Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1)=[O:17]
Reactant: Nc1cnc2[nH]nc(CO)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(CO)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
(5-Amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (0.040 g, 0.675 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.071 g, 0.256 mmol), EDCI (0.049 g, 0.256 mmol) and HOBt (0.033 g, 0.244 mmol) were dissolved in DMF (0.53 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give 2,6-difluoro-N-(3-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.051 g, 49%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 13.37 (s, 1H), 11.05 (s, 1H), 9.93 (br s, 1H), 8.74 (d, 1H), 8.58 (d, 1H), 7.58-7.52 (m, 1H), 7.26 (t, 1H), 5.36 (t, 1H), 4.78 (d, 2H), 3.12 (m, 2H), 1.77 (m, 2H), 1.00 (t, 3H); m/z (ES-MS) 426.1 (98.0%) [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=S.[NH3:34]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[NH:34]
Reactant: COc1cc2c(NC(=S)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Reactant: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2c(NC(=N)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Mercuric(II) oxide (0.059 g) was added to a mixture of 1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea (0.105 g), a 2M solution of ammonia in methanol (3 ml) and chloroform (1 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and a 2M solution of ammonia in methanol as eluent. There was thus obtained the title compound (0.074 g); NMR Spectrum: (CDCl3) 1.39-1.53 (m, 2H), 1.87-2.02 (q, 5H), 2.29 (s, 3H), 2.36 (s, 6H), 2.9 (d, 2H), 4.01 (m, 5H), 5.79 (br s, 1H), 7.16 (s, 1H), 7.19 (m, 3H), 7.87 (s, 1H), 8.57 (s, 1H); Mass Spectrum: M+H+ 449.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[CH2:12][C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:10]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[CH2:12][C@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@@H:10]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=4[F:29])[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1)(=[O:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(N)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(NS(C)(=O)=O)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 16 h

Procedure:
To 50 mg (0.12 mmol) of the product from Step B in 2 mL of methylene chloride was added 0.047 mL (0.58 mmol) of pyridine followed by 0.019 mL (0.24 mmol) of methanesulfonyl chloride. The reaction mixture was stirred for 16 h, concentrated in vacuo, and the residue purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 0% to 65% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 511.0 (M+1).
Reaction SMILES: N1CC[CH2:3][CH2:2]1.C1(=O)CCCC1.[C-]#N.[K+].[CH3:15][C:16]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:19])[C:17]#[N:18]>O>[N:20]1([C:16]2([C:17]#[N:18])[CH2:19][CH2:3][CH2:2][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C#N)N1CCCC1
Reactant: C1CCNC1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: O=C1CCCC1
Product: N#CC1(N2CCCC2)CCCC1
Yield: 76 %

Procedure:
The title compound (2.50 g, 76%) was prepared from pyrrolidine (1.42 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.80-1.90 (10H, m), 2.15 (2H, m), 2.71 (4H, m).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:4]1.CC1C=C(N=C=O)C=CC=1.[C:27]1([CH:37]([N:39]=[C:40]=[O:41])[CH3:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[CH2:8][N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:40]([NH:39][CH:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH3:38])=[O:41])[CH2:4]1
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: CC(N=C=O)c1cccc2ccccc12
Agent: Cc1cccc(N=C=O)c1
Product: CC(NC(=O)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)C1)c1cccc2ccccc12

Procedure:
Proceeding as described above but substituting 3-(RS)-aminomethyl-1-(3,4-methylenedioxybenzyl)pyrrolidine with 3-aminomethyl-1-(3,4-dichlorobenzyl)-pyrrolidine and 3-methylphenylisocyanate with 1-(naphth-1-yl)ethylisocyanate gave 1-[1-(3,4-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl]-3-[1-(naphth-1-yl)ethyl]urea.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH2:19]([O:8][C:6]1[CH:7]=[C:2]([O:1][CH2:10][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:3]([C:10](=[O:12])[CH3:11])=[C:4]([OH:9])[CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 91.5 °C
Yield: 66.5 %

