Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21].[N:26]1C=CC=CC=1.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:4]=[C:3]([NH:26][S:22]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:24])=[O:23])[CH:2]=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=12
Reactant: c1ccncc1
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCS(=O)(=O)Nc1cccc(-n2ncc3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 42 h
Yield: 44.4 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.0 eq, 0.18 mmol), 1-butanesulphonylchloride (23 μl, 1.0 eq, 0.18 mmol) and pyridine (14 μl, 1.0 eq, 0.18 mmol) were added to DMF (1 ml) and the mixture was stirred for 42 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was absorbed onto silica and purified by column chromatography using DCM/MeOH (96:4) as eluent to yield the title compound as a white solid (27 mg, 0.08 mmol, 44%). LCMS: [M+H]+=347, Rt=1.58 min, 100% purity.
Reaction SMILES: [OH-].[K+].[I-].[K+].[OH:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.CO>[CH2:19]([O:5][C:6]1[C:11]2=[N:12][C:13]([CH3:17])=[CH:14][C:15](=[O:16])[N:10]2[CH:9]=[CH:8][C:7]=1[CH3:18])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1cc(=O)n2ccc(C)c(O)c2n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(=O)n2ccc(C)c(OCC=Cc3ccccc3)c2n1
Reaction time: 1 h

Procedure:
To a solution of 6.6 g of potassium hydroxide (85%) and 0.2 g of potassium iodide in 100 ml of water is added 150 ml of methanol and 19.0 g of 9-hydroxy-2,8-dimethyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one and the whole stirred for about 1 hour. To this is added 20.1 g of cinnamyl bromide dissolved in 20 ml of methanol. The mixture is stirred at room temperature for about 18 hours and then worked up to give 9-[ (cinnamyl)oxy] -2,8-dimethyl-4H-pyrido[ 1,2-a] pyrimidin-4-one.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=1)#[N:2].C[Si](C)(C)[C:13]#[N:14].CN(C)C(Cl)=O>ClCCl>[C:13]([C:5]1[C:4]([CH2:3][C:1]#[N:2])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:14]
Reactant: N#CCc1ccc[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: N#CCc1cccnc1C#N
Reaction time: 45 h

