Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1>CO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[NH:27][C:22]3[CH:21]=[C:20]([N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)[CH:25]=[CH:24][C:23]=3[N:26]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: Nc1ccc(-n2cncn2)cc1N
Solvent: CO
Product: COc1ccc(-c2nc3ccc(-n4cncn4)cc3[nH]2)cc1OC(C)C
Yield: 70.5 %

Procedure:
Under reflux, 20 ml of methanol solution containing 4.27 g of 3-isopropoxy-4 -methoxybenzaldehyde and 10.81 g of ferric chloride hexahydrate was added dropwise to 35 ml of methanol solution containing 3.50 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example 2. The resulting mixture was refluxed for 1 hour and then cooled, and the insoluble matter was collected by filtration. This was suspended in ethyl acetate/water and alkalified with liquid ammonia, and then the insoluble matter was removed by Celite filtration. The ethyl acetate layer was collected and dried over magnesium sulfate, and then the solvent was evaporated. By crystallizing the resulting residue with ethyl acetate/hexane, 4.92 g (70%) of the title compound was obtained. Its physical property values coincided with the data obtained in the above step (1).
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:9][C:8]=2[F:22])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>ClCCl>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[S:40]([C:35]3[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=3)(=[O:42])=[O:41])=[C:8]([F:22])[CH:9]=2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)c(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)c3cc(Cl)cc(Cl)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of 1-(4-(4-((cyclobutylamino)methyl)-3-fluorophenyl)piperazin-1-yl)ethanone (55 mg, 0.18 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (0.047 mL, 0.27 mmol), followed by 3,5-dichlorobenzene-1-sulfonyl chloride (50 mg, 0.20 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then concentrated and purified by preparative reverse phase HPLC to yield 41 mg of N-(4-(4-acetylpiperazin-1-yl)-2-fluorobenzyl)-3,5-dichloro-N-cyclobutylbenzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.95 (t, J=1.8 Hz, 1H), 7.72 (d, J=1.8 Hz, 2H), 7.18 (t, J=8.9 Hz, 1H), 6.80-6.74 (m, 1H), 6.74-6.67 (m, 1H), 4.40 (s, 2H), 4.35-4.20 (m, 1H), 3.62-3.51 (m, 4H), 3.25-3.17 (m, 2H), 3.16-3.10 (m, 2H), 2.04 (s, 3H), 2.02-1.88 (m, 4H), 1.55-1.48 (m, 2H); LCMS (m/z) ES+ 514.0 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)=[N:30][N:29](C4CCCCO4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[Cl:40][C:37]1[CH:36]=[CH:35][C:34](/[CH:33]=[CH:32]/[C:31]2[C:17]3[C:18](=[N:19][C:20]([C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)=[CH:21][C:16]=3[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[NH:29][N:30]=2)=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1cc(-c2ccc(O)cc2)nc2[nH]nc(/C=C/c3ccc(Cl)cc3)c12)N1CCNCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
To a solution of 4-[3-[(E)-2-(4-chloro-phenyl)-vinyl]-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.32 g, 2.05 mmol) in dry methanol (20 ml) was added 4N HCl in dioxane (5.1 ml, 20 mmol). The reaction mixture was heated to reflux for 30 minutes then cooled to room temperature and filtered. The precipitate was isolated and dried to afford a chlorhydrate salt of the title compound as an orange solid (0.9 g, 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:13][CH:12]=1
Reactant: CSc1nccc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1nccc(-c2ccc(Cl)cc2)n1
Temperature: 90 °C
Yield: 89.9 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine (3 g, 18.7 mmol), 4-chloro-phenylboronic acid (3.5 g, 22.3 mmol), tetrakis(triphenylphosphine)palladium (0) (0.43 g, 0.37 mmol), sodium carbonate (5.15 g, 48.5 mmol) in 1,2-dimethoxyethane (140 mL) and water (70 mL) was heated at 90° C. for 20 h under nitrogen. The cooled reaction mixture was concentrated In vacuo, diluted with water (50 mL), extracted with CH2Cl2 (2×100 ml), dried (Na2SO4) and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluting with 10:1 to 2:1 cyclohexane:EtOAc afforded the title compound as a white solid (3.98 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([C:17]3[N:21]([CH3:22])[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[N:19][N:18]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH3:30]I>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:30])[C:11]([C:13]2([C:17]3[N:21]([CH3:22])[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[N:19][N:18]=3)[CH2:14][CH2:15][CH2:16]2)=[O:12])=[CH:6][CH:5]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C1(C(=O)Nc2ccc(Cl)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)C1(c2nnc(-c3ccccc3Cl)n2C)CCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% oily, 13 mg) was suspended in DMF (3 ml) and then N-(4-chlorophenyl)-1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclobutanecarboxamide was added thereto under ice cooling, followed by stirring at room temperature for 30 minutes. Methyl iodide (17 μl) was added thereto under ice cooling, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml) and washed with a saturated sodium bicarbonate solution (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=2:98) to obtain 83 mg of N-(4-chlorophenyl)-1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-N-methylcyclobutanecarboxamide (white solid).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:18]2[NH:17][C:16]([CH3:15])=[CH:20][C:19]=2[CH3:21])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Cc1c[nH]c(C)c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
2-Chloronicotinoyl chloride (3.4 g, 20 mmol) (Aldrich, Milwaukee, Wis.) was added to a solution of aluminum chloride (2.7 g, 20 mmol) (Aldrich, Milwaukee, Wis.) in dichloromethane (100 mL) at 0° C., followed by a solution of 2,4-dimethylpyrrole (2.9 g, 30 mmol) in dichloromethane (20 mL). The mixture was then stirred at room temperature for one hour. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.9 g (62%) of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone.
Reaction SMILES: C[O:2][C:3](=[O:14])[CH:4]([NH:9]C(OC)=O)[CH2:5][CH2:6][CH2:7][CH3:8].[ClH:15].C(O)=O>O>[ClH:15].[NH2:9][CH:4]([C:3]([OH:14])=[O:2])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(NC(=O)OC)C(=O)OC
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CCCCC(N)C(=O)O
Yield: 97.3 %

