Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])[NH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[CH2:16]([C:13]1[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([O:36][CH3:37])=[O:35])=[CH:24][CH:23]=2)[CH:15]=[C:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:12]=1)[CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(CCNC(=O)OC(C)(C)C)c[nH]1
Product: CCCCc1nc(CCNC(=O)OC(C)(C)C)cn1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 48 %

Procedure:
4-[2-(t-Butoxycarbonylamino)ethyl]-2-n-butylimidazole (3.0 g) and methyl 4'-bromomethylbiphenyl-2-carboxylate (3.75 g) are treated in the same manner as in Example 1 to give 2-n-butyl-4-(2-t-butoxycarbonylaminoethyl)-1-[2'-methoxycarbonylbiphenyl-4-yl]methylimidazole (2.65 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.O.[NH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
4-Trifluoromethoxyphenylsulfonyl chloride (4.34 g, 16.7 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (2.99 g, 19.5 mmol) and N,N-diisopropylethylamine (9.50 ml, 57.5 mmol) in CH2Cl2 (50 ml) at 0° C. and stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (250 ml), washed with aqueous 1 N HCl solution (50 ml), H2O (50 ml), saturated aqueous NaHCO3 solution (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-one (4.37 g, 81%) as a off-white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([CH3:37])[O:18][N:17]=[C:16]([C:19]3[CH:35]=[CH:34][C:22]([C:23]([NH:25][CH2:26][CH:27]4[CH2:31][O:30]C(C)(C)[O:28]4)=[O:24])=[C:21]([CH3:36])[CH:20]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1>CO>[Cl:13][C:11]1[CH:10]=[C:9]([C:14]2([CH3:37])[O:18][N:17]=[C:16]([C:19]3[CH:35]=[CH:34][C:22]([C:23]([NH:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])=[O:24])=[C:21]([CH3:36])[CH:20]=3)[CH2:15]2)[CH:8]=[C:7]([Cl:6])[CH:12]=1
Reactant: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(Cl)c3)C2)ccc1C(=O)NCC1COC(C)(C)O1
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(Cl)c3)C2)ccc1C(=O)NCC(O)CO
Yield: 84.2 %

Procedure:
A solution of 10% Sulfuric acid (0.1 ml) and 4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-2-methylbenzamide (1 g, 1.9 mmol) in methanol (50 ml) was stirred at 70° C. for 4 hours. The solvent was evaporated and the crude mixture was diluted with ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml×2) and then with water (50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the title compound as a solid (0.7 g). M.p. 98-98° C. LCMS (Method G) 3.65 min, MH+ 491. 1HNMR (CDCl3, 400 MHz): 7.37-7.49 (m, 6H), 6.59 (t, 1H), 4.12 (d, 1H), 3.88 (m, 1H), 3.67 (d, 1H), 3.60 (m, 4H), 2.41 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:2][NH:1][S:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CCN
Product: COC(=O)CCNS(=O)(=O)c1ccccc1

Procedure:
N-(phenylsulfonyl)-β-alanine methyl ester (23) was prepared from methyl β-alaninate and phenylsulfonyl chloride on a 32 mmol scale in the manner described above in Example 13 to yield 6.76 g (86%) of product. Analysis calculated for C10H13NO4S (M.W. 243.28): C, 49.37; H, 5.39; N, 5.76; S, 13.18. Found: C, 49.06; H, 5.46; N, 5.78; S, 12.95.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:6]=1[NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-:19])=[O:18]
Reactant: CCOC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1ccc(NS(C)(=O)=O)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Ethyl 4-[(methylsulfonyl)amino]benzoate (Lumma, W. C. et al. J. Med. Chem. 1987, 30, 758-763) (2.0 g, 0.0082 mol) was added portionwise to fuming nitric acid (10 mL) at 5°-10° C. over 0.25 h. The mixture was further stirred for 0.5 h at 10°-15° C. and then poured into cold water (50 mL). The yellow precipitate was separated by filtration and washed several times with cold water. The cake was recrystallized from ethyl acetate to give 1.7 g (72%) of ethyl 3-nitro-4-[(methylsulfonyl)amino]benzoate as yellow crystals, mp 124° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([O:10]C)=[O:9])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(C(=O)O)CC1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1,1-Cyclopropanedicarboxylic acid dimethyl ester (25 g) was dissolved in methanol (250 mL). The solution was cooled under ice cooling, and 1N aqueous sodium hydroxide (158 mL) was added dropwise thereto. The thus-obtained mixture was brought back to room temperature, and was stirred overnight. Methanol was distilled away, and the residue was washed with chloroform. The aqueous layer was cooled under ice cooling, and concentrated aqueous HCl was added thereto, to thereby adjust to pH 2. The resultant mixture was extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (16.8 g).
Reaction SMILES: NC1C=C(C=CC=1OC)C(O)=O.Cl.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:21]([OH:23])=[O:22])(=[O:16])[CH3:15].[N+:29]([O-])([OH:31])=[O:30]>>[N+:29]([C:24]1[CH:25]=[C:26]([O:27][CH3:28])[C:18]([NH:17][C:14](=[O:16])[CH3:15])=[CH:19][C:20]=1[C:21]([OH:23])=[O:22])([O-:31])=[O:30]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)O)cc1NC(C)=O
Agent: COc1ccc(C(=O)O)cc1N
Agent: Cl
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1NC(C)=O
Temperature: 0 °C
Yield: 72 %

