Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([C@@H:13]3[CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[N:14]3[C:28](=[O:48])[C@@H:29]([CH2:36][N:37]([CH:46]=[O:47])[O:38]CC3C=CC=CC=3)[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1.O>CO.[OH-].[OH-].[Pd+2]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([C@@H:13]3[CH2:17][CH2:16][NH:15][N:14]3[C:28](=[O:48])[C@@H:29]([CH2:36][N:37]([CH:46]=[O:47])[OH:38])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc3[nH]nnc3c2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ccc2[nH]nnc2c1
Reaction time: 3 h
Yield: 75.9 %

Procedure:
To a solution of phenylmethyl (3S)-3-[(1H-1,2,3-benzotriazol-5-ylamino)carbonyl]-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-pyrazolidinecarboxylate (87.2 mg, 0.133 mmol) in methanol (2.7 ml) was added 20% palladium hydroxide on carbon, 50% water (18.73 mg, 0.133 mmol). The mixture was hydrogenated under balloon pressure for 3 h, and was then filtered through a 0.2 μm PTFE membrane. The solution was concentrated in vacuo, and the residue was azeotroped with EtOAc (10 mL). The residue was triturated with 30% EtOAc in hexanes, and the solid was collected by vacuum filtration to give (3S)—N-1H-1,2,3-benzotriazol-5-yl-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-3-pyrazolidinecarboxamide (43.2 mg, 0.101 mmol, 75% yield) as a white solid. LC/MS: (M+H)+: 430.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([CH2:35][C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(Cc2cccnc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccnc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a mixture of 4-{[4-(chloromethyl)-2-methoxyphenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole (0.94 g), ethyl 3-hydroxy-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate (0.55 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, the mixture was further stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate as colorless crystals (0.81 g, yield 68%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH2:11]1)(=[O:1])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.5 %

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (10 mL, 78.45 mmol) and 1,2-dibromoethane (6.5 mL, 78.45 mmol) in 150 mL of DMF was added potassium carbonate (22.7 g, 164.74 mmol). The resulting reaction mixture was stirred at room temperature for 2 days. The solution was diluted with 300 mL of water. The product was extracted into diethyl ether (2×200 mL), and the combined organic extracts were washed with water (1×1000 mL), and dried (MgSO4). Filtration and atmospheric distillation of the ether provided the crude product, which was distilled under reduced pressure (10 mBar) to provide ethyl 1-acetylcyclopropanecarboxylate (6.4273 g, 52%). LCMS: (M+H)+: not detected.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12]O)=[N:10][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>ClCCl>[Br:40][CH2:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: OCc1nc(-c2ccccc2)nn1-c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 193.3 %

