Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])(C)(C)[CH3:2].[ClH:15].C(OCC)(=O)C.CO>C(O)C>[ClH:15].[CH2:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH3:2]
Reactant: CC(C)(CO)NCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63.00 g of tert-butyl(2-hydroxy-1,1-dimethylethylamino)acetate are placed in 500 ml of ethanol. Then, while cooling with an ice bath, about 200 g of hydrogen chloride are introduced over a period of about four hours. The reaction mixture is stirred overnight at ambient temperature. For working up, it is concentrated by evaporation and stirred with toluene. Then the toluene is distilled off. A viscous oil remains, which is reacted further without any additional purification. Rf value: 0.16 (silica gel, ethyl acetate/methanol=9:1); mass spectrum (ESI+): m/z=176 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[CH3:22].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][NH:30][C:11]([C:4]1[C:3]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[CH3:22])=[C:2]([F:1])[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=1)=[O:13]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Reactant: NOC1CCCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOC2CCCCO2)cc2nc[nH]c2c1F
Reaction time: 0.5 h

Procedure:
A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid, O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (1.25 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 equiv.), and diisopropylethylamine (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography; elution with dichloromethane affords the desired product. The product may be recrystallized with an appropriate solvent like methanol if further purification is necessary.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CN(C)C=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].O>N1C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:32][CH2:29][CH2:30][CH3:31])=[O:22])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cc2ccc(CC(=O)O)cc2)cc1
Reactant: CCCN
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Cc1ccc(CS(=O)(=O)c2ccc(C(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(4-isopropyl-benzenesulfonylmethyl)-phenyl]-acetic acid (1 g, 3.00 mmol) in pyridine (15 ml)/N,N-dimethylformamide (15 ml) N,N′-carbonyldiimidazole (0.54 g, 3.31 mmol) was added and the mixture heated to 50° C. for 1 h. At 0° C. propylamine was added. The mixture was stirred at room temperature for 16 h. Then, the mixture was poured into water. The precipitate was collected and dried in a vacuum oven at 70° C. to give the product as a yellow powder (0.89 g, 2.39 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)=[CH:8][C:7]=1[Cl:13]
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester was reacted with 4-chloromethyl-2-(4-chloro-phenyl)-thiazole (example 14 a]) in the presence of cesium carbonate and potassium iodide to yield (2S)-3-{2-chloro-4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester as light yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[S:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:23]=[CH:22][S:21][CH:25]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2cscn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2cscn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(thiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 409.03 g/mol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH:2]=1.[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:32][CH:33]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(Nc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)c2cccnc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
190 mg of 4-[N-(3-pyridyl)amino]benzonitrile was dissolved in 5 ml of N,N-dimethylformamide, and 44 mg of 60% sodium hydride was added thereto under cooling with ice, followed by stirring at 40-50° C. for 30 minutes. Then, 273 mg of 4-benzyloxybenzyl chloride was added to the reaction mixture under cooling with ice, followed by stirring at room temperature for 2 hours. After the reaction mixture was poured into water, the product was extracted with chloroform. After the extract was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 1:1 mixture of ethyl acetate and hexane as the developing solvent) to obtain 234 mg of 4-[N-(4-benzyloxy-benzyl)-N-(3-pyridyl)amino]benzonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[N:28][C:29]([NH2:41])=[C:30]([C:32]4[S:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)[CH:31]=3)[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:30]1[C:29]([NH2:41])=[N:28][CH:27]=[C:26]([C:24]2[CH:23]=[N:22][N:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH:25]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of tert-butyl-4-[4-[6-amino-5-(1,3-benzothiazol-2-yl)-3-pyridyl]pyrazol-1-yl]piperidine-1-carboxylate (0.300 g) in dichloromethane (4 ml). The mixture was stirred for 1 hour, then concentrated under reduced pressure. The residue was dissolved in DCM (60 ml) and the solution was washed with a 0.5M solution of aqueous sodium hydroxide (30 ml). The organic phases were washed with water (15 ml) and brine (15 ml). The aqueous phase was extracted with DCM (3×30 ml), and then the organic layers were combined and concentrated under reduced pressure. The residue was stirred in acetonitrile (10 ml) for 18 hours. The solid was filtered and dried under vacuum. There was thus obtained 3-(1,3-benzothiazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.109 g); Mass Spectrum: M+H+ 377; NMR Spectrum: (DMSOd6 and CF3CO2D) 8.73 (d, 1H), 8.56 (d, 1H), 8.53 (s, 1H), 8.26 (d, 1H), 8.21 (d, 1H), 8.16 (s, 1H), 7.66 (dd, 1H), 7.59 (dd, 1H), 4.52-4.62 (m, 1H), 3.41-3.52 (m, 2H), 3.09-3.21 (m, 2H), 2.24-2.33 (m, 2H), 2.10-2.23 (m, 2H).
Reaction SMILES: [CH2:1]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([NH2:24])=[O:23])=[C:12]1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]([CH3:25])=[C:13]2[CH2:21][C:22]([NH2:24])=[O:23])[CH3:36]
Reactant: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Yield: 55 %