Procedure:
3-amino-4-methoxybenzoic acid (“19”) (Aldrich Chemical; Milwaukee, Wis.) (5 g or 29.9 mmol) was suspended in 40 ml acetic acid. Acetic anhydride (3 ml or 1:04 eq) was added by stirring. The reaction mixture was stirred for 2 hours at room temperature. 25 ml of 0.1N HCl was added and the precipitate was filtered off and washed with 3×10 ml of 0.1N HCl and 5×10 ml water to produce 5.97 g (about 95%). 3-(N-acetyl) amino-4-methoxybenzoic acid (“20”) (5 g or 23.5 mmol) was added to 20 ml of fuming nitric acid at 0° C. on vigorous stirring. The solution was stirred at 0° C. for an additional hour and poured onto 200 g of ice. Precipitate was filtered off, washed with 5×20 mls of water and dried to produce 438 g (about 72%) of 2-nitro-4-methoxy-5 (N-acetyl)aminobenzoic acid (“21”), which was converted into 2-nitro-4-methoxy-5-(N-acetyl)aminoacetophenone (“22”) (about 63% yield) as described. 2-nitro-4-methoxy-5-(N-acetyl)aminoacetophenone (“22”) (1 g or 4.76 mmol) was dissolved in 5 ml of DMF and the solution was added to 5-biotinamidocaproyl chloride prepared separately from 5-biotinamidocaproic acid (155 g or 1 eq.) and 5 ml thionyl chloride. The reaction mixture was stirred overnight at room temperature and added to 100 ml of diethyl ether. Precipitate was purified using small silica gel column and a step gradient of MeOH in CHCl3 to give 1.16 g (about 47%) of 2-nitro-4-methoxy-5-(5-biotinamidocaproamido) acetophenone (“23”). This intermediate was converted into its corresponding alcohol (about 85% yield) and into the reactive NHS ester derivative 5-(5-biotinamidocaproamido)-4-methoxy-1-(2-nitro)phenylethyl-N-hydroxysuccinimidyl carbonate (“25”) with about a 69% yield.
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=[C:12]([Cl:23])[N:11]=1)(=O)=O.ClC1N=C(N2CCOC[C@H]2C)C=C(CCl)N=1.[I-].[Na+]>CC#N.CCOC(C)=O>[Cl:23][C:12]1[N:13]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[CH:15]=[C:10]([CH2:9][S:2][CH3:1])[N:11]=1
Reactant: C[S-]
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Agent: C[C@@H]1COCCN1c1cc(CCl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Reaction time: 16 h
Yield: 91 %

Procedure:
In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g, 646.69 mmol) was added dropwise over 5 minutes to a stirred solution of a mixture of approximately two thirds (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate and one third (R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1 L) at RT (temperature dropped from 20° C. to 18° C. over the addition and then in the next 5 minutes rose to 30° C.). The reaction mixture was stirred for 16 hours and then diluted with EtOAc (2 L), and washed sequentially with water (750 ml) and saturated brine (1 L). The organic layer was dried over MgSO4, filtered and then evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (108 g, 91%); 1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.07 (3H, s), 3.11-3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92-4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s); m/z: (ES+) MH+, 274.36.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:26])[C:23]([C:24]#[N:25])=[CH:6][C:5]2[CH:8]=[C:9]([OH:10])[C:2]([OH:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCC(=O)Nc1cccc(Cl)c1
Reactant: O=Cc1cc(O)c(O)cc1[N+](=O)[O-]
Product: N#CC(=Cc1cc(O)c(O)cc1[N+](=O)[O-])C(=O)Nc1cccc(Cl)c1
Yield: 27.5 %

