Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:13].[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=1)=[O:27]>>[CH3:24][CH:25]([CH3:41])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]2[CH2:40][CH2:39][N:38]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[CH2:37][CH2:36]2)[CH:30]=1)=[O:27]
Reactant: O=C(CCCCCl)c1ccccc1C(F)(F)F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3C(F)(F)F)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 5-chloro-1-[2-(trifluoromethyl)phenyl]-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([OH:9])=O)=[N:4][O:5][N:6]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=1[NH2:13]>>[NH2:1][C:2]1[C:3]([C:7]([NH:13][C:12]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:11]=2[Cl:10])=[O:9])=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=O)O
Reactant: Nc1cc(Cl)ccc1Cl
Product: Nc1nonc1C(=O)Nc1cc(Cl)ccc1Cl

Procedure:
This compound was prepared according to the procedure of Example 45, Step 1, using 4-amino-1,2,5-oxadiazole-3-carboxylic acid and 2,5-dichloroaniline as the starting materials. LCMS for C9H7Cl2N4O2 (M+H)+: m/z=273.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8](OC2CCCCO2)[C:9]([C:11]2[O:12][C:13]3[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[NH:10])[CH:5]=[CH:6][CH:7]=1.C[OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[O:12][C:13]3[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[N:10][OH:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc2cc(C(=N)N(OC3CCCCO3)c3cccc(Cl)c3)oc12
Reactant: CO
Product: CC(=O)Nc1cccc2cc(C(=NO)Nc3cccc(Cl)c3)oc12
Yield: 73 %

Procedure:
To a methanol solution of N-{2-[N-(3-chloro-phenyl)-N-(tetrahydro-pyran-2-yloxy)-carbamimidoyl]-benzofuran-7-yl}-acetamide was added 200 mg of acidic Dowex resin. The resulted solution was stirred at reflux temperature for 1 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified using a chromatotron and eluting with hexane/ethyl acetate (8:2) to give 25 mg N-{2-[N-(3-chloro-phenyl)-N′-hydroxy-carbamimidoyl]-benzofuran-7-yl}-acetamide in 73% yield.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([C:8](=[O:14])[C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[C:6]#[N:7])C.[N+:15]([O-])(O)=O.NNC(N)=N.[OH-].[Na+]>C(O)C>[NH2:2][C:4]1[C:5]([C:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[O:14])=[CH:6][NH:7][N:15]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccco1
Reactant: O=[N+]([O-])O
Agent: N=C(N)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1n[nH]cc1C(=O)c1ccco1
Yield: 96.1 %

Procedure:
A reaction mixture comprising 19.0 g of α-[(dimethylamino)methylene]-β-oxo-2-furanepropanenitrile, 16.1 g of aminoguanidine nitrate, 250 ml of ethanol and 11.0 ml of 10N sodium hydroxide was refluxed for 6 hours and then evaporated to dryness. Water was added to the crude residue and the precipitated solid was collected, giving 17.0 g of the desired product, mp 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.8 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (0.30 g, 1.06 mmol) in anhydrous THF (5 mL) were added dimethyl-piperidin-4-yl-amine (0.27 g, 2.11 mmol), sodium triacetoxyborohydride (0.34 g, 1.60 mmol) and glacial acetic acid (90 μL, 1.59 mmol). The resulting solution was stirred at RT for 17 h, then partitioned between EtOAc and a sat. aqueous solution of NaHCO3. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.10 g, 27%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH3:9][S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[C:14]=1[CH2:23][O:24][CH3:25])(=[O:12])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[C:14]([CH2:23][O:24][CH3:25])[C:15]=2[CH3:22])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1O
Reactant: COCc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(COC)c2C)c1O
Yield: 65.3 %

Procedure:
1.12 g (0.01 mol) of 1-ethyl-5-hydroxypyrazole is dissolved in 30 ml of t-amyl alcohol, and then 2.59 g (0.01 mol) of 4-methanesulfonyl-3-methoxymethyl-2-methylbenzoic acid, 2.06 g (0.01 mol) of N,N'-dicyclohexylcarbodiimide and 0.69 g (0.005 mol) of anhydrous potassium carbonate were sequentially added thereto. The mixture was reacted at a temperature of from 80° to 90° C. for 8 hours under stirring. After completion of the reaction, t-amyl alcohol was distilled off under reduced pressure, and 30 ml of water was added to the residue to dissolve the soluble components. The mixture was subjected to filtration to separate out the insolubles. The aqueous solution thus obtained was washed with chloroform, and concentrated hydrochloric acid was added to adjust pH<1. The precipitated oil component was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography (eluent: ethyl acetate/ethanol=9/1) to obtain 2.3 g of the desired product. (Yield: 66%, melting point: 116°-118° C.)
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1
Reactant: CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (460 mg, 20 mmol) in methanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (750 mg, 3.8 mmol). The mixture was stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound, which crystallized with petroleum ether in a 630 mg (86%) yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][CH:3]=1.[ClH:15].[N:16](OCCC(C)C)=[O:17]>O1CCCC1>[ClH:15].[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[N:16]=[O:17]
Reactant: COc1ccc(-n2nccc2N)cc1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2ncc(N=O)c2N)cc1

