Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[N:15]([C:40]4[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 79 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from (4-cyclopropanecarbonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 25) and 3-(trifluoromethyl)-phenylboronic acid to afford the desired product as a colorless gum (79%). MS (ISP): 596.3 (M+H)+.
Reaction SMILES: CS[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[NH2:16][NH2:17]>CCO>[NH2:6][C:5]1[NH:17][N:16]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[C:7]#[N:8]
Reactant: NN
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Solvent: CCO
Product: N#Cc1c(Nc2ccccc2)n[nH]c1N
Temperature: 0 °C
Yield: 87.9 %

Procedure:
A mixture of compound 6 (3.2258 g, 14.85 mmol) and hydrazine (742 mg, 23.16 mmol) in EtOH (20 mL) was refluxed for 30 min, at which time the reaction was complete as determined by TLC. The reaction mixture was poured into 100 mL ice water. The resulting precipitate was filtered and dried to give compound 7 (2.599 g, 88.1% yield, 99.8% purity) as a white powder.
Reaction SMILES: O.OO.[Br:4][C:5]1[C:6]([F:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]([CH3:16])[NH:10]2.[OH-].[Na+]>CO>[Br:4][C:5]1[C:6]([F:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[C:11]([CH3:16])=[N:10]2
Reactant: CC1Nc2ccc(F)c(Br)c2NC1=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Temperature: 85 °C

Procedure:
A mixture of water (14 mL) and 30% H2O2 (30.0 mL, 294 mmol) was added slowly dropwise to a solution of 8-bromo-7-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (600e) (21.7 g, 84 mmol) in 1 N NaOH (168 mL, 168 mmol) and MeOH (140 mL). The flask was fitted with a reflux condenser and heated at 85° C. for 3 h. LC-MS indicated ca. 87% conversion to the desired product (M+1=257.0/259.0). The reaction mixture was cooled to RT and acidified with 2 N HCl to ca. pH 6 and was diluted with CHCl3/IPA(4:1) (100 mL), added to a separatory funnel. The resulting suspension was filtered through a sintered glass frit, washing with water and dried affording 8-bromo-7-fluoro-3-methylquinoxalin-2(1H)-one (5.83 g, 22 mmol, 22% yield) as a light brown solid. m/z (ESI, +ve ion) 257.0/259.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br. s.), 7.67-7.88 (1H, m), 7.34 (1H, t, J=8.4 Hz), 2.43 (3H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm −104.13 (1F, s). The aq. solution was extracted with CHCl3:i-PrOH 9:1 (6×100 mL), dried over MgSO4, filtered and concentrated affording additional 8-bromo-7-fluoro-3-methylquinoxalin-2(1H)-one (12.51 g, 49 mmol, 58% yield) as a dark brown amorphous solid (ca. 80% purity). The material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.O.[OH-].[K+]>CO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:16])[CH3:1])=[CH:4][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(=O)Nc1ccc(N(C)C)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(N)c([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 65 %

Procedure:
To a solution of N-[4-(dimethylamino)-2-nitrophenyl]acetamide obtained in step 11 above (1.0 eq) in MeOH and water was added KOH (1.5 eq) at room temperature and stirred for 5 hrs. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-(4-amino-3-nitrophenyl)-N,N-dimethylamine. (Yield=65%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl.O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (56.0 g) in 1,2-dichloroethane (550 mL) was added morpholine (37.8 mL) dropwise over 5 min. The mixture was cooled to 10° C. and was treated with NaBH(OAc)3 (64.3 g) in portions over 1 h. After a further 2 h, the mixture was warmed to room temperature, and a water bath was used to keep the temperature below 20° C. After 18 h, water (60 mL) was added while the temperature was kept under 20° C. by the addition of small amounts of ice. After 20 min, the mixture was basified to pH ˜10 with 1 N NaOH (450 mL) and the mixture was stirred for 10 min. The layers were separated, and the organic layer was washed with 1 N NaOH (150 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to yield the title compound as pale yellow viscous oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH3:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])([CH3:11])[C:9]#[N:10]>CN(C)C=O>[CH3:11][C:8]([C:9]1[NH:10][N:3]=[N:2][N:1]=1)([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH3:7]
Reactant: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C#N)c(C)o2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CCCCCCOC(C)(C)c3nnn[nH]3)c(C)o2)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Sodium azide (4.12 g) and 2.97 g of ammonium chloride were added to 27 ml of a solution of 2.70 g of 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}-propiononitrile in N,N-dimethylformamide, and stirred for 1.5 hours at 120° C. To the reaction solution was added ice-cold water, and extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, chloroform: methanol=100:1 to 50:1) and recrystallized from isopropyl ether to provide 1.69 g of the objective compound as colorless crystals. M.p. 87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:43])=[C:37]([S:39](Cl)(=[O:41])=[O:40])[CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:37]4[CH:38]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=4[CH3:43])(=[O:40])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(F)ccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 5-fluoro-2-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=593.7)=92%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([OH:13])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:18]>CN(C)C=O>[CH2:1]([N:8]1[C:12]([O:13][CH3:18])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnn(Cc2ccccc2)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C)cnn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1-benzyl-4-methyl-1H-pyrazol-5-ol (compound 249.2, 2.0 g, 10.6 mmol) in N,N-dimethylformamide (15 mL). The solution was cooled to 0° C., then sodium hydride (600 mg, 15.00 mmol, 60% dispersion in mineral oil) was added in portions and the resulting mixture was stirred for 10 min at 0° C. Iodomethane (878 μL, 14.1 mmol) was added and the resulting mixture was stirred for 3 h at room temperature, then carefully quenched by drop-wise addition of water (10 mL). The mixture was extracted ethyl acetate (3×40 mL) and the combined organic extracts were washed with brine (3×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:8) as eluent to obtain the title compound as a yellow oil (500 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[N:11]=1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc(Cc3cccc(Cl)c3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 343 mg (3.43 mmol) of N-methylpiperazine to give 101 mg (84% of theory) of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([C:25]([NH2:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH:23]=O)[S:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[C:17]3[C:12](=[C:13]([C:25]([NH2:27])=[O:26])[CH:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH2:23][N:29]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[S:20][CH:19]=4)[CH:16]=3)[NH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: NC(=O)c1cc(-c2csc(C=O)c2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Reactant: C1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2csc(CN3CCCCCC3)c2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Yield: 10.6 %