Procedure:
To a stirred suspension of 3-cyanomethylpyridine-N-oxide (30 g, 0.22 mol; for synthesis see Shigenobu Okuda, Michael M. Robison, J. Am. Chem. Soc. 81, 740 (1959)) in dichloromethane (200 ml) is added trimethylsilanecarbonitrile (26 g, 0.26 mol). To this suspension is added dimethylcarbamyl chloride (28 g, 0.26 mol). The mixture is stirred for 45 h. The solvent is removed and the residue dissolved in ethyl acetate. The solution is washed with 1 N NaOH and water and concentrated in vacuo. The product is purified by flash column chromatography on silica gel (15:2 toluene/acetone) affording the title compound. Mass M+H 144.1. Melting point 62-63° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:23][C:22]([NH:15][N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A mixture of methyl [1-[4-phenoxyphenyl]hydrazino]acetate (Intermediate 76, 11 g, 0.004 mol), sodium cyanate (0.9 g, 0136 mol) and trifluoracetic acid (1 ml, 0.0124 mol) in dry toluene (15 ml) was stirred under nitrogen at room temperature for 1 hour. The mixture was poured into 8% sodium bicarbonate solution (75 ml) and extracted with ethyl acetate (2×75 ml). The organic extract was dried (MgSO4) and evaporated to give a pale yellow semi-solid. This was triturated with ether to give the title compound (Intermediate 77) as a white solid (0.6 g, 48%) m.p. 110°-113° C.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=O)=[CH:14][CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[O:10][N:9]=[C:7]([CH3:8])[CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)=NO
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ccc(Br)cc2)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of n-BuLi (81 ml of a 1.6M solution in hexanes) was added to a solution of acetone oxime (4.85 g) in THF (100 ml) at 0° C. The reaction mixture was allowed to warm to rt over 1 h. A solution of methyl 4-bromobenzoate (9.4 g) in THF (30 ml) was then added to the reaction mixture and allowed to stir for 24 h. Water (50 ml) was added to the reaction, the organics were extracted and evaporated to give a brown oil, which was further evaporated from toluene (2×25 ml). The crude product was purified by column chromatography (silica gel, 10-25% gradient of EtOAc in hexane) to give the title compound (D39) as a pale yellow solid (5.4 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][C:8](=[O:19])[NH:7]1.C[O:22][C:23](=[O:40])[CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH:26]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1.Cl>[OH-].[Na+]>[Cl:39][C:34]1[CH:33]=[C:32]([CH:25]([CH:26]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27]2)[CH2:24][C:23]([OH:40])=[O:22])[CH:37]=[CH:36][C:35]=1[Cl:38].[Cl:18][C:13]1[CH:12]=[C:11]([CH:10]2[CH2:9][C:8](=[O:19])[NH:7][CH:6]2[CH2:5][CH2:4][C:3]([OH:20])=[O:2])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COC(=O)CCC1NC(=O)CC1c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(c1ccc(Cl)c(Cl)c1)C1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(c1ccc(Cl)c(Cl)c1)C1CCC(=O)N1
Product: O=C(O)CCC1NC(=O)CC1c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 34.1 g of 3-(3,4-dichlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester and β-(3,4-dichlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid methyl ester in aqueous sodium hydroxide solution (1 N, 108 ml) is heated to 60° C. for four hours. Excess aqueous hydrochloric acid (1 N, 120 ml) is added and the solution is concentrated under reduced pressure to give β-(3,4-dichlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid and 3-(3,4-dichlorophenyl)-5-oxo-2-pyrrolidinepropanoic acid.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1>C1COCC1.O>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: CC#CC(=O)O
Reactant: Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
Dissolved 597 mg (7.10 mmol) 2-butynoic acid in 25 ml THF under N2 and chilled to 0° C. Added 950 μl (7.30 mmol) isobutyl chloroformate and 780 μl (7.10 mmol) N-methylmorpholine and stirred for 10 minutes. Added dropwise a solution of 778 mg (2.84 mmol 6-amino-4-[(3-methylphenyl)amino]-3-quinolinecarbonitrile, stirred for 15 minutes at 0° C. and then at 25° C. overnight. Stripped solvent and slurried residue with water, drying the gummy solid in vacuo briefly. Boiled solid in ethyl acetate and collected. Recrystallized from DMF, using ethanol to crash out the product, and dried in vacuo, giving 401 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=341.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.B.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0° C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0° C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64%) of the title compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[OH:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1>C1(C)C=CC=CC=1>[O:8]1[CH2:9][CH2:10][C@@H:6]([O:5][C:1]([Cl:4])=[O:2])[CH2:7]1
Reactant: O[C@@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.5 ml (24.15 mmol) of a 20% solution of phosgene in toluene are cooled in an ice-bath, a solution of 1.06 g (12.03 mmol) of (R)-(+)-3-hydroxytetrahydrofuran (JPS CHIMIE, Bevaix, Switzerland) in a small amount of toluene is then added dropwise and, after the mixture has been stirred at RT for 2 h, the excess phosgene is expelled with argon. After concentration by evaporation in a rotary evaporator under reduced pressure, the crude title compound is further processed without being further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:20]([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].ClCCl.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]3[CH:15]([OH:19])[CH2:16][CH2:17][CH2:18][C:13]=3[N:12]=[C:11]2[CH:20]([CH3:22])[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To Intermediate 80 (131.02 g, combination of two batches) under nitrogen in methanol (1000 mL) and dichloromethane (DCM) (1000 mL) was added sodium borohydride (29.4 g) slowly in portions over 10 min and the mixture stirred at room temperature under nitrogen. Temp rose from 19° C. to 23° C. Gas evolution still visible for 20-30 mins and temp rose over 40 mins to 26° C. Temp still going up after 1 hr20 min—now 26.2° C. After 2.5 hr water was added carefully and the mixture was partitioned between ethyl acetate and water (should have given the mixture more time to quench before extracting—gas evolution during extraction seen) and the aqueous layer extracted well with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated. This gave the title compound, a white solid, 133.3 gm. LC/MS MH+ 339, 341, Rt 0.76 min (2 min run).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH:11][CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:25](#[N:30])/[CH:26]=[CH:27]/[C:28]#[N:29]>>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=3)=[C:27]([C:28]#[N:29])[C:26]=2[C:25]#[N:30])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: N#C/C=C/C#N
Reactant: CCCCCc1ccc(C=CC=C[C@H]2CC[C@H](CCC)CC2)cc1
Product: CCCCCc1ccc(-c2ccc([C@H]3CC[C@H](CCC)CC3)c(C#N)c2C#N)cc1

