Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7]1)[CH:2]=[CH2:3].Cl[CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16].[H-].[Na+].O>CS(C)=O>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:14][O:12][CH2:11][CH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[O:10]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: C=CCOCC1CCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOCC1CCC(COCC(=O)N(CCC)CCC)O1
Temperature: 25 °C
Yield: 141 %

Procedure:
A mixture of 6.89 g of tetrahydro-5-[(2-propenyloxy)methyl]-2-furanmethanol (0.04 mole) and 7.12 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) are dissolved in 200 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding a pale yellow oil which is vacuum distilled and the fraction distilling at 185°-188° @ 0.5 mm is collected yielding 8.84 g (70%) of the above compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:27][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][CH2:2][CH2:1]2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2c1CCC2
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3CCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A solution of 2-(indan4-yloxy)-ethylchloride (0.58 g, 2.9 mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.4 g, 7.4 mmol) and triethylamine (1 ml, 7.4 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (7% methanol-methylene choride) afforded 0.31 g (30%) of product as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21](Cl)(=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 85.3 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pentanoyl chloride (0.48 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.61 g (85%) of product as an off-white solid: mp 178–179° C.; 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.5 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H), 5.18 (dd, J=5.0 and 12.4 Hz, 1H), 2.99–2.89 (m, 1H), 2.68–2.45 (m, 4H), 2.13–2.09 (m, 1H), 1.69–1.57 (m, 2H), 1.44–1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H); 13C NMR (DMSO-d6) δ 172.72, 171.99, 169.73, 167.83, 166.64, 136.64, 136.07, 131.36, 125.96, 118.15, 116.68, 48.97, 36.32, 30.97, 26.88, 22.03, 21.70, 13.64; Anal. Calcd. For C19H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C, 60.10; H, 5.37; N, 11.58.
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a mixture of 4-{[cyclohexyl(2-methyl-5-phenylthiophen-3-yl)methyl]amino}benzoic acid (300 mg) synthesized above, ethyl β-alaninate hydrochloride (136 mg), 1-hydroxybenzotriazole monohydrate (136 mg) and triethylamine (124 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (232 mg, 66%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)=[N:4][C:5]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:6][C:7]=1[OH:8].C(O)(=O)C.[N:31]([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:14][N:12]1[CH:13]=[C:9]([C:5]2[N:4]=[C:3]3[N:15]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)[N:31]=[N:1][C:2]3=[C:7]([OH:8])[CH:6]=2)[CH:10]=[N:11]1
Reactant: Cn1cc(-c2cc(O)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2cc(O)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ol (170 mg, 0.49 mmol) was added to a solution of acetic acid (3 mL) and H2O (3 mL) at 0° C., followed by the addition of NaNO2 (69 mg, 10 mmol) in H2O (0.3 mL). The reaction mixture was stirred at 0° C. for 1 h, then basified with aqueous 30% NaOH to pH=6-7 and purified by chromatography to afford the title compound (120 mg). MS (m/z): 358 (M+1)+.
Reaction SMILES: C([O:4][CH:5]([CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16]C(=O)C)[C:10]=2[O:9][CH:8]=1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]([O:47][CH3:48])=[O:46].[Cl-].[NH4+]>CO.CN(C=O)C>[OH:4][CH:5]([CH2:20][CH2:21][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:6][C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:10]=2[O:9][CH:8]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)Oc1cccc2c(CC(CCC(c3ccccc3)c3ccccc3)OC(C)=O)coc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)COc1cccc2c(CC(O)CCC(c3ccccc3)c3ccccc3)coc12
Temperature: 25 °C
Yield: 100 %

Procedure:
3-(2-acetoxy-5, 5-diphenylpentyl)-7-acetoxybenzofuran (184 mg) was dissolved in methanol (5 ml) and the obtained solution was stirred at room temperature. To this solution, 1N aqueous sodium hydroxide solution (1 ml) was added and the resulting solution was stirred at room temperature. After confirming vanishment of the materials, the solvent was removed under reduced pressure. Water (5 ml) was added to the obtained residue and the resultant was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. The sodium sulfate was removed by filtration and the solvent was removed under reduced pressure to obtain a crude product. The obtained crude product was dissolved in DMF (3 ml) and the obtained solution was stirred at room temperature. To this solution, potassium carbonate (100 mg) and methyl bromoacetate (0.10 ml) were added and the resultant was stirred at room temperature. After confirming vanishment of the materials, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1-2/1) using silica gel to obtain the desired compound (184 mg, yield: 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([NH:25][C:26]1[CH:38]=[C:37]([CH:39]=[CH2:40])[CH:36]=[CH:35][C:27]=1[C:28]([O:30]C(C)(C)C)=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([CH2:39][CH2:40][C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)[CH:36]=[CH:35][C:27]=1[C:28]([OH:30])=[O:29])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Reactant: Brc1ccc2occc2c1
Agent: [Pd+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(CCc2ccc3occc3c2)ccc1C(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 7.2 %

