Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](O)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:21].C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([Cl:21])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2sccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Cl)c2sccc2c1O
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 143.5 %

Procedure:
A mixture of 4,7-dihydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (267 mg, 1 mmol), POCl3 (217 mg, 1.4 mmol), and toluene (4 ml) was heated in a microwave oven at 140° C. for 15 min. The same procedure was repeated with a second batch. Both batches were combined, conc. aqueous NaHCO3 (40 ml) and EtOAc (40 ml) were added and the mixture was stirred vigorously for 45 min. The organic layer was then separated, dried over MgSO4 and concentrated in vacuo to give a tan solid (410 mg). Purification by flash column chromatography on silica gel using CH2Cl2:EtOAc=9:1 as the eluent yielded the title compound as a tan solid (297 mg, first major fraction). MS-(−)-ion: M−1=284.3.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1>[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([N:60]1[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]1)=[O:8]
Reactant: CN1CCNCC1
Reactant: COc1ccc(COc2cc(C(=O)O)cc(Cl)c2OCc2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(C(=O)N3CCN(C)CC3)cc(Cl)c2OCc2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of 5-chloro-3,4-bis(p-methoxybenzyloxy)benzoic acid (0.75 g: 1.75 mMol.) and 1-hydroxybenzotriazole (0.26 g: 1.1 Eq.) in tetrahydrofuran (15 ml) is added dicyclohexylcarbodiimide (0.40 g: 1.1 Eq.). After 1 hour stirring, to the mixture is added N-methylpiperazine (0.44 ml: 2.3 Eq.), and the mixture is stirred for 1 hour. The reaction mixture is filtered to remove solid and concentrated under reduced pressure to give 1-(5-chloro-3,4-bis(p-methoxybenzyloxy)benzoyl)-4-methylpiperazine (0.86 g). Yield: 96%.
Reaction SMILES: O.S(=O)(O)[O-].[Na+].[CH:7]([CH:9]=O)=O.[NH2:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20]>O.C(O)C.Cl>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[CH:7][CH:9]=[N:18]2
Reactant: O=CC=O
Reactant: COc1cccc(N)c1N
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2nccnc12
Reaction time: 1 h
Yield: 77.9 %

Procedure:
Glyoxal sodium bisulphite hydrate (10.0 g) in water (80 ml) was warmed to 60° C. then a solution of 2,3-diaminoanisole (3.40 g) in ethanol (40 ml) was added. The stirred mixture was then heated to 80° C. for 1 h before addition of concentrated hydrochloric acid (6 drops). Heating was continued for 1 h. It was allowed to cool overnight, concentrated in vacuo and poured into aqueous potassium carbonate (40 ml). Ethyl acetate (3×100 ml) extracts were washed with water (100 ml) and saturated brine (50 ml) then dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to afford the title compound as a yellow solid (3.07 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:13]([C:14](Cl)=[C:5]2[C:4]([CH3:16])=[N:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS(C)=O>O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:13]([C:14]([NH:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:5]2[C:4]([CH3:16])=[N:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: NCc1ccccc1
Reactant: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(C)c2nc3ccccc3c(NCc3ccccc3)c12
Temperature: 85 °C

Procedure:
A mixture of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b] quinoline (1.2 g, 0.005 mol), benzylamine (1.2 ml) and DMSO (3 ml) was heated at 80-90° C. for 3-4 hours. The reaction mixture was cooled to room temperature and then was poured into water. The mixture was extracted with CH2Cl2 (3×50 ml) and then the CH2Cl2 layers were combined and evaporated. The residue was purified by column chromatography on silca gel eluting with ethyl acetate to afford the product which was crystallized from ether/hexane to afford 1.2 g of 1,3-dimethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 105° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]12([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23](Cl)=[O:24])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.O>C1COCC1>[C:10]12([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:24])[CH2:11][CH:12]3[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]3)[CH2:19]1)[CH2:17]2
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccccc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h
Yield: 82.8 %