Procedure:
Using 1-(trans-4'-n-propylcyclohexyl)-4-(p-n-pentylphenyl)-1,3-butadiene and fumaronitrile, 3-(trans-4'-n-propylcyclohexyl)-6-(p-n-pentylphenyl)phthalonitrile was obtained by the same method as in Example 1. m.p. was 97° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[OH:15].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23][C:24]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23][C:24]1([C:30]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]2[OH:15])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
To the solution of tert-butyl 4-amino-3-hydroxypiperidin-1-carboxylate (20 g, 92 mmol) obtained in step 4 of Preparation Example 1 and 1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarboxylic acid (5.0 g) obtained in Step 2 in 70 ml of dimethylformamide, were added hydroxybenzotriazole(HOBt; 3.1 g, 23.1 mmol) and diisopropylethylamine (DIEA; 9.0 ml, 53.4 mmol). The reaction mixture was cooled to 0° C. and was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl; 5.1 g, 26.7 mmol) thereto. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with 200 ml of ethyl acetate, washed with 10% citric acid solution, a saturated sodium bicarbonate solution and brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 4.3 g of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:5]2[CH:17]=[C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:19]=[CH:20][C:4]=2[N:3]=1.[CH3:31][C:32]1[N:36]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][CH:39]=2)[C:35]2[CH:47]=[CH:48][C:49]([C:51](=[O:60])[NH:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)=[CH:50][C:34]=2[N:33]=1>[Pd].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:5]3[CH:17]=[C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:19]=[CH:20][C:4]=3[N:3]=[C:2]2[CH3:1])=[CH:13][CH:12]=1.[NH2:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:36]2[C:35]3[CH:47]=[CH:48][C:49]([C:51](=[O:60])[NH:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=4)=[CH:50][C:34]=3[N:33]=[C:32]2[CH3:31])=[CH:43][CH:42]=1
Reactant: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2cc(C(=O)NCc3ccccn3)ccc2n1Cc1ccc(N)cc1
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(N)cc1

Procedure:
Methanol (30 ml) and 5% palladium/carbon (0.20 g) are added to a mixture (2.32 g) of 2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole, and the solution is stirred at room temperature under a nitrogen environment until the raw materials dissolved. Solid materials are separated through filtration. The filtrate is concentrated and a residue is obtained. The residue is purified through medium pressure silica gel column chromatography (eluate: ethyl acetate/methanol=85/15), and 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole and 1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole are separated. These materials are crystallized in mixed solvents of chloroform and diethylether. The crystals are separated through filtration, dried and thus, 1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.354 g) (197) and 1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.330 g) (198) are obtained. 1H-NMR (CDCl3, δ): 3.00 (3H, s), 4.98 (2H, s), 5.88 (2H, s), 7.55 (2H, d, J=8.6 Hz), 7.69 (2H, d, J=8.6 Hz), 7.90 (1H, d, J=8.6 Hz), 7.96 (1H, dt, J=7.1 and 0.6 Hz), 8.12 (1H, J=8.0 Hz), 8.18 (1H, dd, J=8.5 and 1.4 Hz), 8.55 (1H, dt, J=8.0 and 1.7 Hz), 8.62 (1H, d,J=1.1 Hz), 8.77(1H, dd, J=5.9 and 1.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.[CH:39]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][N:41]([C:48](=O)[CH2:49]Cl)[CH2:40]2>>[CH:39]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][N:41]([CH2:48][CH2:49][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=1)[CH2:40]2
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CC4CCC(CC4)C3)cc2)c1
Yield: 41.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.7 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].CO.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1nc(-c2cccc(NC(=O)OC(C)(C)C)c2)no1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2noc(CCC(=O)O)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A 100-mL round bottomed flask was charged with methyl 3-[3-(3-tert-butyloxycarbonylaminophenyl)-1,2,4-oxadiazol-5-yl]propionate (4.04 g, 11.6 mmol), lithium hydroxide (1.39 g, 58.2 mmol), methanol (15 mL), water (15 mL) and THF (15 mL). The resulting solution was then stirred for 2 h at room temperature. The solvents were then removed under reduced pressure and the residue dissolved into water (60 mL). The resulting solution was cooled to 0° C. and acidified to pH 5 by the addition of 2 N hydrochloric acid. The mixture was then extracted with ethyl acetate (4×50 mL) and the combined extracts dried over sodium sulfate. Filtration and concentration under reduced pressure afforded an 83% yield of 3-[3-(3-tert-butyloxycarbonylaminophenyl)-1,2,4-oxadiazol-5-yl]propionic acid as a white solid. m.p. 143-144° C.; 1H NMR (DMSO-d6) δ (ppm) 12.42 (bs, 1H), 9.60 (s, 1H), 8.24 (s, 1H), 7.57 (m, 2H), 7.42 (t, 1H,J=7.9 Hz), 3.26 (t, 2H,J=6.9 Hz), 2.84 (t, 2H,J=6.9 Hz), 1.49 (s, 9H); m/z=332 (M−H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.C([O-])(O)=O.[Na+].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[N:11]=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(-c2ccccn2)nn1
Temperature: 0 °C
Yield: 95 %