Procedure:
17.4 g (92 mmol) of 5-amino-1-(4-methoxyphenyl)pyrazole [sic] from Step 1.1 was dissolved in 200 mL of tetrahydrofuran, 52.4 g of 32% hydrochloric acid was added, and the mixture was cooled to 0–5° C. Then 11.8 g (101 mmol) of isopentyl nitrite was added dropwise with agitation so that the temperature did not exceed 5° C. Gradually, a brownish precipitate formed which after an additional 2-hour agitation period in an ice bath was removed by suction filtration and washed with a small amount of tetrahydrofuran. Drying gave 16.4 g (64 mmol, 70% of the theoretical) of 5-amino-1-(4-methoxyphenyl)-4-nitrosopyrazole hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:13]O.P(Br)(Br)[Br:16].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[C:3]=1[CH2:13][Br:16]
Reactant: OCc1c(Br)cccc1OC(F)(F)F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(Br)c1CBr
Temperature: -10 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred solution of 2-bromo-6-[(trifluoromethyl)oxy]benzoic acid (1.116 g, 3.92 mmol, Parkway Scientific), in THF (45 ml), under nitrogen, was added 1.0 M borane-tetrahydrofuran complex (12 ml, 12 mmol) carefully over about 2 minutes. The solution was then heated at gentle reflux for 24 h and allowed to cool. Methanol (20 ml) was added dropwise. The solution was heated at reflux for 30 min and allowed to cool. The solvent was evaporated in vacuo and acidified with dilute aqueous HCl. The mixture was extracted with chloroform and then filtered through a hydrophobic frit. The chloroform was evaporated in vacuo to give {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol as a colourless oil (1.07 g). {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol (1.06 g, 3.91 mmol) in dichloromethane (14 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (0.37 ml, 3.91 mmol) in DCM (3.5 ml) was then added dropwise over about 12 min. The temperature was allowed to rise to ambient temperature over about 3 h then stirred for a further 2 h. Saturated aqueous sodium bicarbonate (12 ml) was then added in portions with stirring and the mixture left in a fridge over weekend. The mixture was extracted into chloroform three times. The combined chloroform extracts were filtered through a hydrophobic frit and the solvent was evaporated in vacuo to give 1-bromo-2-(bromomethyl)-3-[(trifluoromethyl)oxy]benzene as a colourless oil (0.6 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:17]=1)=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH:29]=[CH:28][C:18]2[N:17]=[C:16]([NH:15][C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3N)c2c1
Yield: 90.5 %

