CH3:21])[CH:15]([CH3:16])[CH:14]([NH2:17])[CH2:13][C:12]([CH2:19][CH3:20])([CH3:18])[NH:11]1)[CH3:9].[C:22]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12>O1CCOCC1>[CH2:8]([C:10]1([CH3:21])[CH:15]([CH3:16])[CH:14]([NH:17][C:22](=[O:32])[C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[CH2:13][C:12]([CH2:19][CH3:20])([CH3:18])[NH:11]1)[CH3:9]
Reactant: CCC1(C)CC(N)C(C)C(C)(CC)N1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C1C=CC(=O)O1
Solvent: C1COCCO1
Product: CCC1(C)CC(NC(=O)c2ccccc2C(=O)O)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
49.0 g of maleic anhydride in 300 ml of dioxane are heated to 80° C. At this temperature 99.2 g of 2,6-diethyl-2,3,6-trimethyl-4-aminopiperidine are added dropwise in the course of 30 minutes. After a short time a light brown precipitate is formed. The reaction is continued for 1 hour at reflux temperature. The reaction mixture is then cooled to room temperature, and the precipitate is filtered off. The resultant residue is dissolved in 500 ml of warm water. A brownish solution is formed which is discoloured with active carbon, and then evaporated to dryness under vacuo. The solid residue is suspended in about 200 ml of warm ethanol, the suspension is cooled to room temperature, filtered and dried. 2,6-Diethyl-2,3,6-trimethyl-4-β-carboxy-acrylamidopiperidine (compound no. 42) is obtained: m.p. >250° C. If, instead of 49.0 g of maleic anhydride an equivalent amount of phthalic anhydride is used and otherwise the procedure described above if followed, 2,6-diethyl-2,3,6-trimethyl-4-o-carboxybenzamidopiperidine (compound no. 43 ) is obtained; m.p. 196°-197° C.
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:27])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CC(C)CC(C)(C)C
Solvent: ClCCl
Product: CCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4a powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0.° C. under argon. To the cooled suspension was added 308 mg (1.09 mmole) of Ti(OiPr)4 and 356 mg (1.52 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butyhydroperoxide in isooctane (3.8M, 4.30 ml, 16.4 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution fo 2.00 g (10.9 mmole) of E-2-dodecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20°. The solution was then placed in the freezer (-30° C.) and allowed to stand for 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 3.50 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers were combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O: petroleum ether afforded 1.98 g of white solid, mp 62°-4° C. 1H NMR δ3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.69 (dd, 1, J=7, 6 Hz), 1.6-1.2 (m, 16), 0.88 (t, 3, J=6 Hz). Mass Spectra: M-31(-CH2OH)(0.4)169, M(100)55.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](OC(OCC)OCC)C>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:17]=[N:16][N:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncccc1OCc1ccccc1
Product: c1ccc(COc2cccn3cnnc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A flask was charged with 3-(benzyloxy)-2-hydrazinylpyridine (10.0 g, 46.5 mmol) and triethoxymethane (77.3 ml, 465 mmol). The mixture was heated at reflux for 1 hour and then stirred overnight at ambient temperature. The solids were filtered and rinsed with EtOH and dried on high vacuum to afford 8-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine (8.05 g, 35.7 mmol, 76% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:10]=[N:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>>[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:34])[CH3:35])[C:28]=1[NH:36][C:37](=[O:38])[N:14]([CH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:12]=1)[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=1)([CH3:25])[CH3:26]
Reactant: CCCCCCCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCn1cc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 62 using [(1-heptylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (1.1 g) and 2,6-diisopropylphenyl isocyanate (1.13 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(1-heptylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)urea (1.35 g) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=O)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 282 mg (1 mmole) of oleic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 265 mg (Yield: 48%) of the title compound having the following structure as a red oil.