Procedure:
To a suspension of (1,3-diphenyl-1H-1,2,4-triazol-5-yl)methanol (350 mg, 1.39 mmol) and triphenylphosphine polymer bound (679 mg, 2.02 mmol) in dichloromethane (6 mL) was added at 0-5° C. carbon tetrabromide (670 mg, 2.02 mmol). The ice bath was removed and the mixture was stirred at RT for 18 h. The suspension was filtered, washed with dichloromethane and evaporated to give 844 mg of yellow oil. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless solid (267 mg, 850 μmol, 61.0%).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[NH2:9][C:10]([NH2:12])=[O:11].C1C=CC=CC=1>C(OCC)(=O)C>[C:10]([N:12]1[CH2:7][CH2:6][CH:2]([Br:1])[C:3]1=[O:4])(=[O:11])[NH2:9]
Reactant: NC(N)=O
Reactant: O=C(Cl)C(Br)CCBr
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)N1CCC(Br)C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 30 g of 2,4-dibromobutyryl chloride (J. Med. Chem., p1995, 30. 1987) and 13.63 g of urea dissolved into 150 ml of benzene was heated at 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature, then a very excessive amount of ethyl acetate was added thereto. The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine, then the resulting solution was dried over magnesium sulfate and evaporated. The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) and cooled. To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to make the amount of the solution about 50 ml, then which was poured into ethyl acetate. The layer of ethyl acetate was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was washed well with n-hexane, whereby 15.7 g of the objective compound was obtained in 66% yield.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]([OH:15])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30].O>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH3:12])[C:6]([C:13]([NH:29][NH2:30])=[O:15])=[CH:5][N:4]=1
Reactant: CCCNc1nc(SC)ncc1C(=O)O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCCNc1nc(SC)ncc1C(=O)NN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
2-Methylthio-4-n-propylaminopyrimidine-5-carboxylic acid (22.6 g) obtained in Step 1 was dissolved in THF (360 mL), then carbonyldiimidazole (16.9 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Then, a THF (100 mL) solution of hydrazine monohydrate (14.5 mL) was added dropwise to the reaction mixture over 30 minutes, followed by stirring at room temperature for 2.5 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture. Precipitated crystals were collected by filtration and the resulting crystals were washed with water and dried thoroughly under reduced pressure to give 2-methylthio-4-n-propylaminopyrimidine-5-carbohydrazide (20.1 g, yield 84%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:39])[N:3]=1.C(N(CC)CC)C.[C:47](OC(=O)C)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:39][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:23]=1[C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=1)(=[O:49])[CH3:48]
Reactant: COc1ccc(COc2cccc(N)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COc2cccc(NC(C)=O)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-(2-amino-6-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate (0.10 g, 0.189 mmol) obtained in the step (1) of Example 1-11 in dichloromethane (10 mL) including triethylamine (0.02 g, 0.227 mmol) was added acetic anhydride (0.08 g, 0.889 mmol). The stirring was continued at 0° C. for 5 hrs. The mixture was allowed to warm to room temperature, and the stirring was continued for 30 min. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1-1/2) to give tert-butyl 3-(6-{2-(acetylamino)-6-[(4-methoxybenzyl)oxy]phenyl}-2-amino-3-cyano-4-pyridinyl)-1-piperidinecarboxylate as a pale yellow oil (0.102 g, yield; 94.5%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH2:13]>S(=O)(=O)(O)O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:13][CH:12]([C:11]([O:20][CH3:21])=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: COC(=O)CC(CSc1nc2ccccc2s1)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
16.8 g of finely powdered 2-mercaptobenzothiazole are suspended in 150 ml of 70% sulfuric acid and 16.6 g of dimethyl itaconate are added dropwise at 0°-10° in the course of half an hour, with stirring. After further 16 hours at 0°-10°, the reaction mixture is poured into ice water and extracted with ethyl acetate. The organic phase is separated, dried and the solvent is evapourated. The solid residue is recristallied from cyclohexane yielding dimethyl 3-(benzothiazol-2-ylthio)-propane-1,2-dicarboxylate, melting at 46°-47°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[C:10]1([C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH2:21][C:19]2[S:20][C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: Cc1ccc(Br)c(F)c1
Product: Cc1ccc(Br)c(F)c1Cc1ccc(-c2ccccc2)s1

Procedure:
4-Bromo-3-fluorotoluene and 5-phenyl-2-thiophenecarboxaldehyde were treated in a manner similar to Reference Example 116 to give the target compound as pale blue powders. APCI-Mass m/Z 361/363 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>C(O)C>[CH3:23][Si:8]([CH3:7])([CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: C1CNCCN1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCNCC1
Temperature: 70 °C

Procedure:
piperazine (3.14 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities. Excess piperazine was removed by sublimation.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:21])CC>ClCCl>[F:21][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)C1CCC(O)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCC(F)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of tert-butyl 4-hydroxycyclohexanecarboxylate (1500 mg, 7.45 mmol) in dichloromethane (anhydrous, 20 ml), DAST was (1571 mg, 22.4 mmol) added at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. The mixture was diluted with dichloromethane, quenched with sodium bicarbonate. The organic layer was separated, the aqueous phase was extracted with EtOAc. The combined organic layer were washed with water, brine, dried with androus sodium sulphate. The product was purified (flash chromatography, 10 to 20% EtOAc/hexanes) and obtained as a 210 mg of yellow oil (25%). 1H NMR (300 MHz, CDCl3): δ 5.60-5.80 (m, 1H), 4.99-5.09 (m, 2H), 4.73 (d, 2H), 3.34 (br, 2H), 2.29-2.32 (m, 2H), 1.44-1.46 (m, 9H).
Reaction SMILES: NC1C=C(C2SC3C=CC=CC=3N=2)C([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=CC=1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)=[N+]=[N-]>>[NH2:25][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][C:29]=1[O:11][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Reactant: [N-]=[N+]=Nc1ccc(-c2nc3ccccc3s2)cc1
Product: Nc1ccc(-c2nc3ccccc3s2)cc1OS(=O)(=O)C(F)(F)F
Yield: 12 %