Procedure:
3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.072 mmol), hexahydro-1H-azepine (71.4 mg, 0.720 mmol, 10 eq), acetic acid (0.4 μL, 0.007 mmol, 0.1 eq) were dissolved in DMSO (2 mL) in a 5 mL A-vial reaction tube. The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (309 mg, 0.72 mmol, 10 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and was then concentrated and purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined and concentrated in a Glas-Col evaporator, giving 3.8 mg (9.5%) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)=[O:7]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccco1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccco2)cc1
Yield: 46 %

Procedure:
In a manner similar to that described in Example 3, furoyl chloride (0.044 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.033 g of 4-[4-(2-furoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+288.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[N:8][S:7][N:6]=1.[CH3:18][NH:19][CH2:20][CH2:21][CH3:22]>C(COC)OC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]1[C:5]([O:4][CH2:3][CH2:2][N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])=[N:6][S:7][N:8]=1
Reactant: Clc1cccc(Cl)c1-c1nsnc1OCCBr
Reactant: CCCNC
Solvent: COCCOC
Product: CCCN(C)CCOc1nsnc1-c1c(Cl)cccc1Cl
Yield: 58.4 %

Procedure:
In dimethoxyethane, were mixed and stirred 0.35 g of 3-(2-bromoethoxy)-4-(2,6-dichlorophenyl)-1,2,5-thiadiazol e, 0.3 g methylpropylamine at 50° C. for 6 hours. The reaction mixture was concentrated, and was purified by silica gel chromatography to obtain 0.2 g of 3-(2,6-dichlorophenyl)-4-[2-(N-methyl-N-propylamino)ethoxy]-1,2,5-thiadiazole.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].S(=O)(=O)(O)[OH:17]>>[NH:6]1[C:7]2[C:15](=[CH:14][C:13]3[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[C:3](=[O:17])[C:4]1=[O:5]
Reactant: O=C(C=NO)Nc1ccc2c(c1)CCC2
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc3c(cc2C1=O)CCC3
Temperature: 80 °C
Yield: 77 %