Procedure:
0.12 g of 5-bromobenzofuran, 0.20 g of cesium carbonate, 30 mg of tetrabutylammonium bromide and 48 mg of polymer supported di(acetato)dicyclohexylphenylphosphine palladium(II) were added to 2.0 mL of toluene solution containing 0.10 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, 48 mg of polymer supported di(acetato) dicyclohexylphenyl-phosphine palladium(II) was added and stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 2.4 mL of tetrahydrofuran, 0.6 mL of water, 0.44 mL of acetic acid, 0.42 g sodium formate and 50 mg of 3.9% palladium-carbon (ethylenediamine complex) were added to the obtained residue and stirred at 50° C. for 12 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 10 mL of trifluoroacetic acid was added to the obtained residue and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was purified with reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 8.6 mg of 2-(benzamido)-4-(2-(benzofuran-5-yl)ethyl)benzoic acid as white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[CH3:7])=[CH:2]1.[N-:9]=[N+:10]=[N-:11].[Na+].O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([N:9]=[N+:10]=[N-:11])[CH3:7])=[CH:2]1
Reactant: CC(Cl)c1ccsc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])c1ccsc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
A mixture of 1-(thien-3-yl)chloroethane (5.0 g, 34 mmol) and sodium azide (2.65 g, 41 mmol) in DMF was stirred at room temperature for three days. The reaction mixture was poured into H2O (500 ml) and extracted with CH2Cl2 (3×200 ml). The organic extracts were washed with H2O (5×100 ml), dried over MgSO4 and concentrated in vacuo to give the product (5.02 g, 96% yield) as a brown oil; IR (neat) 2110 cm-1 ; 1H NMR (CDCl3) δ1.55 (d, J=7 Hz, 3H, CHCH3), 4.67 (q, J=7 Hz, 1H, CHCH3), 6.98-7.43 (m, 3H, thiophene-H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][C:18]#[N:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of 4-benzyloxyphenol (9.4 g, 47 mmol), bromoacetonitrile (6.8 g, 56.7 mmol) in acetone (50 mL) with K2CO3 (2 g, 14.5 mmol) was heated to reflux 1 min, then at 40° C. for 1 h with stirring. The reaction mixture was filtered, the solids washed with acetone, and the filtrate concentrated in vacuo to afford a tan oil which crystallized on standing, providing 10.70 g of (4-benzyloxyphenoxy)-acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1)(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=4[S:34]([N:37]4[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: NC1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 1-((2-bromophenyl)sulfonyl)piperidin-4-amine. MS (ESI): mass calcd. for C24H25FN4O3S, 468.16; m/z found, 469.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.09-8.05 (m, 1H), 7.83 (d, J=1.1, 1H), 7.75-7.68 (m, 2H), 7.66-7.55 (m, 2H), 7.43-7.39 (m, 1H), 7.34-7.26 (m, 2H), 4.39-4.35 (m, 2H), 3.76-3.68 (m, 2H), 3.47 (d, J=13.4, 2H), 3.21-3.11 (m, 1H), 2.60-2.50 (m, 2H), 1.96-1.87 (m, 2H), 1.56-1.43 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.BrN1C(=O)CCC1=O.[CH:19]1([CH2:22][N:23]2[C:31]3[N:30]=[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([NH:39][CH3:40])=[CH:35][CH:34]=4)[NH:28][C:27]=3[C:26](=[O:41])[N:25]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:24]2=[O:50])[CH2:21][CH2:20]1.C(N(CC)CC)C>>[CH:19]1([CH2:22][N:23]2[C:31]3[N:30]=[C:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]([CH3:40])[C:4](=[O:6])[C:3]5[CH:7]=[CH:8][CH:9]=[N:10][C:2]=5[CH3:1])=[CH:37][CH:38]=4)[NH:28][C:27]=3[C:26](=[O:41])[N:25]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[C:24]2=[O:50])[CH2:21][CH2:20]1
Reactant: Cc1ncccc1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Product: Cc1ncccc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Yield: 34 %