Procedure:
This compound was prepared in a similar way to the compound of Example XIV from 2-(4-azidophenyl)benzothiazole. The yield was 12%, (Found: M+ 374. C14H9F3N2O3S2 requires MW 374).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]3[S:19][C:20]([CH2:22][OH:23])=[CH:21][C:15]=3[N:14]=[CH:13]2)=[CH:8][CH:7]=1.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:23][CH2:22][C:20]2[S:19][C:16]3[C:17](=[O:18])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:24])[CH3:1])=[CH:7][CH:8]=4)[CH:13]=[N:14][C:15]=3[CH:21]=2)[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: CN(C)CCOc1ccc(-n2cnc3cc(CO)sc3c2=O)cc1
Product: CN(C)CCOc1ccc(-n2cnc3cc(COCC4CC4)sc3c2=O)cc1

Procedure:
3-[4-(2-Dimethylaminoethoxy)phenyl]-6-hydroxymethyl-3H-thieno[3,2-d]pyrimidin-4-one was reacted with cyclopropylmethyl bromide by method V. The product with the molecular weight of 399.52 (C21H25N3O3S) was obtained in this way; MS (ESI): 400 (M+H+).
Reaction SMILES: C[Si](C)(C)[C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[Br:20]Br>C(#N)C>[Br:20][C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: C[Si](C)(C)c1cc2c(o1)C(=O)c1ccccc1C2=O
Reactant: BrBr
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)c2oc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To the solution of 0.8 gram (3.0 mmoles) of 2-trimethylsilyl-naphtho[2,3-b]furan-4,9-dione in 20 mL of acetonitrile at room temperature, 0.53 grams (3.3 mmoles) of bromine in 20 mL of acetonitrile was added dropwise over 5 minutes. The mixture was further stirred for 30 minutes at room temperature, and then evaporated to dryness. The residue was crystallized in ethanol/water. Pure crystal product was filtered and dried under vacuum. 0.75 grams of product (yield 90%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 6.96 (s, 1H), 7.76-7.82 (m, 2H), 8.18-8.25 (m, 2H). Mass (M+H) is 277 and 279.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH:29]([CH3:31])[CH3:30])=[C:13]([C:15]2[NH:27][C:18]3=[N:19][C:20]([C:23]([O:25]C)=[O:24])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH:29]([CH3:31])[CH3:30])=[C:13]([C:15]2[NH:27][C:18]3=[N:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc(OCc4ccccc4)ccc3OC(C)C)[nH]c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(C(=O)O)nc2[nH]1
Yield: 65 %

Procedure:
A solution (2 ml) of methyl 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-5-carboxylate (35 mg) and 1N aqueous sodium hydroxide solution (0.2 ml) in methanol was stirred at room temperature for 18 hr. The reaction mixture was adjusted with 1N hydrochloric acid to pH 3, and the precipitated crystals were collected by filtration and washed with acetonitrile to give the title compound (22 mg, yield 64%) as colorless crystals. purity 98%. M+H: 404. 1H NMR (DMSO-d6) δ: 1.37 (6H, d, J=5.0 Hz), 4.67-4.72 (1H, m), 5.17 (2H, s), 7.16-7.52 (7H, m), 7.73-8.13 (3H, m).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:24]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C:24]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:23][N:22]=[C:21]([O:7][C:6]3[CH:1]=[CH:2][C:3]([CH3:8])=[CH:4][CH:5]=3)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: Cc1ccc(O)cc1
Reactant: COc1ccc(-c2nc(S(C)(=O)=O)ncc2C(=O)N2CCOCC2)cc1OC
Solvent: CC#N
Product: COc1ccc(-c2nc(Oc3ccc(C)cc3)ncc2C(=O)N2CCOCC2)cc1OC
Temperature: 65 °C
Yield: 75 %