Procedure:
Add 2-Hydroxyimino-N-indan-5-yl-acetamide (4.66 g, 22.84 mmol) in small portions at 65° C. to concentrated sulfuric acid (22 mL) and heat the mixture at 80° C. for 15 minutes. Cool to room temperature, pour into ice water (200 mL) and filter the precipitate. Dissolve the solid in warmed ethanol and leave to cool overnight. Filter the precipitate and wash with ethyl ether. Dry the solid to yield the title compound (3.3 g, 77%). 1H NMR (DMSO-d6, 300 MHz) δ 1.98 (quintuplet, J=7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 6.74 (s, 1H), 7.28 (s, 1H). MS (ES−): 186 (M−H).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].[CH:27](N1CCOCC1)=[O:28]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:27]=[O:28])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.0 ml (35.3 mmol) of TMP are initially introduced at −20° C. in 30 ml of THF, and 21.5 ml (34.2 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 11.8 g (34.0 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 70 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 90 min. The solution is cooled to −60° C., and 3.6 ml (36.0 mmol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 2 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is recrystallised from toluene. 5-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
0.72 g (2.97 mmol) of 2,4-Dichloro-3-nitroquinoline and 0.56 g (2.97 mmol) of N-(tert-butoxycarbonyl)-1,4-diaminobutane were heated in 12 ml of triethylamine at 70° C. and stirred for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with water, and dried (MgSO4). The solvent was distilled off under reduced pressure. The residue was triturated with n-hexane-diethyl ether (1:1 (v/v)) and collected by filtration to obtain 0.97 g (2.46 mmol) of 4-[4-(tert-butoxycarbonylamino)butylamino]-2-chloro-3-nitroquinoline shown below as yellow powder (mp: 125-126.5° C.). ##STR41## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3340, 3280, 1680, 1540, 1520. 1H-NMR (CDCl3) δ (ppm) :1.46 (9H, s), 1.63 (2H, m), 1.78 (2H, m), 3.19 (2H, q, J=6.4 Hz), 3.47 (2H, q, J=61 Hz), 4.68 (1H, br), 6.41 (1H, b r), 7.52 (1H, t, J=7.7 Hz), 7.74 (1H, t, J=7.8 Hz), 7.91 (1H, d, J=8.4 Hz), 8.11 (1H, d, J=8.4 Hz).
Reaction SMILES: [NH2:1][NH2:2].CO[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH3:25])=[C:12]2[CH2:26][C:27]([NH2:29])=[O:28]>CO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][CH2:7][CH2:6][C:5]([NH:1][NH2:2])=[O:30])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[CH3:25]
Reactant: COC(=O)CCNc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(NCCC(=O)NN)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrazine was added to 151 mg (0.4 mmol) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid methyl ester in 5 mL of MeOH and the mixture heated at reflux for 1.0 hour and stirred at room temperature for 16 hours. After diluting with water, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (MgSO4) and concentrated at reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>C(Cl)Cl>[CH3:21][C:15]1[CH:14]=[N:13][C:12]([CH2:11][S+:10]([O-:29])[C:8]2[NH:7][C:6]3[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[C:17]([CH3:18])[C:16]=1[O:19][CH3:20]
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1

Procedure:
This object is achieved according to the present invention, which is characterized by the steps of reacting 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl-thio]-1H-benzimidazole (below denoted Compound I) with m-chloroperoxybenzoic acid in a methylene chloride solution at a substantially constant pH of about 8.0 to 8.6; extracting the reaction with aqueous NaOH; separating the aqueous phase from the organic phase; and adding an alkyl formate to the aqueous phase, resulting in crystallization of omeprazole.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[C:19]4([CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[C:12]([NH:14][CH:15]3[C:19]4([CH2:20][CH2:21][CH2:22][CH2:23]4)[CH2:18][NH:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(Nc2nccc(NC3CN(C(=O)OC(C)(C)C)CC34CCCC4)n2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Nc2nccc(NC3CNCC34CCCC4)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
To a solution of tert-butyl 4-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (550 mg, 1.33 mmol) in DCM (20 mL) was added CF3COOH (5 mL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and adjust to pH=8˜9 with the saturated NaHCO3 aqueous solution, then diluted with H2O (20 mL) and extracted withed EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), then dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow solid (450 mg, 100%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C1C=CC=CC=1.C=CCCCC.C1(C)C=CC=CC=1.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Nc1ccccn1
Agent: O=C(O)c1ccccc1
Solvent: C=CCCCC
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 0.04 h

Procedure:
Under the same reaction procedure and conditions as in Example 1 (benzaldehyde 0.5 mmol, aniline 0.3 mmol, bezoic acid 0.03 mmol, 1-hexene 2.5 mmol, toluene 0.87 mmol), various 2-aminopyridine derivatives 0.1 mmol as shown in the following table 3, were added to each 500 ml pressure reactor. The mixture was stirred at normal temperature for 2-3 minutes and then combined with Rh(PPh3)3Cl 0.01 mmol. While the reactor was stopped with a stopper, the reactants were heated at 130° C. for 1 hour with stirring. After completion of the reaction, gas chromatography was conducted to determine the yields of heptanophenone, products from various aminopyridine derivatives. The results are presented in Table 3, below.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][NH2:15])=[O:13])=[CH:7][CH:6]=1.[C:16](=S)=[S:17]>O.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[O:13][C:16](=[S:17])[NH:15][N:14]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(CC(=O)NN)cc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cc2n[nH]c(=S)o2)cc1

Procedure:
A solution of potassium hydroxide (0.7 g) in water (2 cm3) was added to a stirred solution of (4-methoxyphenyl)acetic acid hydrazide (1.99 g) in ethanol (30 cm3). carbon disulfide (0.7 cm3) was added and the reaction was heated to reflux for 6 hours and then left to cool. The reaction mixture was evaporated to dryness under reduced pressure and the solid residue dissolved in water. The pH was adjusted to 1 with concentrated hydrochloric acid, resulting in formation of a white precipitate. The precipitate was isolated by filtration; washed with water and ether and air dried to give 5-(4-methoxybenzyl)-1,3,4-oxadiazole-2(3H)-thione (1.96 g). M+ =222; 1H NMR: δ 3.80(3H,s); 3.95(2H,s); 6.90(2H,d); 7.20(2H,d); (solid).