Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].O.C([O-])(O)=O.[Na+].[Br:10][C:11]1[C:12]([CH2:17][C:18]#[N:19])=[N:13][CH:14]=[CH:15][CH:16]=1>C(O)C>[Br:10][C:11]1[C:12]([CH2:17][C:18]([NH:2][OH:3])=[NH:19])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: N#CCc1ncccc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(Cc1ncccc1Br)NO
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of hydroxylamine hydrochloride (924 mg, 13.3 mmol), water (4 mL), NaHCO3 (1.12 g, 13.3 mmol), 3-bromo-2-cyanomethylpyridine (Intermediate 1) (1.31 g, 6.65 mmol) and ethanol (14 mL) was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, the ethanol was removed in vacuo and the white solid collected by filtration, washing with water (3×10 mL). The wet solid was dried in vacuo at 40° C. for 1 hour to yield 2-(3-Bromo-pyridin-2-yl)-N-hydroxy-acetamidine as a solid (Intermediate 2).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=[CH:13][C:12]=2[O:23][CH3:24])=[C:6]([CH2:25][S:26][CH:27]([CH3:29])[CH3:28])[CH:5]=1>CN(C=O)C>[CH2:21]([O:20][C:18]([CH2:17][C:15]1[CH:14]=[CH:13][C:12]([O:23][CH3:24])=[C:11]([CH:16]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][C:6]=1[CH2:25][S:26][CH:27]([CH3:28])[CH3:29])=[O:19])[CH3:22]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)OC)cc2CSC(C)C)c1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)O)cc2CSC(C)C)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
4-(5-Ethoxycarbonylmethyl-2-methoxy-phenoxy)-3-isopropylsulfanylmethyl-benzoic acid methyl ester (0.5 g, 1.16 mmol) and sodium methylthiolate (0.16 g, 2.3 mmol) were combined in DMF (20 mL) and stirred at 65° C. for 1 hour. After an acidic work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15]C)=[O:14])[C:7]([CH3:17])=[C:6]2[C:18]1[C:27]2[C:22](=[C:23]([CH3:28])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=[O:14])[C:7]([CH3:17])=[C:6]2[C:18]1[C:27]2[C:22](=[C:23]([CH3:28])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)#[N:2]
Reactant: COC(=O)Cn1c(C)c(-c2ccnc3c(C)cccc23)c2cc(C#N)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2c(-c3c(C)n(CC(=O)O)c4ccc(C#N)cc34)ccnc12
Reaction time: 1 h

Procedure:
The product from step b) was taken up in THF (10 ml) treated with a solution of lithium hydroxide (252 mg) in water (10 ml) and stirred for 1 hour. The solution was concentrated to remove the THF and acidified with saturated aqueous potassium hydrogen sulphate. The solid was collected by filtration, washed with water, washed with a little cold propan-2-ol, washed with a little cold ether and dried to give the title compound as a yellow/orange solid (606 mg).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].O.[NH2:12][NH2:13]>C(O)CCC>[I:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:9]([NH2:10])=[N:12][NH:13][C:2]=12
Reactant: N#Cc1nccc(I)c1F
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2c(I)ccnc12
Temperature: 105 °C