Procedure:
A mixture of 2′,4′,6′-trihydroxyacetophenone (20 g, 0.12 mol, dried in the oven at 140° C.) and anhydrous potassium carbonate (50 g, 0.36 mol) in hexamethylphosphoramide (160 mL) was treated with benzyl chloride (30 mL, 0.26 mol), and the suspension heated at 90-93° C., under an argon atmosphere, for 1.5 h. The mixture was then cooled and filtered. The filtrate was added to 300 mL ice-cold water and acidified to pH 4 with 6N hydrochloric acid. The resulting suspension was heated to 70° C. for 1 h, and then cooled at 4° C. for 16 h. The deposited sticky solid was filtered off and washed with water. This solid was air-dried, and recrystallized from boiling methanol/acetone (2:1). Cooling the solution afforded the product 8 as off-white crystals (27.55 g, 66.5% yield). 1H NMR (300 MHz, CDCl3): δ 2.56 (s, 3H, CH3), 5.06 (s, 4H, CH2), 6.10 and 6.16 (2s, 2H, 3′,5′-Ar—H), 7.40 (m, 10H, Ar—H), 14.01 (s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.Br[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][C:22]#[N:23])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: N#CCBr
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCC#N)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
A mixture of the product from Example 38b (56 mg, 0.17 mmol), 2-Bromoacetonitrile (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (53 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]Cl.[C-:19]#[N:20].[Na+].CC(C)=O>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][C:19]#[N:20]
Reactant: [C-]#N
Reactant: Cc1ccc(C)c(OCc2ccccc2CCl)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Yield: 97.9 %

Procedure:
2-(2,5-Dimethylphenoxymethyl)benzyl chloride (Purity: 86.8%, 1.50 g, 5 mmol), 95% sodium cyanide (0.31 g, 6 mmol), triethylbenzylammonium chloride (0.06 g, 0.25 mmol), acetone (4 ml) and water (2 ml) were added. The mixture was heated under reflux for 5 hours. After completion of the reaction, water (100 ml) was added. The resulting mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)benzyl cyanide (1.23 g, Yield: 97.8%).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]4)[C:16]3=[O:27])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:33][N:34]([CH2:36][CH2:37]Cl)[CH3:35]>O>[CH:3]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([O:26][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])[CH2:22][CH2:21]4)[C:16]3=[O:27])=[CH:11][CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=c1n(-c2ccc(OC3CCCC3)cc2)ccn1[C@H]1CC[C@H](O)CC1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCO[C@H]1CC[C@H](n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)CC1
Reaction time: 8 h

Procedure:
Sodium hydride (42 mg) was added to a mixture of trans-1-(4-cyclopentyloxy-phenyl)-3-(4-hydroxycyclohexyl)-1,3-dihydroimidazol-2-one (0.30 g) and DMF (10 ml) and, after gas evolution ceased, dimethylaminoethyl chloride (94 mg) was added. After eight hours, the reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 413.56 (C24H35N3O3) was obtained in this way; MS (ESI): 414 ([M+H]+).
Reaction SMILES: [I-:1].[Na+].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]>C(O)CCCC.[Cu](I)I>[I:1][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: [I-]
Reactant: CC(C)CCc1ccccc1Br
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCO
Product: CC(C)CCc1ccccc1I
Temperature: 130 °C
Yield: 84 %

Procedure:
Charge a pressure tube with sodium iodide (734 mg, 4.9 mmol) and copper iodide (23 mg, 0.12 mmol). Add trans-N,N′-dimethyl-cyclohexane-1,2-diamine (34 mg, 0.24 mmol) dissolved in 0.5 ml of pentanol. Add 1-bromo-2-(3-methyl-butyl)-benzene dissolved in 0.5 ml of pentanol. Purge with nitrogen, cap the tube and heat at 130° C. for 3 days. Load onto a silica gel cartridge eluting with hexane to obtain the title compound as a colorless liquid (587 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=O.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH:5]=[CH:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C

