Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[B:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[Li:22]>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[B-:6]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.[Li+:22]
Reactant: [Li]c1cccs1
Reactant: c1csc(B(c2cccs2)c2cccs2)c1
Solvent: C1CCOC1
Product: [Li+]
Product: c1csc([B-](c2cccs2)(c2cccs2)c2cccs2)c1

Procedure:
The trithienyl boron is further dissolved in dry tetrahydrofuran (30 ml), one equivalent of 2-thienyllithium is added dropwise to the mixture at 0° C. under nitrogen. The precipitate formed is filtered and dried to obtain pure lithium tetra(2-thienyl)borate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH2:17])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-]=C=S.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:50]=[CH:49][C:36]4[N:37]=[C:38](NC5N(C(C)C)C=CN=5)[NH:39][C:35]=4[CH:34]=3)=[O:32])[CH:28]=2)[CH:23]=[N:22]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:38]3[NH:39][C:35]4[CH:34]=[C:33]([C:31](=[O:32])[NH:30][C:27]5[CH:28]=[C:29]6[C:24]([CH:23]=[N:22][NH:21]6)=[CH:25][CH:26]=5)[CH:50]=[CH:49][C:36]=4[N:37]=3)[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: CC(C)n1ccnc1Nc1nc2ccc(C(=O)Nc3ccc4cn[nH]c4c3)cc2[nH]1
Agent: [N-]=C=S
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3nc4ccc(C(=O)Nc5ccc6cn[nH]c6c5)cc4[nH]3)sc2C1