Procedure:
4 g of pyridinylpyridazinone 7 dissolved in an excess (40 ml) of phosphorus oxychloride are refluxed for 8 hours. After cooling, the reaction mixture is poured into 250 ml of ice-cold water and then neutralized, dropwise, with a saturated aqueous solution of NaHCO3. After extraction with dichloromethane (5×100 ml), the organic phase is dried over MgSO4 and then concentrated under reduced pressure, to give the chlorinated pyridazine 8a with a yield of 95%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[S:16]1[CH:17]=[CH:18][C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])=[CH:15]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCOc1cccc(-c2ccsc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCCOc1cccc(-c2ccsc2)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.3 %

Procedure:
0.65 g of 3-[3-(5-bromopentyloxy)phenyl]thiophene, 0.37 g of potassium phthalimide and 0.14 g of potassium carbonate were dissolved in 5 ml of dimethylformamide, and the mixture was heated at 50° C. with stirring for 5 hours. Ethyl acetate and water were added, and the organic layer separated was worked up in a customary manner. The product was purified by silica gel column chromatography [hexane / ethyl acetate=7/1 →5/1] to give 0.36 g of N-[5-[3-(3-thienyl)phenoxy]pentyl] phthalimide as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1.C(N(CC)CC)C.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>C(Cl)Cl>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:19][C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([S:28][CH3:27])=[CH:30][CH:31]=3)=[O:37])[CH:15]=2)[N:10]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NC(=O)Nc2ccc3nc(N4CC5CCC4CC5)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-azabicyclo[2.2.2]oct-2-yl)quinolin-6-amine (21 mg, 0.08 mmol, Example 119, Step B), triethylamine (0.013 mL, 0.09 mmol) in 1 mL methylene chloride was added 4-(methylthio)phenylisocyanate (15 mg, 0.09 mmol). The resulting mixture was stirred at r.t. for 2 h. The solvent was removed under vacuum and the residue was purified by preparative thin layer chromatography eluting with hexane/ethyl acetate (1:1) to afford the product, MS: m/z 419 (MH+), as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][CH2:12][CH2:11][N:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[N:15]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[C:17]([CH2:24][CH:25]=O)[CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][N:13]2[CH2:25][CH2:24][C:17]2[CH:16]=[N:15][N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=23)=[CH:6][CH:7]=1
Reactant: CN1CCNC(c2ccc(Br)cc2)C1
Reactant: O=CCc1cnn2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN(CCc2cnn3ccccc23)C(c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.2 %

Procedure:
To a solution of 3-(4-bromo-phenyl)-1-methyl-piperazine (1.0 g, 3.92 mmol), pyrazolo[1,5-a]pyridin-3-yl-acetaldehyde (753 mg, 4.70 mmol) and acetic acid (1.2 mg) in tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (1.92 g, 8.62 mmol) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash silica gel column chromatography (heptane/ethyl acetate) gave 3-{2-[2-(4-bromo-phenyl)-4-methyl-piperazin-1-yl]-ethyl}-pyrazolo[1,5-a]pyridine (786 mg, 50% yield). LCMS (m/z): 401.00 (M+1).