Procedure:
3-Chloro-4-cyclohexylbenzaldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 l round-bottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature ovenight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The crystals of product are collected by filtration, washed with water (4×150 ml) and air dreid. Recrystallization from acetone-water gives 3-chloro-4-cyclohexylcinnamic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:24]I>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH3:24])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: COC(=O)CCC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1
Product: COC(=O)CCC(=O)N(C)c1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
(prepared from 4-cyano-4'-[(3-methoxycarbonylpropionyl)amino]biphenyl by methylation with methyl iodide)
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:12][C:13]1[S:16][N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-fluorobenzamidine hydrochloride (0.385 g) in DCM (5 mL) was added perchloromethyl mercaptan (0.219 mL). The resulting mixture was cooled to 0° C., treated with 6 N NaOH (2 mL) and stirred for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was dried (MgSO4) and concentrated. Chromatography of the residue (0-20% EtOAc-hexanes) gave the title compound as a yellow-orange solid (0.43 g).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[N:8]([CH3:21])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH2:23]>O1CCOCC1.[Ag]>[CH3:21][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]3[C:5]([CH:6]=[O:23])=[CH:4][CH:3]=[CH:11][CH:7]=3)[C:11]=2[N:10]=[C:9]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(C(Br)Br)cccc21
Reactant: O
Agent: [Ag]
Solvent: C1COCCO1
Product: Cn1c(-c2ccccc2[N+](=O)[O-])nc2c(-c3ccccc3C=O)cccc21
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of silver hyperchlorate (57 mg, 0.27 mmol) in water (2 mL) was added to a solution of 4-dibromomethyl-N-methyl-2-(2-nitrophenyl)-benzimidazole (39 mg, 0.9 mmol) in 1,4-dioxane (2 mL). The mixture was refluxed for 5 h to afford a grey suspension. After cooling to room temperature, the precipitate was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was washed with water and brine, dried over Na2SO4. Concentration using a rotary evaporator and subsequent column chromatography on silica gel using hexane/ethyl acetate (1:3) as the eluent to give N-methyl-2-(2-nitrophenyl)-benzimidazole-4-benzaldehyde (24 g, 93%) as a light-yellow solid. Rf=0.23 (hexane/ethyl acetate=1:3); 1H NMR (250 MHz, CDCl3) δ 3.68 (s, 3H), 7.47 (t, J=7.8 Hz, 1H), 7.66-7.74 (m, 2H), 7.77-7.86 (m, 2H). 7.90 (d, J=7.6 Hz, 1H), 8.28 (dd, J,=7.9 Hz, J2 =1.5 Hz, 1H), 10.81 (s, 1H). HRMS: Calcd for C1H11N3O3 281.0800, found 281.0814.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.[CH2:10](Cl)Cl.CO>>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: ClCCl
Reactant: Oc1ncc(I)cc1Cl
Solvent: CO
Product: Cn1cc(I)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Step 23.2 using 3-chloro-5-iodo-pyridin-2-ol. tR: 3.30 min (HPLC 1); tR: 0.71 min (LC-MS 2); ESI-MS: 270 [M+H]+ (LC-MS 2); Rf=0.79 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH:25]O.O>C(O)(C)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:25])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: OO
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Solvent: CC(C)O
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 88 %

Procedure:
HCl, 1.376 g of 2-mercaptobenzimidazole, and 0.134 g of benzyl triethyl ammonium chloride as an interphase transfer catalyst were mixed in 24 ml of dichloromethane. 0.9534 g of NaOH (40%)/12 ml water mixture solution was dripped into the above mixture while stirring. The temperature of the resulting solution was raised to 40° C. for about 2 hours. Then, dichloromethane was removed from the mixture under a reduced pressure. The solid obtained was stirred with 50 ml of water, and filtered to obtain 3.28 g of solid Lansoprazole precursor: 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methylthio]-1H-benzimidazole. At room temperature, 3.28 g of the above precursor, 0.1625 g of polyethylene glycol-400 as an interphase transfer catalyst, and 0.3936 g of Mo(acac)2 as an oxidation catalyst were mixed in 45 ml of isopropanol (abbreviated as IPA). To the resulting mixture 3.06 g of 35% H2O2 aqueous solution was added in 5–10 minutes. The reaction was carried out for about one hour, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Lansoprazole with a yield of about 88% (HPLC purity>98%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]#[N:20])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.N1CCOCC1>N1CCOCC1>[C:5]1([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]3[NH:20][N:3]=[N:2][N:1]=3)[CH2:15][CH2:16]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCCN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCN1
Product: c1ccc(N2CCN(CCc3nnn[nH]3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Sodium azide (65 g; 1.0 mol), 4-phenyl-1-(2-cyanoethyl)-piperazine (215 g; 1.0 mol), and morpholine hydrochloride (124 g; 1.0 mol) were dissolved in 1 liter of morpholine, and heated at 120°-125° C with stirring for 4 hours. After the reaction mixture was allowed to cool to room temperature, it was filtered, and the solvent was removed in vacuo. The residue was mixed in water, and the pH of the resulting solution was adjusted to 5. Crude 5-[(4-phenyl-1-piperazyl)ethyl]tetrazole was collected by filtration and was dried; yield -- 170 g. The crude product was recrystallized from water and dried; yield -- 155 g (60% yield; m.p. 190°-194° C).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])[N:5]=[N:6][C:7]=1[NH2:8].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[NH2:8][C:7]1[N:6]=[N:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=2[CH3:18])=[N:3][C:2]=1[NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])=[CH:24][CH:25]=1
Reactant: Cc1c(-c2nnc(N)c(Cl)n2)cccc1[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2nnc(N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)cccc1[N+](=O)[O-]
Yield: 33.9 %