Procedure:
4.07 grams of 2-methoxycarbonylaminohexanoic acid methyl ester were heated in 15 ml of a mixture consisting of equal parts of concentrated hydrochloric acid, 100 weight percent formic acid and water for 24 hours under reflux. The acid mixture was removed in a vacuum, the oily residue treated twice with 20 ml of acetone and freed from acetone again in a vacuum. The now crystalline residue was intensively stirred with 10 ml of acetone, filtered with suction and dried over diphosphorus pentoxide. There were obtained 3.26 grams (97.3%) of D,L-norleucine hydrochloride pure by thin layer chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[C:32]([C:35]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)(=[O:34])[NH2:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:38]3[CH2:37][CH2:36][C:35]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)([C:32]([NH2:33])=[O:34])[CH2:40][CH2:39]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Reactant: NC(=O)C1(c2ccccc2)CC[NH2+]CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(C(N)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Yield: 52.3 %

Procedure:
5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 130 mg, 0.306 mmol), 4-carbamoyl-4-phenylpiperidin-1-ium trifluoroacetate (1.1 eq, 69 mg, 0.337 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.1 eq., 149 mg, 0.337 mmol), and triethylamine (3 eq, 0.13 mL, 0.92 mmol) was stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide (98 mg, 52%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.10 (dd, J=9.75, 3.63 Hz, 1H) 2.18 (s, 3H) 2.20-2.28 (m, 1H) 2.46 (d, J=14.03 Hz, 2H) 3.65 (t, J=10.31 Hz, 1H) 3.75-3.88 (m, 1H) 3.95-4.07 (m, 1H) 4.15-4.28 (m, 1H) 5.17-5.50 (m, 2H) 7.00 (d, J=8.38 Hz, 2H) 7.12-7.50 (m, 10H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-])=O)[CH:17]=3)[NH:12][C:11]2=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Pd].C(O)C>[NH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:24])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:19]2=[O:20]
Reactant: [H][H]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1CCCCn1ccnc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2[nH]c(=O)n(CCCCn3ccnc3)c(=O)c2c1