Procedure:
3-Fluoro-4-iodopicolinonitrile (25.6 g) was dissolved in n-butan-1-ol (250 mL) then hydrazine hydrate (100%, 23.3 mL) was added. The reaction was heated at 105° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, rinsed with water, and dried for 30 minutes under vacuum to give 7-iodo-1H-pyrazolo[4,3-b]pyridine-3-amine (25 g) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.35-5.55 (2H, m) 7.73-7.74 (1H, m) 7.939-7.94 (1H, m). MS [M+H] found 261.0.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][NH+:6]=[C:5]([CH2:9]Cl)[C:4]=1[CH3:11].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[SH:21]>>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:21][C:13]2[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]=2)[C:4]=1[CH3:11]
Reactant: Cc1c(Cl)cc[nH+]c1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Cl-]
Product: Cc1c(Cl)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
For example, 4-chloro-2-chloromethyl-3-methylpyridinium chloride could be reacted with 1H-benzimidazole-2-thiol according to the procedure described under Example 12 to give 2-[(4-chloro-3-methyl-2-pyridinyl)methylthio]-1H-benzimidazole. Conversion of this product with, for instance, 1,1-dideuterio-3-methoxy-1-propanol or 1,1-dideuterio-2,2,2-trifluoroethanol following the protocol described under Example 14 would then give rise to formation of 2-[(4-(1,1-dideuterio-3-methoxyprop-1-oxy)-3-methyl-2-pyridinyl)methylthio]-1H-benzimidazole and 2-[(4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl)methylthio]-1H-benzimidazole, respectively. Finally, oxidation of these compounds according to the procedure used in Example 46 would provide rac-2-[(4-(1,1-dideuterio-3-methoxypropan-1-oxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole and rac-2-[(4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, respectively.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12](Br)=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.CN(C)[CH:30]=[O:31]>C1COCC1>[CH:1]1([N:7]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([CH:30]=[O:31])=[C:11]([CH3:16])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1C=O

Procedure:
To a cold (-70° C.), stirred solution of 4-bromo-3-methylbenzoic acid N-cyclohexyl-N-cyclopentyl amide (4 g, 0.011 mol) in THF (40 mL) was added t-butyl lithium (13 mL of 1.7 M solution) via syringe over 10 min. The originally colorless solution became a dark red. Dimethylformamide (DMF) (884 mg) was added. The cold bath was removed and the reaction allowed to warm to 0° , during the course of which, the reaction became much lighter in color. The reaction was diluted with ethyl acetate, washed with 0.5 N KHSO4 and the organic layer was dried (Na2SO4). The drying agent was filtered, the filtrate concentrated in vacuo and the crude product purified by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents to give title compound of Step(a), m.p. 57°-59° C. Anal. Calcd for C20H27NO2 : C, 76.64; H, 8.68; N, 4.47. Found: C, 76.21; H, 8.71; N, 4.11.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].N1CCCC1>C(O)C>[C:25](/[C:27](=[CH:19]/[C:18]1[CH:21]=[CH:22][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:1])[F:24])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)/[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCO
Solvent: C1CCNC1
Product: CCOC(=O)/C(C#N)=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (3.0 g, 9.0 mmol) in ethanol (11.5 mL) was added ethyl 2-cyanoacetate (0.95 mL, 8.9 mmol) and pyrrolidine (0.97 mL, 12 mmol). A yellow precipitate formed immediately and additional ethanol (10 mL) was added. The reaction was stirred at room temperature for 18 hours and then concentrated onto Celite®. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent afforded the title compound as a white solid (2.1 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.36-8.31 (m, 2H), 8.29 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.85-7.79 (m, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.46, 162.24, 154.18, 141.89, 135.36, 134.76, 132.41, 131.53, 127.22, 122.47, 121.33, 115.51, 103.28, 62.82, 14.19; ESIMS m/z 429 ([M+H]+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:35]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([O:31][CH2:29][CH3:30])[CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)ccc1OC

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-ethoxy-4-methoxy benzaldehyde. MS (ESI) m/z 591.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N=C=N.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: NC1CCCCC1
Reactant: Nc1ccccc1C(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1C(=O)NC1CCCCC1
Temperature: 40 °C

Procedure:
To a dry reaction vial was added cyclohexylamine (40 uμmol, 1.0 eq) and PS-carbodiimide resin (72 μmol, 1.8 eq). The solution of 2-amino-benzoic acid (44 μmol, 1.1 eq), diisopropyl ethyl amine (10 μLl) and HOBt (44 μmol, 1.1 eq) in THF (500 μL) was added to the above vial. The reaction mixture was heated at 40° C. for 6 h on a shaker. The resin was removed by filtration and washed with 10% MeOH/CH2Cl2. The solvent was removed in vacuo and the residue was applied to solid phase extraction cartridge (basic silica, 200 mg) and eluted with 50% EtOAc/CH2Cl2. After removal of the solvents, the crude 2-amino-N-cyclohexyl-benzamide was obtained and used for the following reaction.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>>[CH:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[O:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:15]
Reactant: O=Cc1cccc(O)c1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(Oc2cccc(C=O)c2)cc1