Procedure:
In a manner analogous to Example 3(b), 0.95 g (10 mmoles) of phenol in 10 ml of THF are treated with 332 mg 11 moles) of sodium hydride (80% in oil). There is then slowly introduced a solution of 3.2 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoyl chloride in 30 ml of THF. The reaction is permitted to proceed at ambient temperature for 4 hours. The reaction medium is poured into water, extracted with ethyl ether, washed with water, dried on magnesium sulfate and evaporated. The residue is chromatographed on silica, eluting with a 60:40 mixture of hexane and dichloromethane. After evaporation and precipitation in hexane, 3 g (83% yield) of the expected ester having a melting point of 165°-166° C. are isolated.
Reaction SMILES: COC1C=CC(N=[N:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([S:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:23])=[O:22])[C:12]=2[OH:42])=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([S:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:23])=[O:22])[C:12]=1[OH:42]
Reactant: CCCCCCCCCCCCCCCCCCS(=O)(=O)c1cc2ccccc2c(N=Nc2ccc(OC)cc2)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCS(=O)(=O)c1cc2ccccc2c(N)c1O
Yield: 96.3 %

Procedure:
To a suspension of 14 g (0.024 mole) 1-(p-methoxyphenylazo)-3-octadecanesulfonyl-2-naphthol in 500 ml hot ethanol was added a solution of 12 g (0.060 mole) sodium dithionite in 60 ml water. The mixture was stirred and refluxed for one hour, then cooled and filtered to give 11 g of solid, which can be recrystallized from hexane to give a solid, m.p. 84°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15](F)[CH:14]=2)[N:8]=1.[C@H:23]1([NH2:30])[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][NH:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:29][C@H:26]3[CH2:27][CH2:28][C@H:23]([NH2:30])[CH2:24][CH2:25]3)[CH:14]=2)[CH:10]=[N:11][CH:12]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(CNc2cncc(-c3ccnc(F)c3)n2)c1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCc4cccc(F)c4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
To N-(3-fluorobenzyl)-6-(2-fluoropyridin-4-yl)pyrazin-2-amine (30 mg, 0.101 mmol) was added DMSO (0.6 ml) and trans-cyclohexane-1,4-diamine (115 mg, 1.006 mmol). The reaction mixture then was stirred at 105° C. until completion as indicated by LCMS, about 40 hours. To the crude reaction mixture, after cooling to room temperature mixture was added 0.75 ml of DMSO, the resulting mixture filtered and purified by prep LC. After lyphilization, 34 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 393.2 (MH+), retention time=0.54 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[OH:23][CH:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:22][NH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: NCCCc1ccc(C(N)=O)s1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(CCCNCC(O)COc2ccccc2)s1

Procedure:
921 mg of 5-(3-aminopropyl)-2-thiophenecarboxamide and 0.68 ml of 2,3-epoxypropyl phenyl ether were heated to 90° in 15 ml of dimethylsulfoxide for 14 hours. The reaction mixture was poured into water and extracted with methylene chloride. The dried methylene chloride solutions were evaporated in vacuo and the residue was chromatographed on silica gel, whereby there were obtained 800 mg of 5-[3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]-2-thiophenecarboxamide, m.p. 129°-130°, ε276 =12130.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[CH3:15]O>OS(O)(=O)=O>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: CO
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CO)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 36 h