Procedure:
A mixture of 2.0 g of 3-[4-(1H-imidazol-1-yl)butyl]-6-nitro-2,4(1H,3H)-quinazolinedione, 1.0 g of 10% palladium-on-carbon catalyst and 200 ml of ethanol is shaken in a Parr hydrogenater under 45 pounds of hydrogen pressure until the hydrogen uptake is complete. The reaction mixture is heated to the boil and the catalyst is filtered off. The ethanolic solution is concentrated to a low volume and the desired product is recovered by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][N:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[CH2:18]2)[CH2:14]1)=[O:12]
Reactant: Cc1cccc(Cl)n1
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cccc(C)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-6-methyl-pyridine. MS (ESI): mass calculated for C21H25N3O3, 367.45; m/z found 368.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=[O:10])[S:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:7]1[C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:9][C:8]1=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2[nH]c(=O)sc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)sc(=O)n2Cc1ccccc1
Yield: 68.2 %

Procedure:
A solution of 6-methoxybenzthiazol-2-one (1, 0.036 g, 0.2 mmol), anhydrous K2CO3 (0.110 g, 0.8 mmol, 4 eq) and benzyl bromide (0.035 L, 0.3 mmol, 1.5 eq) was stirred in anhydrous DMF (2 mL) at 120° C. for 2 h. The reaction mixture was cooled and poured in to water, extracted with EtOAc. The EtOAc layer washed with water (2×10 mL), dried over Na2SO4 and evaporated to dryness. The crude mixture was purified by Combiflash, using hexane-ethylacetate (7:3) as a solvent afforded W-124 as a solid (0.037 g, 68%) as colorless oil; 1H NMR (CDCl3): δ 7.36-7.25 (5H, m), 7.0 (1H, d, J=2.4 Hz), 6.85 (1H, d, J=8.8 Hz), 6.77 (1H, dd, J=8.8 and 2.8 Hz), 5.12 (2H, s), 3.79 (3H, s); MS: 274.0 (M+H+).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].C(OCC)C.[CH:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:12]>O1CCCC1>[OH:12][CH:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15% Isopropyl magnesium bromide in diethyl ether (23.5 mL, 24.0 mmol) was added to a stirred solution of 3-formylbenzonitrile (2.62 mg, 20.0 mmol) in dry tetrahydrofuran (18 mL), at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 1 hour, then at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and 1M hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified with silica column chromatography (eluting with 9% to 25% ethyl acetate in heptane) to afford the title compound (1.164 g).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:1]([C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]([OH:2])=[O:10])=[O:11])=[CH:15][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 25 parts of 1,3-isobenzofurandione and 108.5 parts of fluorobenzene were added portionwise 50 parts of aluminium chloride. Upon completion, the whole was heated slowly to reflux and stirring was continued for 1.50 hours at reflux temperature. The reaction mixture was cooled and poured onto a mixture of crushed ice and 60 parts of concentrated hydrochloric acid. The product was extracted twice with dichloromethane. The combined extracts were washed with a sodium hydroxide solution 10%. The aqueous phase was separated, washed with 2,2'-oxybispropane and acidified with concentrated hydrochloric acid while cooling. The whole was stirred for 1 hour at room temperature. The precipitated product was filtered off and dissolved in benzene. The solution was distilled azeotropically to dry. The solid residue was stirred in hexane. The product was filtered off and dried in vacuo at about 50° C., yielding 33.5 parts (87.7%) of 2-(4-fluorobenzoyl)benzoic acid; mp. 129.2° C. (intermediate 90).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1([CH3:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1([CH3:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: COC(=O)C=CC1(C)CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC1(C)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a solution of 220 g (1.19 mmol) of 3-(4-methyltetrahydropyran-4-yl)acrylic acid methyl ester in methanol (15 mL) was added 40 mg of palladium-carbon, replaced with hydrogen gas, and then stirred for 12 hours at room temperature. After the reaction mixture was filtered through Celite, the solvent was removed under a reduced pressure. The obtained residue was purified by column chromatography (silica gel 20 g, developing solvent: ethyl acetate) to obtain 222 mg (yield 100%) of 3-(4-methyltetrahydropyran-4-yl)propionic acid methyl ester (IX-144). Its physical property is shown below.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:21](Cl)=[O:22])[S:19][CH:20]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:21]([C:18]1[S:19][CH:20]=[C:16]([C:14]2[CH:13]=[N:12][C:11]3[N:10]([N:9]=[CH:8][C:7]=3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]=2)[CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cc(-c2cnc3c(-c4ccccc4)cnn3c2)cs1
Reaction time: 8 h