Procedure:
The amine (0.5 mmol) from above was converted to corresponding isothiocyanate using general procedure A, which was then reacted with 3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester. MS: m/z 531 (M+H)+.
Reaction SMILES: C(O)(=O)C.[Cl-].[NH4+:6].[F:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20](=[NH:23])OC)=[N:12]1>>[F:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([C:20]([NH2:6])=[NH:23])=[N:12]1
Reactant: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
The solution of methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanol obtained from Example 5A is mixed with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride and stirred under reflux overnight. The solvent is evaporated in vacuo, the residue is thoroughly triturated with acetone, and the precipitated solid is filtered off with suction. It is added to 2 l of water, 31.8 g of sodium carbonate are added while stirring, the mixture is extracted three times with a total of 1 l of ethyl acetate, and the organic phase is dried with magnesium sulphate and evaporated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][CH2:7][N:8]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH2:9][CH2:10]1)=[O:11])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To isonipecotic acid ethyl ester (1.08 mL) dissolved in tetrahydrofuran (10 mL), triethylamine (1.40 mL) was added, and benzenesulfonyl chloride (1.02 mL) was added thereto at 0° C. The resultant mixture was stirred at room temerature for 21 hours. Ice was added to the mixture, followed by stirring for 10 minutes. Ethyl acetate and 0.5N hydrochloric acid were added thereto to thereby give two layers. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride. The resultant mixture was dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1), to thereby give the title compound (1.66 g) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>CCOCC.CCCCCC>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: C#CCOC1CCCCO1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)C#CCOC1CCCCO1
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
To 24.4 parts of 3-tetrahydropyranyloxy-1-propyne dissolved in 300 parts by volume of anhydrous ether and cooled to -50° C is added 74 parts by volume of 2.4 molar n-butyl lithium in hexane. The mixture is stirred for 45 minutes and allowed to warm to 30° C and then 19.3 parts of trimethylsilyl chloride in 50 parts by volume of dry ether is added and the mixture allowed to stand for about 12 hours. The mixture is cooled to 5° C and water is added. The ethereal layer is washed with water, saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent is removed and the residual liquid is distilled at 0.20 mm at 67°-69° to provide 1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne (Tetrahedron 29, 883 (1973).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:21]4[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=4)=[O:26])=[CH:7][CH:6]=3)=[CH:9][O:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Nc1ccc(-c2coc3ncnc(N)c23)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc(-c3coc4ncnc(N)c34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A 0° C. suspension of Example 13E (50 mg, 0.22 mmol) in dichloromethane (3 mL) was treated with p-tolylisocyanate (0.031 mL, 0.24 mmol), warmed to room temperature, and stirred overnight. The resulting precipitate was collected by vacuum filtration, washed with dichloromethane, and dried to provide 55 mg (70%) of the desired product. MS (ESI(+)) m/e 360 (M+H)+; 1H NMR (DMSO-d6) δ 8.80 (s, 1H), 8.60 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.6 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.52 (br s, 2H), 2.25 (s, 3H); Anal. Calcd. for C20H17N5O2: C, 66.84; H, 4.77; N, 19.49. Found: C, 66.58; H, 4.65; N, 19.42.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([N:27]1[CH2:30][CH:29](O)[CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(#N)C.CCOC(C)=O.CCCCCC>[CH:14]([N:27]1[CH2:30][CH:29]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH2:28]1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc(OC3CN(C(c4ccccc4)c4ccccc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Phenylphenol (8.51 g, 50 mmol), 1-benzhydrylazetidin-3-ol (11.97 g, 50 mmol) and triphenylphosphine (13.11 g, 50 mmol) were stirred in acetonitrile (250 mL) for 20 minutes at room temperature, until all the reagents were fully dissolved. Diisopropyl Azodicarboxylate (9.84 mL, 10.11 g, 50 mmol) was added dropwise. A white precipitate forms and the initial reaction is mildly exothermic. The yellow colour is immediately discharged. After 5 minutes, the reaction is heated to reflux temperature, whereupon the precipitate dissolved, and stirred at this temperature for 3.25 hours. The mixture was cooled to room temperature, and scratched with a spatula to induce crystallisation. The mixture was cooled on ice, and the solids collected by filtration. The solids were washed with further cold acetonitrile and dried thoroughly to give the ether (15.42 g, 79%) as a white powder; mp 141-142° C.; Rf 0.68 (2:1 hexane:EtOAc); LCMS retention time 2.57 mins, m/z 392.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 7.60-7.52 (m, 4H), 7.46-7.39 (m, 6H), 7.31-7.26 (m, 5H), 7.19 (tt, 2H, J=7.2 and 2.0 Hz), 6.90 (d, 2H, J=8.8 Hz), 4.88 (app qn, 1H, J=5.6 Hz), 4.53 (s, 1H), 3.67-3.63 (m, 2H) and 3.02-2.98 (m, 2H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23]([OH:25])=[O:24].C1COCC1.C([Li])CCC.Cl>O.CCCCCC>[CH2:13]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[C:3]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[CH:21]=[CH:22][C:23]([OH:25])=[O:24])[CH:4]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1cc(-c2cccc(C=CC(=O)O)c2)c(Br)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCOc1cc(-c2cccc(C=CC(=O)O)c2)cc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
3-(1-Bromo-4-pentyloxynaphthalene-2-yl)cinnamic acid (100 mg, 0.275 mmol) and THF (2 ml) were mixed in a reaction vessel replaced with argon, and this solution was cooled to -78° C. A hexane solution (1.6M, 0.38 ml) of n-butyllithium (0.6 mmol) was added, and the mixture was stirred for 1 hour. Water (1 ml) and conc. hydrochloric acid were added to make this solution acidic (pH=1), and the aqueous layer was extracted 4 times with ethyl acetate (5 ml). The organic layers were combined, washed 3 times with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1) to give 3-(4-pentyloxynaphthalene-2-yl)cinnamic acid (46.2 mg, 59%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(OCC)(=O)C>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1Cc1ccc(S(C)(=O)=O)cc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)benzyl)piperidine-1-carboxylate (3.99 g, 9.38 mmol) was dissolved in MeOH (70 mL) and cooled to −30° C. NaOH (0.375 g, 9.38 mmol) dissolved in water (7 mL) was added during 10 min and the resulting colourless solution continued to stir at −30° C. for 20 min. Hydroxylamine (50% by weight in water, 0.575 mL, 9.38 mmol) was added dropwise. The resulting solution was stirred at −30° C. for 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M HCl (30 mL, 180 mmol) and the mixture continued to stir at 80° C. for 20 min. The mixture was dissolved between ethyl acetate and water. The aqueous layer was extracted three more times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered through celite and the solvent was evaporated. The residue was purified using reversed phase chromatography, gradient acid buffer and acetonitril, started 35% and ended 40%. Methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.05 g, 28.4%) was isolated.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[N:17]=[C:18]=[S:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[C:11]=1[NH:17][C:18](=[S:19])[N:3]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:1][CH3:2]
Reactant: CCNCCC(=O)O
Reactant: Cc1cccc(C)c1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCC(=O)O)C(=S)Nc1c(C)cccc1C
Yield: 39.3 %

Procedure:
A mixture of 3-ethylaminopropionic acid (19.8 g), 2,6-dimethylphenyl-isothiocyanate (16.3 g), triethylamine (20 g) and methylene chloride (200 mL) was heated at reflux for 3 hours. The cooled reaction mixture was extracted with 1N NaOH (150 mL). The aqueous layer was separated and acidified with 2N HCl. The solid formed was collected by filtration. Recrystallization from ethanol afforded the title compound (11 g) as a white solid, m.p. 115°-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[CH:9].[C:16](=[O:18])=[O:17]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:16]([OH:18])=[O:17]
Reactant: O=C=O
Reactant: C#Cc1ccc(-c2ccccc2)cc1Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br