Procedure:
4-Hydroxymethyl-3-nitro-benzoic acid (step (a), 2.0 g, 10.2 mmol) was dissolved in 100 mL of MeOH, treated with 10 drops of concentrated H2SO4 and stirred at 70° C. After 36 h, the solution was concentrated in vacuo and redissolved in EtOAc. The EtOAc solution was washed with 1N NaOH and brine, dried over MgSO4, and concentrated to afford the title compound as a light-yellow solid upon drying under vacuum. MS m/z: 210.1 (M−1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:12]=1)=[O:19]
Reactant: c1ccc2ccccc2c1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1cccc2ccccc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (28.0 g, 0.21 mole) was suspended in 200 ml of anhydrous dichloromethane and was cooled to −30° C. A solution of naphthalene (25.6 g, 0.2 mole) and isobutyryl chloride (21.3 g, 0.20 mole) in 50 ml of anhydrous dichloromethane was slowly added to this suspension. After the addition was completed, the reaction mixture was stirred at −30° C. for 1 h. The reaction mixture was then allowed to warm up to room temperature. The reaction mixture was poured onto 300 g of ice water, and the organic layer was separated. The organic layer was successively washed twice with a 5 wt % aqueous hydrochloric acid solution (150 ml) and once with a 2 wt % aqueous sodium bicarbonate solution (150 ml). After drying over anhydrous magnesium sulfate the solution was concentrated under reduced pressure. The yield of 2-methyl-1-(1-naphthalenyl)-1-propanone was 39.7 g or 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:16]([N+:26]([O-])=O)[CH:15]=2)[O:11][N:10]=1>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:16]([CH:15]=2)[NH2:26])[O:11][N:10]=1
Reactant: COc1ccccc1-c1noc(-c2ccc(N3CCOCC3)c([N+](=O)[O-])c2)n1
Solvent: CCO
Product: COc1ccccc1-c1noc(-c2ccc(N3CCOCC3)c(N)c2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Stannous chloride dihydrate (147.53 mg; 0.65 mmol; 5 eq.) was added to a solution of example 2 (50 mg; 0.13 mmol; 1 eq.) in EtOH (10 mL), and the reaction mixture was stirred at 70° C. for 3 hours. After cooling, the solution was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed four times with brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow solid. The latter was triturated in Et2O and filtrated to afford the title compound (38 mg, 82%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: CCCCOc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 72.7 %

Procedure:
The title compound (0.190 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and 3-butoxyphenylboronic acid (0.224 g, 1.16 mmol) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.44-7.41 (m, 2H), 7.27 (t, J 7.9, 1H), 7.17-7.10 (m, 2H), 6.81-6.84 (m, 1H), 5.50 (s, 2H), 4.01 (t, J 5.3, 2H), 1.72-1.65 (m, 2H), 1.50-1.41 (m, 2H), 0.93 (t, J 7.4, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-])=O)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]>CO.[Fe]>[NH2:13][C:7]1[CH:6]=[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:4]([O:3][CH3:2])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Temperature: 60 °C

Procedure:
Concentrated hydrochloric acid (30 ml) was added to a suspension of 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.67 g) in methanol (150 ml) and the mixture was heated to 60° C. When the 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide had dissolved, iron powder (5.6 g, 100 mmol) was added in portions to the reaction mixture which was then heated for 90 minutes. After cooling, the insolubles were removed by filtration through diatomaceous earth, the volatiles were removed from the filtrate by evaporation and the residue was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with hydrochloric acid (pH2). Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 2-amino-5-methoxy-4-(3-morpholinopropoxy)benzamide as a hydrochloride salt 4.67 g, 75%) as beige crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]([S:38]([CH3:37])(=[O:40])=[O:39])[C:21]3=[O:29])[CH2:18][CH2:19]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One (1) g of 1-[1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (cf. International Publication WO 96/13262) and 0.53 ml of triethylamine were suspended in 30 ml of chloroform. To the suspension 0.29 ml of methanesulfonyl chloride was added, followed by 2 hours' stirring at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction liquid, which was then extracted with chloroform. The extract was dried over sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform, chloroform/methanol=19/1) to give 860 mg of 1-[1-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one. The product was dissolved in 25 ml of trifluoroacetic acid, stirred for 30 minutes at room temperature and then the trifluoroacetic acid was distilled off. To the residue ether and chloroform were added and whereby obtained crystals were recovered by filtration, to give 860 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([CH:17]3[CH2:19][CH2:18]3)[C:13]=2[C:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.O[Li].O>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([CH:17]3[CH2:18][CH2:19]3)[C:13]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(CNC(c2ccc(Cl)cc2)c2c(C)nn(C3CC3)c2C(=O)[O-])cc1
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNC(c2ccc(Cl)cc2)c2c(C)nn(C3CC3)c2C(=O)O)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
In a 100-mL flask was introduced 4-((4-chlorophenyl)((4-methoxybenzyl)amino)methyl)-1-cyclopropyl-3-methyl-1H-pyrazole-5-carboxylate (Step 23.6) (2.22 g, 4.89 mmol) and LiOH.H2O (0.616 g, 14.67 mmol) in dioxane (15 mL) and H2O (6 mL). The reaction mixture was stirred for hr at rt, quenched with 0.5N HCl (100 mL), and diluted with EtOAc (100 mL). The resulting suspension was filtered to afford the title compound (2.30 g, 4.59 mmol, 94% yield) as a colorless solid. tR: 3.86 min (HPLC 1); tR: 0.87 min (LC-MS 2); ESI-MS: 426 [M+H]+ (LC-MS 2).
Reaction SMILES: [NH2:1][C:2]1([CH2:5][OH:6])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1.ClCCl>[Si:15]([O:6][CH2:5][C:2]1([NH2:1])[CH2:4][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: NC1(CO)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1(N)CC1
Reaction time: 20 h
Yield: 87.1 %