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carbonyl chloride (5-4, 5.0 mg, 0.015 mmol, 1 equiv), diisopropylethylamine (60 TL, 0.030 mmol, 2.0 equiv), and N,N-dimethylethane-1,2-diamine (41 TL, 0.016 mmol, 1.1 equiv) in dichloromethane (1 mL) was mixed and allowed to stand for 8 hours. The reaction mixture was washed with aqueous half-saturated sodium bicarbonate solution (0.5 mL). The organic layer was dried over sodium sulfate and concentrated to give N-[2-(dimethylamino)ethyl]-4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)thiophene-2-carboxamide (5-5) as a yellow solid. LRMS m/z: Calc'd for C21H22N5OS (M+H) 392.2, found 392.3.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[O-:26]S([O-])(=S)=O.[Na+].[Na+]>CO.OO.O>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:26])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.4 g of 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole was suspended in 6 ml of methanol at room temperature. 0.02 g of Na2WO4·2H2O oxidation catalyst was dissolved in 0.109 g H2O2 (35% aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 5.5 hours while stirring. 10 ml of 10% Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom, followed by adding a diluted acetic acid aqueous solution to a pH value of about 8. The resulting pH=8 mixture was extracted with ethyl acetate to obtain a crude product of Pantoprazole with a LC purity of about 52.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:29])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH2:30](O)[CH2:31][CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1CCc1ccc([N+](=O)[O-])cc1
Reactant: OCCCCO
Product: O=C1c2ccccc2C(OCCCCO)(c2ccc(Cl)cc2)N1CCc1ccc([N+](=O)[O-])cc1
Yield: 46.4 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-[2-(4-nitrophenyl)ethyl]-2,3-dihydroisoindol-1-one (562 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (306 mg, 63%). 1H NMR (300 MHz, CDCl3): 8.11-8.08 (m, 2H, O2N—C—CH), 7.91-7.88 (m, 1H, C(O)═C═CH), 7.55-7.53 (m, 2H, Ar—H), 7.30-7.14 (m, 7H, Ar—H), 3.66 (m, 2H, N—CH2), 3.45 (t, J=8.1 Hz, 2H, HO—CH2), 3.16-3.11 and 3.03-2.99 (m, 2H, OCH2), 3.00-2.89 and 2.73-2.66 (m, 2H, NCH2CH2), 1.75-1.63 (m, 5H, CH2 and OH). 13C NMR (75 MHz, CDCl3): 168.23, 147.02, 146.62, 145.32, 137.69, 134.84, 132.74, 131.98, 129.99, 129.48, 128.74, 127.87, 123.65, 123.51, 123.10, 94.54, 62.79, 62.43, 40.51, 34.21, 29.60, 26.07. HPLC: Rt=3.45 min. Anal.: calc. for C26H25ClN2O5: C, 64.93; H, 5.24; N, 5.82. Found: C, 64.82; H, 5.18; N, 5.68.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Cl[CH2:9][CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1C=CC=CC=1.CN(C)C=O>[C:19]([O:18][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][CH2:9][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])(=[O:21])[CH3:20]
Reactant: CS(N)(=O)=O
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCC(CCCNS(C)(=O)=O)OC(C)=O
Reaction time: 1 h

Procedure:
Sodium hydride (2 g., 0.083 mole) is suspended in benzene (60 ml.) and dimethylformamide (120 ml.). Methanesulfonamide (7.6 g., 0.08 mole) is added and the suspension is heated on the steam bath for two hours. After the mixture is cooled in an ice bath, 1-chloro-4-acetoxynonane (18.5 g., 0.084 mole) is added dropwise with stirring over one hour. The suspension is heated on the steam bath for twenty hours and separated between ethyl acetate and water. After being washed with water, the organic layer is dried over anhydrous magnesium sulfate. Evaporation of the ethyl acetate in vacuo and distillation through a short path column gives the title compound, 11.6 g. (52%), b.p. 182°-185° C./0.08 mm. Anal. Calcd. for C12H25NO4S: C, 51.58; H, 9.02; N, 5.01. Found: C, 52.33; H, 8.84; N, 4.91.