Procedure:
Acetonitrile (10 ml) potassium carbonate (0.5 g), paracresol (2.7 g) and the pyrimidine obtained in Example 432 (1 g) are placed in a reactor together with 3 drops of TDA--1[tris(3,6-dioxaheptyl)amine] as catalyst. The mixture in heated to 65° C. for one hour, and the solvent in evaporated. The mixture in taken up in water and extracted with ether, dried over MgSO4 and evaporated. A white solid in obtained in a yield of 75%, m.p. 152° C.
Reaction SMILES: [CH:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)[C:7]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[CH:15]=[C:10]([C:8]2[C:7]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:6][N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:9]=2)[CH:11]=[CH:12][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(C)n1cc(-c2cc[n+]([O-])cc2)c(-c2ccc(Cl)s2)n1
Product: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Yield: 29 %

Procedure:
4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine-N-oxide (6.1 mmol) was stirred in 20 mL of phosphorous oxychloride at 120° C. for 5 h. The solvent was then evaporated and the residue was treated with methanol and evaporated again. The residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 3:1) to afford 623 mg of 2-Chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (29% yield).
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:1])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a DMF solution (15 ml) of N-(3-bromo-phenyl)-acetamide (1.19 g) obtained in Step A, 60% oily sodium hydride (279 mg) was added, followed by stirring at room temperature for 10 minutes. To this, methyl iodide (434 μl) was added, followed by stirring at room temperature for 21 hours. To this, water (30 ml) was added, followed by extraction with ethyl acetate (30 ml×2), and the organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, followed by purification by silica gel column chromatography (dichloromethane/methanol=200/1), to obtain the desired compound (1.20 g, 94%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:8])=[CH:3][CH:2]=1.O.NN>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:9])[CH3:8])=[CH:3][CH:2]=1
Reactant: CC(c1ccncc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(N)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[1-(Pyridin-4-yl)ethyl]isoindoline-1,3-dione (283 mg, 1.12 mmol) in methanol (3 mL) was mixed with hydrazine monohydrate (272 μL, 5.61 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of n-hexane. 1.86 g of aniline (0.02 mol, 1 eq) and 2.76 g of potassium carbonate (0.02 mol, 1 eq) are added. The reaction mixture is heated to 50° C. and stirred for 4 hours. After the reaction the solid inorganic salt is filtered, washed with 2×10 mL of n-hexane and the filtrate is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 6.50 g of the title compound (VIe) (85%) as a yellow solid.
Reaction SMILES: [Br:1][CH:2]([C:5]1[N:6]=[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:8]2[C:9](=[O:11])[CH:10]=1)[CH2:3][CH3:4].[I:17]N1C(=O)CCC1=O>C(#N)C>[Br:1][CH:2]([C:5]1[N:6]=[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:8]2[C:9](=[O:11])[C:10]=1[I:17])[CH2:3][CH3:4]
Reactant: CCC(Br)c1cc(=O)n2c(C)cccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCC(Br)c1nc2cccc(C)n2c(=O)c1I
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 2-(1-bromopropyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.46 g, 12.3 mmol) and N-iodosuccinimide (4.15 g, 18.4 mmol) in acetonitrile (100 mL) was stirred at 80° C., under nitrogen, overnight. After removal of acetonitrile in vacuum, the resulting solid was dissolved in methylene chloride, washed with water, saturated Na2S2O3, saturated sodium bicarbonate, and brine; and then the organic layers dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to provide the desired product (4.53 g, 90.4%). LCMS calculated for C12H13BrIN2O (M+H)+: m/z=406.9. Found: 407.1.