Procedure:
To a stirring solution of (1-aminocyclopropyl)methanol (9.69 mmol), 4-(dimethylamino)pyridine (0.484 mmol), and triethylamine (21.32 mmol) in anhydrous dichloromethane (25 mL) was added chloro(1,1-dimethylethyl)dimethylsilane (10.66 mmol). After stirring 20 h, the reaction was quenched with saturated aq ammonium chloride and extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to afford the crude title compound (1.70 g, 78% yield) as a colorless liquid. MS(ES)+ m/e 202.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)Oc1ccccc1C2=C1C2CC3CC(C2)CC1C3
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Hydroxy alkene 5a (0.577 g, 1.5 mmol) was dissolved in 20 mL of CH2Cl2 with 1.25 mL (1.22 g, 15.5 mmol) of pyridine. Acetyl chloride (0.6 mL, 0.662 g, 8.4 mmol) was dissolved in 5 mL of CH2Cl2 and added dropwise to the solution with 5a. A precipitate formed immediately. After stirring for 2 hours, the solvent was removed to give a yellow-orange solid. This material was treated with 50 mL of CH2Cl2 to leave a white solid which was separated by filtration. The CH2Cl2 solution was then concentrated and chromatographed over silica with 5% ethyl acetate/hexane to give 0.502 g (77.2%) of 5c as a white solid: mp 162°-163° C.; 1H NMR (CDCl3 delta 1.80-2.05 (m, 12H), 2.265 (s, 3H), 3.45-3.55 (m, 2H), 6.833 (dd, 1H, J=8.38, 2.32 Hz), 6.961 (d, 1H, J=2.33 Hz), 7.072 (ddd, 1H, J=8.11, 5.45, 2.08 Hz), 7.12-7.28 (m, 4H); 13C NMR (CDCl3) delta 20.96, 27.78, 32.50, 36.88, 39.36, 110.08, 115.72, 116.41, 122.75, 124.38, 126.44, 126.90, 127.42, 127.68, 146.81, 149.24, 154.86, 155.48, 169.18. ##STR41##
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][C:9]=1[N:10]=[CH:11]N(C)C)=[O:4].[CH3:34][N:35]([CH3:46])[CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1>C(O)(C)C>[Si:17]([O:16][CH2:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:45]([C:42]3[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][N:35]([CH3:46])[CH3:34])=[CH:44][CH:43]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)([C:30]([CH3:32])([CH3:33])[CH3:31])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N=CN(C)C
Solvent: CC(C)O
Product: CN(C)CCOc1ccc(-n2cnc3cc(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)sc3c2=O)cc1

Procedure:
5-(tert-Butyldiphenylsilanyloxymethyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with 4-(2-dimethylaminoethoxy)phenylamine by method A with addition of isopropanol in addition. The product with the molecular weight of 583.83 (C33H37N3OSSi) was obtained in this way; MS (ESI): 584 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:36])[C:28](N2C=C[N+](C)=C2)=[O:29])=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28](=[O:29])[N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH3:36])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccc(Cl)cc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptan, 1:5) (77%, white crystals). HPLC-MS m/z=423.1 (M+1), Rt: 5.3 min.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:11]=[N:12][C:13]([O:16]C)=[CH:14][CH:15]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][N:11]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(-c3ccccc3)cc2)nn1
Agent: Cl
Product: O=c1ccc(S(=O)(=O)c2ccc(-c3ccccc3)cc2)n[nH]1

Procedure:
The product of step A was treated with concentrated hydrochloric acid according to step C of Example 2 to obtain the title compound. Mp. 219-220° C.