Procedure:
The reaction of 4, 5-dihydroxy-2-nitrobenzaldehyde (185 mg, 1.01 mmol) and N-(3-chlorophenyl) cyanoacetamide (197 mg, 1.01 mmol) was effected in the same manner as in Example 1 to give the objective N-(3-chlorophenyl)-2-cyano-3-(4, 5-dihydroxy-2-nitrophenyl)propenamide (100 mg, 28% in yield) as brown powdery crystals.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[CH:4]=1.[H-].[Na+].[CH3:18][O:19][C:20](=[O:29])[CH:21](Br)[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH3:18][O:19][C:20](=[O:29])[CH:21]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([N:2]([CH3:1])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[N:7]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: CN(c1ccccc1)c1cn[nH]c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(N(C)c2ccccc2)cc1=O
Temperature: 50 °C
Yield: 52.7 %

Procedure:
A solution of 5-(methyl-phenyl-amino)-2H-pyridazin-3-one (74.3 mg, 0.36 mmol) in tetrahydrofuran (1.8 mL) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (19.7 mg, 0.49 mmol). Upon complete addition of the sodium hydride, the cooling bath was removed and additional tetrahydrofuran (1.8 mL) was added to facilitate stirring. The reaction was stirred at 25° C. for 2.25 h. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 0.11 g, 0.46 mmol). The reaction was then warmed to 50° C., where it stirred overnight. After this time, the reaction was cooled to 25° C. and stirred overnight. At this point, the reaction was partitioned between water (25 mL) and methylene chloride (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix 8 g, 15-35% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(methyl-phenyl-amino)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (67.4 mg, 51%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[H-].[Na+].[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C1COCC1>[CH3:21][O:20][C:18](=[O:19])[CH:17]([C:11](=[O:12])[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:2](=[O:3])[CH3:1])[C:16]([O:23][CH3:24])=[O:22]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)C(=O)c1ccccc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of O-acetylsalicyloyl chloride (Alfa Aesar, 1.0 g, 5.05 mmol) in THF (10 mL) at 0° C. was added sodium hydride (60% dispersed in mineral oil, 263 mg, 6.57 mmol). It was stirred at 0° C. for 15 min prior to the addition of a solution of dimethyl malonate (0.67 g, 5.05 mmol) in THF (5 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 min and then at rt for 2.5 h, and was concentrated. The residue was taken up in water (50 mL), acidified by 1 N HCl aqueous solution, and extracted with EtOAc (2×100 mL). Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the intermediate (2-(2-acetoxy-benzoyl)-malonic acid dimethyl ester) (1.45 g) as an oil. The intermediate (1.26 g, 4.28 mmoL) was treated with (1/1) MeOH/10% aq HCl (26 mL) and heated to 75° C. (oil bath temperature) for 30 min and then at rt overnight. White precipitate formed during the reaction was collected, rinsed with water and dried in vacuo to give the title compound (555 mg). MS ESI(+) m/e: 221 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=2)[N:20]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:31]([N:29]([CH3:30])[C:28]1[C:19]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)=[N:20][C:21]2[C:26]([N:27]=1)=[CH:25][C:24]([C:34]([O:36][CH3:37])=[O:35])=[CH:23][CH:22]=2)([CH3:32])[CH3:33]
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4n3C(=O)OC(C)(C)C)c(N(C)C(C)C)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4[nH]3)c(N(C)C(C)C)nc2c1
Yield: 68.7 %