Procedure:
Prepared analogously to Example 4.3.a. from 3-bromo-4-ethynylbiphenyl and carbon dioxide. Yield: 2.5 g (89% of theory); C15H9BrO2 (M=301.13); calc.: molecular ion peak (M+H)+: 301/303 (Br); found: molecular ion peak (M+H)+: 301/303 (Br); Rf value: 0.3 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)([O:3]C)=O.[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C(O)(=O)C>O>[C:12]1([N:18]2[C:1](=[O:3])[C:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)C1CCCCC1=O
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=c1c2c([nH]n1-c1ccccc1)CCCC2

Procedure:
32.9 Parts of a mixture containing 60% 2-carboethoxyclohexanone and 40% of 2-carbomethoxycyclohexanone purchased from Aldrich Chemical Company, Milwaukee, Wisconsin 53233, and 21.6 parts of phenylhydrazine purchased from Eastman Organic Chemicals Company, Rochester, N. Y. 14650, were admixed in 200 parts of toluene containing 2.0 parts of acetic acid. The mixture was refluxed for two hours with water removal. The resulting yellow suspension was cooled to 0°. The solid was collected, washed with hexane and dried. The yield was 37.1 parts of white solid with m.p. 178°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:11])[CH2:9][CH3:10].N1C=CC=C[CH:13]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][S:24]([C:18]1[CH:23]=[CH:22][C:21]([CH3:13])=[CH:20][CH:19]=1)(=[O:26])=[O:25])[CH2:9][CH3:10]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCC(N)Cc1sccc1Cl
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@H](Cc1sccc1Cl)NS(=O)(=O)c1ccc(C)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
Five grams of 3-chloro-2-(2-aminobutyl)thiophene is dissolved in 10 ml of methylene chloride in a 3-neck round bottomed flask blanketed with an inert atmosphere at 0° C. Pyridine (2.2 ml) is added in one portion followed by 3.37 ml of benzenesulfonyl chloride. The latter reagent is added at such a rate as to allow the methylene chloride solution to warm to 15° C. After warming to ambient temperature, the mixture is stirred for 4 hours and diluted with 100 ml of diethyl ether. The solution is poured into a separatory funnel and washed with water, dilute 1N HCl, saturated aqueous sodium bicarbonate and brine. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo to provide (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide (6.7 g) as an orange oil. MS: m/z (E1, 70EV) 330 (20%). 1H NMR (200 MHz; CDCl3): δ 0.82 (3H, t, CH3); 1.6 (2H, m, CH2), 2.85 (2H, d, CH2), 3.45 (1H, m, CH), 6.8 (1H, d, CH), 7.1 (1H, d, C H), 7.4-8.2(5H, m, Ph).
Reaction SMILES: [C:1]1([S:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C1COCC1.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(/C=C/c1ccc2[nH]ccc2c1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(CCc1ccc2[nH]ccc2c1)c1ccccc1
Yield: 85 %

Procedure:
A suspension of (E)-5-(2-(phenylsulfonyl)vinyl)-1H-indole (5.0 g) in 50 ml methanol, 10 ml THF and 10% Pd/C (1.0 g) was subject to hydrogenation at 45-50 psi. Upon completion of the reaction the catalyst was filtered off and the solvent removed under vacuum to provide the title compound in about 85-90% yield as an off-white solid. 1H NMR CDCl3 δ=8.15 (bs, NH), 7.93-8.00 (m, 2H), 7.53-7.70 (m, 3H), 7.38 (s, 1H), 7.30 (d, 1H), 7.20 (dd, 1H), 6.93 (dd, 1H), 6.42-6.48 (m, 1H), 3.37-3.46 (m, 2H), 2.99-3.17 (m, 2H). ESI Mass (M+23) 308.4
Reaction SMILES: N1C=CC(C2CCCC(=NO)C=2)=CC=1.[O:15]=[C:16]([CH3:33])[CH2:17][CH2:18][CH:19]([C:25]([C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[O:26])C(OCC)=O>>[N:30]1[CH:31]=[CH:32][C:27]([C:25](=[O:26])[CH2:19][CH2:18][CH2:17][C:16](=[O:15])[CH3:33])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(CCC(C)=O)C(=O)c1ccncc1
Agent: ON=C1C=C(c2ccncc2)CCC1
Product: CC(=O)CCCC(=O)c1ccncc1