Procedure:
A mixture of 5-chloro-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-6-amine (1.05 g, 3.95 mmol), (4-aminophenyl)(morpholino)methanone (1.630 g, 7.90 mmol), and N,N-diisopropylethylamine (1.243 mL, 7.11 mmol) in 1,4-dioxane (60 mL) was heated at reflux for 2 days. The volatiles were removed under vacuum. To the residue was added water (60 mL). The precipitating material was collected by suction filtration. The filter cake was purified by ISCO (120 g silica gel, solid loading, 3-8% MeOH/CH2Cl2) to provide the desired product, (4-(6-amino-3-(2-methyl-3-nitrophenyl)-1,2,4-triazin-5-ylamino)phenyl)(morpholino)methanone (0.595 g, 1.339 mmol, 33.9% yield), as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:3]=1.O.[NH2:24][NH2:25].Cl.O>C(O)C>[NH2:9][C:8]1[C:7]2[C:6]([Cl:10])=[N:5][C:4]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:3][C:2]=2[NH:25][N:24]=1
Reactant: C[C@@H](NC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1)c1ccccc1
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2c(Cl)n1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound (R)-1-(4,6-dichloro-5-cyanopyridin-2-yl)-3-(1-phenylethyl)urea (0.10 g, 0.29 mmol) in ethanol (8.0 mL) was added hydrazine hydrate (0.59 mL, 0.59 mmol, 1M solution in THF) and stirred at 80° C. for 2 h. After the precipitation of white solid, the reaction mixture was cooled to room temperature and a 2M solution of HCl in water (0.29 mL, 0.59 mmol) was added stirred at same temperature for 2 h. After confirming the completion of reaction by TLC, the reaction mixture was concentrated under reduced pressure to give crude product which was purified by preparative HPLC to afford (R)-1-(3-amino-4-chloro-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.88 (s, 1H), 9.05 (s, 1H), 7.44 (s, 1H), 7.36-7.32 (m, 4H), 7.23 (d, J=8.00 Hz, 2H), 5.42 (s, 2H), 4.84-4.82 (m, 1H), 1.38 (d, J=8.00 Hz, 3H), MS ES calc'd. for C15H15ClN6O [M+H]+ 331. Found 331.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=C(O)[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH:13]=[CH2:14].[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C.O>[CH3:10][O:11][CH:12]1[CH2:13][CH2:14][C:6]2[C:16](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:15]1
Reactant: C=CC(OC)OC
Reactant: COc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)OC(OC)CC2
Reaction time: 3 h
Yield: 34.5 %

Procedure:
A 500-milliliter flask fitted with a dropping funnel was charged with 12.4 g of 3-methoxyphenol, 0.2 g of p-toluenesulfonic acid monohydrate and 100 ml of diethyl ether for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 14.3 g of acrolein dimethyl acetal under room temperature. After the dropwise addition, the solution was stirred for 3 hours while being cooled with ice. The reaction solution was alkalized with the addition of 5 ml of a 5% sodium hydroxide aqueous solution and 30 ml of water. Subsequently, 200 ml of diethyl ether was added thereto for extraction. Thus obtained organic layer was washed with 30 ml of water, the diethyl ether was removed by distillation in vacuo therefrom, and the resulting residue was purified by distillation to obtain 6.7 g of a colorless liquid (yield 32%).