Procedure:
A solution of methyl 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (180.0 mg, 0.36 mmol) in 20% TFA/DCM (30 mL) was stirred overnight at room temperature and then quenched by the addition of water (100 ml). The reaction mixture was adjusted to pH 7 with aq. sodium bicarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column with 0.1%-1% methanol in dichloromethane to afford methyl 3-(isopropyl(methyl)amino)-2-(5-methoxy-1H-indol-2-yl)quinoxaline-6-carboxylate as a light yellow solid (100.0 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[C:24]=1[OH:30].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:26]4[CH:27]=[CH:28][N:23]=[C:24]([OH:30])[C:25]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: Oc1nccnc1O
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccnc(O)c3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C
Yield: 6.5 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (80 mg, 0.18 mmol), pyrazine-2,3-diol (50 mg, 0.44 mmol), 8-hydroxyquinoline (12 mg, 0.083 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (15 mg, 0.079 mmol). The mixture in a sealed tube was heated at 130° C. for 4 h. The mixture was then purified by HPLC to give the titled compound (5 mg). MS 428.0 and 430.0 (M+H, Cl pattern).
Reaction SMILES: BrC1C=CC2N(CC3CC3)C([CH2:9][O:10][CH2:11][C:12]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=NC=2C=1.BrC1C=CC2N=C(COCC3(C4C=CC=CC=4)CCN(C(OC(C)(C)C)=O)CC3)N(CC3CC3)C=2C=1.[F:73][C:74]([F:95])([F:94])[C:75]1[CH:76]=[C:77](CO)[C:78]2[N:82]=[CH:81][N:80]([CH2:83][O:84][CH2:85][CH2:86][Si:87]([CH3:90])([CH3:89])[CH3:88])[C:79]=2[CH:91]=1.S(Cl)(Cl)=O.OCC1(C2C=CC=CC=2)CCN(C(OC(C)(C)C)=O)CC1.[H-].[Na+]>O1CCCC1>[C:25]1([C:12]2([CH2:11][O:10][CH2:9][C:77]3[C:78]4[N:82]=[CH:81][N:80]([CH2:83][O:84][CH2:85][CH2:86][Si:87]([CH3:90])([CH3:89])[CH3:88])[C:79]=4[CH:91]=[C:75]([C:74]([F:73])([F:94])[F:95])[CH:76]=3)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(CO)cc(C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(Br)ccc3n2CC2CC2)(c2ccccc2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(COCc2nc3ccc(Br)cc3n2CC2CC2)(c2ccccc2)CC1
Agent: [H-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c2ncn3COCC[Si](C)(C)C)(c2ccccc2)CC1

Procedure:
The conversion of the alcohol to chloromethyl derivative and the subsequent alkylation were done using similar procedure as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (5) and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. (6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol (25 mg, 0.072 mmol) was converted to chloromethyl derivative as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate using thionyl chloride (0.030 mL, 5.7 eq) and the crude chloromethyl derivative was alkylated with tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (25.2 mg, 1.2 eq) using sodium hydride (9 equiv) in tetrahydrofuran (3 mL) at ambient temperature for 3 days. The crude product was purified by silica gel chromatography using a gradient of 10%-80% ethyl acetate in dichloromethane. Fractions containing required compound were combined and evaporated in vacuo to give tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (25 mg) containing required product and piperidinyl alcohol reagent in the ratio of 2:3 by proton NMR. Material used without additional purification. LC/MS (HPLC method 8): tR=3.8 min, 642(MNa)+.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([OH:29])=[O:28])[CH:21]=[CH:20]3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].[BH4-].[Na+].Cl>C1COCC1>[CH2:13]([C:12]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C:27]([OH:29])=[O:28])[CH:21]=[CH:20]2)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:31])[C:2]([CH3:32])([CH3:33])[CH3:1])=[C:7]([CH3:30])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Treat a solution of 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid (0.15 g, 0.34 mmol) in THF (6 mL) with NaBH4 (0.025 g, 0.67 mmol) and stir the reaction mixture at RT for 1 h. Quench the reaction first with water (5 mL) and then with 1N HCl (2 mL). Remove the THF under vacuum. Dilute the mixture with EtOAc (50 mL), wash with brine (2×), dry over NaSO4 and filter. Concentrate the filtrate to give the title compound (0.15 g). MS (ES) m/e 447 (M−1).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[CH3:11][C:12]([CH3:23])([CH2:21][F:22])[C:13](=[O:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:11][C:12]([CH3:23])([C:13]([OH:20])([C:1]#[C:2][CH2:3][CH2:4][CH3:5])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:21][F:22]
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Reactant: C#CCCC
Agent: Cl[Ti+3]
Agent: CC(C)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC#CC(O)(Cn1cncn1)C(C)(C)CF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
To a stirred solution of pent-1-yne (1.5 g, 22 mmol) in dry tetrahydrofuran (40 ml) was added n-butyl lithium (9 ml of 2.6M, 23 mmol) at -78° C. under a nitrogen atmosphere followed by chlorotitanium tri-isopropoxide (22 ml of 1M, 20 mmol). After 15 minutes, a solution of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)butan-2-one (prepared as in DE 2,820,361) (4.0 g, 22 mmol) in dry tetrahydrofuran (20 ml) was added dropwise. Upon complete addition the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then poured onto ice and extracted with ether (2×250 ml). The ethereal solution was washed with saturated brine solution then dried over anhydrous magnesium sulphate and the solvent removed. The resulting yellow oil was chromatographed (silica gel, petrol/diethyl ether elution) to give a yellow gum (2.8 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:35])[CH3:34]>>[CH3:34][C:33]1[N:35]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1
Reactant: CC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (about 0.153 mmol) of the compound from Example 108A and 22 mg (0.306 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 12 mg (17% of theory)