Procedure:
An improvement in the process for preparing 3-(4-pyridinyl)-2-cyclohexen-1-one oxime by heating ethyl 5-oxo-2-[(4-pyridinyl)carbonyl]hexanoate under aqueous acidic conditions to produce 1-(4-pyridinyl)-hexan-1,5-dione, heating said hexan-1,5-dione with a basic condensing agent to produce 3-(4-pyridinyl)-2-cyclohexen-1-one, and converting said cyclohexen-1-one to its oxime, said improvement being a one pot sequence consisting of first heating ethyl 5-oxo-2-[(4-pyridinyl)carbonyl]hexanoate with excess aqueous sulfuric acid, neutralizing the excess acid, shaking the resulting warm mixture well with isopropyl alcohol to extract the 3-(4-pyridinyl)-2-cyclohexen-1-one, draining off the heavier warm aqueous layer, adding hydroxylamine hydrochloride to the isopropyl alcohol solution of 3-(4-pyridinyl)-2-cyclohexen-1-one, stirring the mixture at reflux, basifying the mixture and evaporating the reaction mixture to dryness, and isolating the 3-(4-pyridinyl)-2-cyclohexen-1-one oxime from the residue.
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][C:23]=1[Cl:35])=[O:20])=[O:13].C=O.[CH3:38]CN(C(C)C)C(C)C.ClCCl>C1COCC1>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]2)=[CH:24][C:23]=1[Cl:35])=[O:20])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1nc2ccccc2[nH]1)c1nc[nH]c1C(=O)Nc1ccc(OC2CCNCC2)cc1Cl
Agent: C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.2 %

Procedure:
A flask was charged with N4-(1H-benzo[d]imidazol-2-yl)-N5-(2-chloro-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide hydrochloride (115 mg, 0.22 mmol), formaldehyde, 30% wt (0.030 mL, 4 mmol), DIEA (0.080 mL, 0.5 mmol), dichloromethane (20 mL) and THF (20 mL), and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was filtered, and the precipitate was discarded. The product was purified by reverse phase HPLC using ammonium acetate and acetonitrile as eluent to afford 60 mg (55% yield) of N4-1H-benzimidazol-2-yl-N5-(2-chloro-4-{[1-(methyl)piperidin-4-yl]oxy}phenyl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.91 (d, 9 Hz, 1H), 7.46 (s, br, 2H), 7.21 (d, 3 Hz, 1H), 7.12-7.03 (m, 3H), 4.44-4.42 (m, 1H), 2.61-2.50 (m, 2H), 2.20-2.17 (m, 5H), 1.96-1.89 (m, 2H), 1.67-1.61 (m, 2H). MS (EI): 494 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.[Br:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[Br:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:14][N:15]([CH:16]1[CH2:17][CH2:18][CH2:19]1)[C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: Fc1ccc(CNC2CCC2)cc1Br
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: Cn1cnc(C(=O)N(Cc2ccc(F)c(Br)c2)C2CCC2)c1
Yield: 13.8 %

Procedure:
A solution of methyl-1H-imidazole-4-carboxylic acid (1.17 g), N-(3-bromo-4-fluorobenzyl)cyclobutanamine (2.40 g) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (3.09 g) in methanol (25 mL) was stirred at room temperature for 4 hr. After the reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-92:8) to afford the title compound (469 mg).
Reaction SMILES: Cl.COC(=O)CCCCCN.[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[C@@H:25]2[C@@H:20]([NH:21][C:22]([NH:24]2)=[O:23])[CH2:19][S:18]1.NC1C=C2C(C([Cl:57])=C(OCCC3C=CC=CC=3)OC2=O)=CC=1.CCN(CC)CC>S(Cl)(Cl)=O.O>[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[C@@H:25]2[C@@H:20]([NH:21][C:22]([NH:24]2)=[O:23])[CH2:19][S:18]1.[C:12]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([Cl:57])=[O:35])(=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[C@@H:25]2[C@@H:20]([NH:21][C:22]([NH:24]2)=[O:23])[CH2:19][S:18]1
Reactant: Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1
Agent: COC(=O)CCCCCN
Agent: Cl
Agent: O=C(O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(Cl)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(Biotinylamino)caproic acid was prepared from N-hydroxysuccinimido biotinate (Jasiewicz et al., Exp. Cell Res. 100, pp 213-217 (1976)) and 6-aminocaproic acid methyl ester hydrochloride by a previously described method (Hofmann et al., Biochemistry 23, pp 2547-2553 (1984)). 6-(Biotinylamino)caproic acid chloride was prepared by incubating 6-(biotinylamino)caproic acid (0.36 g, 1 mmole) in 4 ml of thionyl chloride at 25°-35° C. for 1 h, and excess thionyl chloride was removed under reduced pressure. The residue was dissolved in DMF and 7-amino-4-chloro-3-(2-phenylethoxy)isocoumarin (0.34 g, 1 mmole) and Et3N (0.1 g, 1 mmole) were added and the reaction mixture was stirred at r.t. overnight. The product was purified from column chromatography and eluted with CH2Cl2 :MeOH=10:1, yield, 28%, mp 163°-167° C., NMR was consistent with the assigned structure, mass spectra (FAB+) m/e=655 (M+1). Anal. Calc. for C33H39N4O6ClS.H2O: C, 58.87; H, 6.14; N, 8.32; Cl, 5.27. Found: C, 58.72; H, 6.22; N, 8.90; Cl, 5.50.