Procedure:
4-Fluorobenzonitrile and 3-hydroxybenzaldehyde were processed as described in Example 48A to provide the title compound.
Reaction SMILES: [N:1]1([C:4]2[C:5]3[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:6]=3[N:7]=[C:8]([CH2:10][CH3:11])[N:9]=2)[CH2:3][CH2:2]1.[I-].[Na+].C(OCC)(=O)C>CC(C)=O>[CH2:10]([C:8]1[N:9]2[CH2:2][CH2:3][N:1]=[C:4]2[C:5]2[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:6]=2[N:7]=1)[CH3:11]
Reactant: CCc1nc(N2CC2)c2c(n1)c(C)nn2C
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCC1=Nc2c(C)nn(C)c2C2=NCCN12
Yield: 35.3 %

Procedure:
The above aziridine (6 g, 0.03 mol) is dissolved in 100 ml of acetone and refluxed with 6 g of sodium iodide for two hours. The solution is evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with saturated NaHCO3 solution, dried over MgSO4, and evaporated in vacuo. The resulting solid (2.3 g, 38% yield) melts at 148°-150° C. after recrystallization from ethyl acetate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C-:11]#[N:12].[Na+]>CC#N.CCOC(C)=O.[Cu]I>[C:11]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)#[N:12]
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: [C-]#N
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 5-iodoindole (0.36 g; 1.48 mmol), NaCN (0.15 g; 3 mmol), Pd(Ph3)4 (0.23 g; 0.22 mmol) and CuI (0.06 g; 0.3 mmol) in anhydrous CH3CN (3 ml) was refluxed for 2.5 h under N2. After cooling to room temperature, the mixture was diluted to 20 ml with EtOAc and filtered through a pad of Celite. The filtrate was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure, dissolved in a small volume of CH2Cl2 and filtered through a small pad of SiO2, which was washed with fresh CH2Cl2. The combined filtrates were evaporated to dryness under reduced pressure to give the title compound (0.2 g; 95%) as colourless solid. 1H-NMR (CDCl3) 6.62 (tr, 1H, J=2.5 Hz); 7.33 (tr, 1H, J=2.5 Hz); 7.39-7.47 (m, 2H); 7.98 (s, 1H); 8.51 (broad s, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:23]([NH:31][C:32](=[O:35])[CH:33]=[CH2:34])([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:24]>O1CCCC1>[C:23]([NH:31][C:32](=[O:35])[CH2:33][CH2:34][O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:26][C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:24])[CH3:25]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=CC(=O)NC(C)(C)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)CC(C)(C)NC(=O)CCON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 23.31 g of dibenzylhydroxylamine, 1.23 g of potassium-tert-butoxide and 20.0 g of N-tert-octylacrylamide in 100 ml of dry tetrahydrofuran to afford the title compound as a white crystalline solid: mp 96°-98° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[CH3:37][C:32]1[C:31]([CH2:30][O:3][C:4]2[CH:28]=[CH:27][C:7]([CH2:8][N:9]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]3)=[CH:6][CH:5]=2)=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: Cc1ncccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3C)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (212 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[4-(2-methyl-3-pyridylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (581 mg, yield: 85%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Nc3ccc(F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-fluoroaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a colorless foam (Yield=17%). MS ISP (m/e): 390.4 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.02 (s, 1H), 8.83 (s, 1H), 7.64 (d, 1H), 7.60-7.50 (m, 2H), 7.45-7.35 (m, 2H), 7.24 (dxd, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 7.02 (s, 1H), 6.24 (qa, 1H), 3.59 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: S(O[CH2:12][CH:13]([CH:17]1[CH2:19][CH2:18]1)[CH:14]1[CH2:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:20]#[N:21].[Na+]>CS(C)=O>[CH:17]1([CH:13]([CH:14]2[CH2:15][CH2:16]2)[CH2:12][C:20]#[N:21])[CH2:18][CH2:19]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC(C2CC2)C2CC2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC(C1CC1)C1CC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
209 g of 2,2-dicyclopropylethanol tosylate (prepared from 2,2-dicyclopropylethanol and para-toluenesulfonyl chloride) in solution in 45 ml of DMSO, are slowly added to 40 g of sodium cyanide in 45 ml of dimethyl sulfoxide (DMSO), with stirring and at 95° C. The heating is continued for one hour. After filtration of the precipitate and washing with ethyl ether, the filtrates are pooled, washed with a saturated solution of sodium chloride, dried and evaporated. The expected product is obtained after distillation under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[N:23](COCC[Si](C)(C)C)[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[CH:14][CH:13]=3)[C:9](=[O:11])[NH:10][C:3]=12.[ClH:36]>CCO>[ClH:36].[ClH:36].[NH:20]1[C:21]2[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=2[N:23]=[C:19]1[O:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]3[NH:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.053 g) and 2N HCl in EtOH (5.0 ml) was stirred at 60° C. for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH—AcOEt to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride (0.030 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:17][O-].[Na+].CI.Cl>CO>[CH3:17][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 120 °C