Procedure:
[4-[[3-(2-Amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanois acid ethyl ester. 1-Decyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (310 mg, 3.35 mmol) was reacted with 96 mg (2.4 mmol) of 50% NaH/mineral oil and then 0.32 mL (2.4 mmol) of ethyl 4-bromobutyrate as described in Example 50, Part D to give a product that was chromatographed on silica gel (eluted with 3% MeOH/methylene chloride) to give 590 mg (55% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 93-95° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C1C=CC=CC=1.C(O)=O.C=O>C(O)C>[CH3:1][NH:8][CH2:9][CH2:10][C:11]([OH:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC(CCNCc1ccccc1)(COc1ccccc1)c1ccccc1
Agent: C=O
Solvent: CCO
Solvent: O=CO
Product: CNCCC(O)(COc1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 62.4 %

Procedure:
45 g (0.13 mole) of N-benzyl-3-hydroxy-3-phenyl-4-phenoxybutylamine prepared as described in (c) were dissolved in 400 ml of ethanol, and 7.8 g of formic acid and 20 g of 35% strength formaldehyde solution were added in succession at the boiling point. After 3 hours, the alcohol was distilled off, 200 ml of 2N sodium hydroxide solution were added to the residue and the mixture was extracted with 3 times 2 ml of ether. The solution was dried and then evaporated down, the residue was taken up in 250 ml of acetic acid and the solution was hydrogenated in a shaken flask, using 5 g of palladium on carbon as the catalyst. When absorption of hydrogen was complete, the mixture was filtered, the filtrate was evaporated down, 2N sodium hydroxide solution was added and the mixture was extracted with 3 times 200 ml of ether. After the solvent had been distilled off, the product solidified. 22 g (65%) of N-methyl-3-hydroxy-3-phenyl-4-phenoxybutylamine of melting point 98°-99° C. were obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[O:6][CH3:7].C(N(CC)CC)C.C1(C)C=CC=CC=1.[Br:25][CH:26]([CH3:30])[C:27](Br)=[O:28]>O>[Br:25][CH:26]([CH3:30])[C:27]([N:2]([C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:1])=[O:28]
Reactant: CNc1cccc(OC)c1
Reactant: CC(Br)C(=O)Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(N(C)C(=O)C(C)Br)c1
Reaction time: 8 h