Procedure:
A solution of 520 mg of cis-N-tert-butoxycarbonyl-2-[2-(4-chlorostyryl)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 10 mL of methanol was combined with 5 mL of a 4 N solution of hydrogen chloride in ethyl acetate, and reacted at 50° C. for 24 hours. After the solvent was distilled off, the residue was basified by addition of a 10% aqueous solution of sodium hydroxide, and extracted with chloroform. After concentrating, the residue was purified by column chromatography on silica gel (chloroform:methanol=10:1) to obtain 378 mg of the desirable compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCCBr
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CCCCCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.96 g) and nonyl bromide (0.57 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.20 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-[(1-nonylpyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.81 g) was obtained.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1>C1(C)C=CC=CC=1>[C:1]([O:12][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COc1cc(CO)ccc1O
Reactant: CCCCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
Decanoic acid (10.0 g, 58.1 mmol), vanillyl alcohol (8.05 g, 52.2 mmol), and lipase PS-C “Amano” I (enzyme immobilized on ceramic: 1.44 g) were measured and placed in a flask (500 ml), and toluene (200 ml) was added. Under an argon atmosphere, the mixture was heated with stirring in an oil bath at 40° C. for 2 hours. This reaction mixture was concentrated under reduced pressure, and dehydration was promoted by azeotropic effect. Toluene (150 ml) was further added to the concentrate, and the mixture was heated with stirring in an oil bath at 40° C. for 20 hours. The reaction mixture was again concentrated under reduced pressure, and heptane (200 ml) was added. The mixture was stirred at room temperature for 2.5 hours, and immobilized enzyme and precipitated vanillyl alcohol were removed by filtration. The filtrate was concentrated under reduced pressure to give a mixture (15.8 g) of vanillyl decanoate and decanoic acid. As a result of the analysis, the yield of vanillyl decanoate was 98% and the purity was 97.9 area % by HPLC. The mixture contained 8.6 wt % of decanoic acid relative to vanillyl decanoate.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])=[CH:10][CH:9]=1)#[N:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 22 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 10 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 22.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12].[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:42])=[O:41])[CH2:31][CH2:32]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12]
Reactant: Cc1cc(N2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(N2CCN(S(=O)(=O)c3ccccc3)CC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
N5-(1H-Benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-imidazole-4,5-dicarboxamide (1 equivalent), dichloromethane, benzenesulfonyl chloride (1.5 equiv), and DIEA (1.5 equiv.) were added and stirred at room temperature. After 1 hour, LC-MS indicated the reaction was complete. The reaction mixture was evaporated under reduced pressure. The resulting crude product was purified by reverse phase HPLC (aqueous ammonium acetate/acetonitrile to give N5-1H-benzimidazol-2-yl-N4-{2-methyl-4-[4-(phenylsulfonyl)piperazin-1-yl]phenyl}-1H-imidazole-4,5-dicarboxamide in 43% yield. 1H-NMR (400 MHz, DMSO-d6): δ 10.9 (s, br, 1H), 8.36 (s, 1H), 7.80 (m, 2H), 7.73-7.64 (m, 4), 7.43 (m, 2H), 7.33 (m, br, 1H), 6.97 (m, br, 2H), 3.31 (s, br, 4H), 3.09 (s, br, 4H). 2.24 (s, 3H). MS (EI): 585 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:24])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:24])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH:18]=1)[CH3:12]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(Br)n2)c1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (127 mg, 0.63 mmol) was coupled to aniline (60) (120 mg, 0.63 mmol) using Method C to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:33][CH2:34]O)(=[N:29][C:30](=[O:32])[CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:56]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:33][CH2:34][Br:56])(=[N:29][C:30](=[O:32])[CH3:31])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CC(=O)N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N=S(=O)(CCBr)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Yield: 49.7 %

Procedure:
To a suspension of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-(2-hydroxy ethyl)-N-acetyl sulfoximide (90 mg, 0.000168 mol) in DCM (15 mL) was added triphenyl phosphine (44 mg, 0.000168 mol) with stirring followed by carbon tetrabromide (55 mg, 0.000168 mol) at 25-30° C. Reaction mixture was stirred at same temperature for 3 hr. Subsequent work up and column purification (100-200 mesh silica gel, 50% ethyl acetate in hexane) gave 50 mg of titled product in 50% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]([Cl:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: COC1=C(C(=O)O)N(C)S(=O)(=O)c2ccccc21
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC1=C(C(=O)Cl)N(C)S(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21801.5 %

Procedure:
6.2 gm (23 millimols) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide were suspended in 60 ml of benzene and 8.2 ml (0.11 millimols) of thionyl chloride and 0.5 ml of anhydrous dimethylformamide were added to the suspension. The reaction mixture was refluxed for 6 hours, stirred overnight at room temperature and evaporated in vacuo. The residue was dissolved in a little toluene, and the solution was evaporated, yielding 6.9 gm (100% of theory) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide.
Reaction SMILES: [NH:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1>CC#N.CCOC(C)=O>[N:32]12[CH2:37][CH2:36][CH:35]([CH2:34][CH2:33]1)[C@@H:30]([O:29][C:28]([N:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38])[CH2:31]2
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cccc(CN(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A suspension of methyl 4-[[3-(anilinomethyl)phenoxy]methyl]benzoate (380 mg, 1.1 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (described in the co-pending International Patent Application No. PCT/EP2013/075529 (published as WO 2014/086855) as Intermediate 16) (300 mg, 1.33 mmol) in anhydrous CH3CN (5 mL) was heated to 100° C. for 15 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (20 mL) The layers were separated and the organic phase was dried over Na2SO4, filtered and the solvent was removed in vacuo to yield the title compound (419 mg, 76% yield) which was used directly in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:37]>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:37]=2)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
(1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol) was dissolved in m-xylenes (4 mL) and heated at 135° C. Solid ammonium acetate (200 mg, 2.58 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product {1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (162 mg, 0.329 mmol): LCMS-ESI+: calc'd for C21H26BrN5O4: 492.4 (M+). Found: 492.3/494.3 (M+H+).