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 2-methylnicotinic acid (Aldrich) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, N-bromosuccinimide was used in place of N-chlorosuccinimide, the reaction was performed using 0.66 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 1 equivalent of triethylamine was added as the final reagent to the reaction mixture. Purification was performed by chromatography using silica eluted with 95:5 ethyl acetate/methanol to give the product as a light brown solid (34%). MS, M+H)=553.2361.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][C:29]([NH2:31])=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([NH2:31])=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(N)=O)C2=O)CC1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-bromoacetamide, to give the desired product as a white solid (6%).
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.N1C2C=CC=CC=2NC=1.[O-]Cl.[Na+].[OH-].[Na+].S(S([O-])=O)([O-])(=O)=[O:41].[Na+].[Na+]>O1CCCC1.C(#N)C.O.C(O)(C)C.C(O)C.CO>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:41])[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: O=S([O-])S(=O)(=O)[O-]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: CC#N
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorinated pantoprazole derivatives IV and V can be produced by reaction of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]thio]-1H-benzimidazole with NaOH and about 3 to about 5 molar equivalents of NaOCl under conditions especially developed to produce these derivatives. Those conditions include admixing 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]thio]-1H-benzimidazole compound VI with a quantity of NaOCl of about 3 to about 5, preferably about 1.5 to about 2.5 molar equivalents and a quantity of NaOH of about 1.5 to about 2.5 molar equivalents. Preferred relative quantities of these reagents are about 1.8 molar equivalents of each with respect to benzimidazole VI. Compound VI, NaOCl and NaOH are admixed in a water miscible protic solvent, such as methanol, ethanol and i-propanol, or water miscible aprotic solvent such as acetonitrile and tetrahydrofuran. The reaction is conducted at ambient or elevated temperature, preferably ambient temperature. In all other respects, the reaction conditions can be the same as those of the process previously described for oxidizing 2-[(pyridinyl)methyl]thio-substituted benzimidazoles selectively to 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles. After completing the reaction, the mixture is treated with aqueous sodium metabisulfite to pH 8.5 and stirred at room temperature for 1 hour. The two phases from the resulting reaction are separated, and the solvent is evaporated with vacuum. Isolation of compounds IV and V can be performed by chromatography. Compounds IV and V will be produced in mixture with pantoprazole. In fact, pantoprazole may be the major product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=2)[CH:6]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=2)[S:31]([C:29]2[N:28]=[CH:27][N:26]([CH3:25])[CH:30]=2)(=[O:33])=[O:32])[CH:6]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCCCc1ccc(CNCc2cccc(CC(=O)OC)c2)cc1
Product: CCCCc1ccc(CN(Cc2cccc(CC(=O)OC)c2)S(=O)(=O)c2cn(C)cn2)cc1

Procedure:
The title compound of Step B was prepared following the procedure described in Step B of Example 1 from {3-[(4-butyl-benzylamino)- methyl]-phenyl}-acetic acid methyl ester, prepared in Step A of Example 9, and 1-methyl-1H-imidazole-4-sulfonyl chloride. 1H NMR (400 MHz, CDCl3) δ 747 (s, 1H), 7.34 (s, 1H), 7.18-7.02 (m, 8H), 4.38 (s, 4H), 3.71 (s, 3H), 3.68 (s, 3H), 3.52 (s, 2H), 2.55 (t, 2H), 1.55 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H); MS 470 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(#N)C.C(N(CC)CC)C.[CH:34]1[CH:39]=[CH:38][C:37]([O:40][C:41](OC2C=CC=CC=2)=[N:42][C:43]#[N:44])=[CH:36][CH:35]=1>>[C:43](/[N:42]=[C:41](\[O:40][C:37]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)/[N:7]1[CH2:8][CH2:9][C@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:44]
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 88.2 %

Procedure:
To a stirred solution of (3R,4S)-4-((R)-3-Phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylic acid methyl ester (654 mg, 0.00207 mol) in anhydrous acetonitrile (11.0 mL, 0.211 mol) at rt was added triethylamine (0.579 mL, 0.00413 mol) and diphenyl cyanocarbonimidate (762 mg, 0.00310 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product as a colorless solid (841 mg, 88% in yield). MS (ESI): (M+H)+=461.1.