Reaction SMILES: C([C:8]1([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[C:10](=[O:21])[CH:9]1C([O-])=O)C1C=CC=CC=1.C1CC=CCC=1>C(O)(=O)C>[CH2:32]1[O:31][C:28]2[CH:29]=[CH:30][C:25]([CH:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=4)[C:10](=[O:21])[CH2:9]3)=[CH:26][C:27]=2[O:33]1
Reactant: CCCOc1ccc2c(c1)C(=O)C(C(=O)[O-])C2(Cc1ccccc1)c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: C1=CCC=CC1
Product: CCCOc1ccc2c(c1)C(=O)CC2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of benzyl-(1RS ,2SR)-(3,4-methylenedioxyphenyl)-5-prop-1-yloxy-3-oxo-indane-2-carboxylate (8.2 g, 18.4 mmol) in warm acetic acid (130 ml), was added under argon 10% Pd/C (4.1 g) followed by 1,4-cyclohexadiene (17.4 ml, 185 mmol). The reaction was exothermic and gas evolution was observed. The reaction was allowed to stir under argon at room temperature for 2 h. The mixture was filtered through a pad of celite and concentrated in vacuo. Flash chromatography of the residue (silica gel, 3:7 ethyl acetate:hexane) afforded the title compound as a pinkish solid (5.08 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9](=[O:31])[NH:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:31][C:9]1[C:5]2[C:6]([CH3:8])=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:11]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:10]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one (16.10 g, 37.8 mmol, Intermediate 4B), potassium carbonate (17.75 g, 128 mmol) and benzyl bromide (6.3 ml, 53.0 mmol) in DMF (100 ml) was stirred at RT for 2 hr. Quenched with water and extracted into ether. Washed organics with brine, dried over MgSO4, filtered, concentrated in vacuo and triturated with hexanes to provide 3-(benzyloxy)-6-chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridine. MS: [M+H]+ m/z 516.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]=1[CH:27]=O.N1CCCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:19]1[NH:20][C:21]2[C:26]([C:18]=1[CH3:17])=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(S(=O)(=O)N(C)C)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 5-dimethylaminosulfonyl-2-oxindole (96 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was held in a sealed tube at 90° C. overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 76 mg (57% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (mixture of isomers).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21]([NH2:25])=[O:23])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(N)=O)n(C)n1
Yield: 60 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using ammonia instead of isopropylamine, to the title compound (19 mg, 60%) which was obtained as a white solid. MS: m/e=327.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH3:14].[H-].[Na+]>CN(C=O)C>[CH2:13]([O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:11]([CH3:12])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:14]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
4,N-Dimethylbenzenesulphonamide was reacted with ethyl-8-bromooctanoate in DMF under the influence of sodium hydride to obtain 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid ethyl ester
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8](N)=[O:9].C(OCC)(=[O:19])C>O>[CH3:3][O:4][C:5]1[C:6]([F:16])=[C:7]([CH:11]=[C:12]([F:15])[C:13]=1[F:14])[C:8]([OH:19])=[O:9]
Reactant: CCOC(C)=O
Reactant: COc1c(F)c(F)cc(C(N)=O)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
226 ml (0.226 mole) of a 1N aqueous solution of sodium hydroxide were added to a suspension of 46.4 g (0.226 mole) of 3-methoxy-2,4,5-trifluorobenzamide (XXV) [prepared as described in Step (E5) above] in 900 ml of water, and the mixture was heated under reflux with stirring for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature and then shaken with ethyl acetate to remove unreacted material. The aqueous layer was separated and acidified with hydrochloric acid to precipitate a crystalline substance, which was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 37.1 g of 3-methoxy-2,4,5-trifluorobenzoic acid (XXVI) as colorless needles having the same properties as the product of Preparation 1.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]2[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1ncccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H]1CNCCN1c1ncccc1Br
Temperature: 240 °C
Yield: 21.7 %

Procedure:
A mixture of 3-bromo-2-chloropyridine (2 g, 9 mmol, Aldrich), (R)-(−)-2-methylpiperazine (1.5 g. 15 mmol) and N,N-diisopropylethylamine (1 mL, 5.8 mmol) in NMP (1 mL) was heated in a microwave synthesizer for 60 min at 240° C. The reaction mixture was concentrated and purified by silica gel chromatography, eluting with 10% MeOH in dichloromethane to give 0.5 g (22%) of (2R)-1-(3-bromopyridin-2-yl)-2-methylpiperazine MS (ESI, pos. ion). MS m/z: 256 (M+1), and 0.75 g (33%) of (3R)-1-(3-bromopyridin-2-yl)-3-methylpiperazine. MS m/z: 256 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]6[CH2:30][CH2:31][N:32]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:34]6)[CH:23]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCNCC6)c5)cc4c3C2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5cccc(CN6CCN(C(C)=O)CC6)c5)cc4c3C2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
To a stirred solution of methyl-2-{8-[3-(piperazin-1-ylmethyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (1.5 g, 3.11 mmol) in dry DCM (50 mL) was added 4-dimethylaminopyridine (1.9 g, 15.57 mmol) and then acetic anhydride (0.35 mL, 3.72 mmol) was added at 0° C. and stirred for 5 min. The reaction mass was maintained at room temperature and stirred for 1 h. The progress of the reaction was monitored by TLC, and after completion the reaction mass was diluted with water and extracted with DCM. The DCM layer dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give methyl-2-{8-[3-((4-acetylpiperazin-1-yl)methyl)phenyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (1.4 g, 85.88%) with HPLC purity 99.25%; m/e=525 (M++1).