Procedure:
150 mg (0.57 mmol) of the compound of Example 24A were dissolved in 1.5 ml of methanol, 0.25 ml (1.14 mmol) of a 25% strength solution of sodium methoxide in methanol and 0.04 ml (0.62 mmol) of methyl iodide were added and the mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 120° C. for 30 min. After cooling, the reaction was acidified with 1 M hydrochloric acid and concentrated slightly on a rotary evaporator. The precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 96 mg (94% pure, 57% of theory) of the title compound.
Reaction SMILES: C[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.S(Cl)([Cl:14])=O.ClCl>ClC1C=CC=CC=1>[Cl:14][C:5]1[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccccc1C=NO
Agent: ClCl
Solvent: Clc1ccccc1
Product: Clc1nsc2ccccc12
Yield: 97.6 %

Procedure:
In a 300 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 100 g of monochlorobenzene was placed in advance, to which 33.4 g (0.2 mol) of 2-(methylthio)benzaldehyde oxime was added under nitrogen atmosphere. 25.2 g (0.21 mol) Of thionyl chloride was added dropwise thereto while stirring at a temperature of from -10° to -15° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, 15.6 g (0.22 mol) of chlorine was continuously blown into the reaction mixture while stirring at a temperature of from 70° to 80° C. and allowed to react for 1 hour at the same temperature. After the termination of the reaction, the solvent was distilled off to give 33.1 g of 3-chloro-1,2-benzisothiazole.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([C:24]#[N:25])[C:20](=[NH:23])SC)[CH2:14][CH2:13]1.[CH:26]([NH2:30])([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([C:24]#[N:25])[C:20]([NH:30][CH:26]([CH3:27])[CH2:28][CH3:29])=[NH:23])[CH2:14][CH2:13]1
Reactant: CCC(C)N
Reactant: CSC(=N)N(C#N)CC1CCN(CC2COc3ccccc3O2)CC1
Solvent: c1ccncc1
Product: CCC(C)NC(=N)N(C#N)CC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A mixture of 3 g 1-[(2,3-dihydro[4H]1,4-benzodioxin-2-yl)methyl]4-[(N-cyano S-methyl isothioureido)methyl]piperidine, 10 ml pyridine and 30 g sec butylamine are heated to the reflux. After evaporation to dryness the resulting oily product is taken up in isopropyl ethyl allowing the recovery of a solid as colourless crystalls. They are recrystallized from isopropanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].CO.C(=O)([O-])[O-].[NH4+:43].[NH4+]>ClCCl.CO>[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:43])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 78 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 78% of theory, C26H27N7O3 (485.6) Rf value: 0.31 (silica gel; dichloromethane/methanol=5:1) ##EQU43##
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]#[C:1][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:11]=1[C:12]#[N:13]
Reactant: C#CC1CCCCC1
Reactant: N#Cc1c(N)cccc1Br
Product: N#Cc1c(N)cccc1C#CC1CCCCC1

Procedure:
Prepared as in Example 21c from ethynylcyclohexane and 2-amino-6-bromobenzonitrile as a brown oil (100%). 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.77 (m, 10H), 2.70 (m, 1H), 6.13 (s, 2H), 6.64 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H). MS 225 (MH+).