Procedure:
A solution of N-methyl-m-anisidine (265 g), triethylamine (269 ml) and toluene (550 ml) was stirred at 0° C. as 2-bromopropionyl bromide (202.6 ml) was added dropwise. The mixture was mechanically stirred overnight at room temperature. Water was added to the reaction and the aqueous layer was collected and extracted with ethyl acetate. All organic phases were combined, washed with 2N HCl, and dried (Na2SO4). The solvent was evaporated to yield an oil which was purified using Kugelrohr distillation. The distillate was dissolved in isopropyl ether. The solid product, 2-Bromo-N-(3-methoxyphenyl)-N-methyl-propanamide, m.p. 55°-56° C., crystallized from this solution.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[C:5]([CH3:23])=[C:6]([C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:22])[C:20]=2[OH:21])=[O:15])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C.[CH3:32][CH2:33][S:34][C:35](Cl)=[O:36].C(OCC)(=O)C>O1CCCC1>[F:24][CH:2]([F:1])[O:3][C:4]1[C:5]([CH3:23])=[C:6]([C:14]([C:16]2[CH:17]=[N:18][N:19]([CH3:22])[C:20]=2[O:21][C:35]([S:34][CH2:33][CH3:32])=[O:36])=[O:15])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1OC(F)F
Reactant: CCSC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OC(F)F)c2C)cnn1C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-1-methylpyrazol-4-yl 3-(difluoromethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone (89 mg) in dry tetrahydrofuran (5 mL) were added triethylamine (50 mg) and 96% S-ethyl chlorothiolformate (40 mg) at room temperature. After the reaction solution was stirred for 1 hour, 150 mL of ethyl acetate was added. The mixture was washed twice with a saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[CH:11]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCCCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCCCCCNC(=O)c1ccccc1
Yield: 28.1 %

Procedure:
Using the general method of Example 186 1-(8-aminooctyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.85 mmol) was reacted with benzoyl choride (450 μL, 3.85 mmol) to provide 0.45 g of N-[8-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide as an off white powder, m.p. 133.1-136.7° C. Analysis: Calculated for C25H29N5O.0.25 H2O: % C, 71.49; % H, 7.08; % N, 16.67. Found: % C, 71.37; % H, 7.05; % N, 16.62.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])[CH3:2].[C:12]([CH2:14][C:15](O)=[O:16])#[N:13].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([O:10][C:15](=[O:16])[CH2:14][C:12]#[N:13])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: N#CCC(=O)O
Reactant: CCCC(O)CC(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(CC(=O)OCC)OC(=O)CC#N

Procedure:
A mixture of 100.14 g of ethyl-3-hydroxyhexanoate, 63.75 g of cyanoacetic acid, and 4.58 g of 4-dimethylaminopyridine (DMAP) in 625 ml of CH2Cl2 was stirred in a 2 L three-neck round bottom flask equipped with a mechanical stirrer. About 31 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (154.75 g in 250 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:10][CH:9]=1.[ClH:26].CO>>[ClH:26].[OH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([NH:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(O)cc1)NCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.06 g of (E)-3-[4-[(2-methoxyethoxy)methoxy]phenyl]-N-(3-pyridylmethyl)-2-propenoic acid amide was dissolved in 100 ml of 25% HCl/methanol and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give (E)-3-(4-hydroxyphenyl)-N-(3-pyridylmethyl)-2-propenoic acid amide hydrochloride as a colorless solid, which was then dissolved in 40 ml dimethylformamide and stirred with 10.2 g of potassium carbonate and 2.5 ml of ethyl bromoacetate at room temperature for 2 hours. After addition of ethyl acetate, the reaction mixture was filtered to remove insoluble products. The resulting filtrate was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (chloroform:methanol=50:1), followed by recrystallization, to provide the compound of interest (2.31 g, 58%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5]2[C:18]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:4]=2[NH:3]1.[H-].[Na+].[CH3:30][CH2:31][N:32]([CH2:35][CH2:36]Cl)[CH2:33][CH3:34].Cl.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH2:31]([N:32]([CH2:35][CH3:36])[CH2:33][CH2:34][N:3]1[C:4]2[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([C:24]([F:27])([F:25])[F:26])[C:5]=2[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]1=[O:1])[CH3:30]
Reactant: CCN(CC)CCCl
Reactant: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCn1c(=O)n(Cc2cccc(C(F)(F)F)c2)c2c(C(F)(F)F)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
To a solution of 2-oxo-7-(trifluoromethyl)-1-[3-(trifluoromethyl)benzyl]-2,3-dihydro-1H-benzimidazole-5-carbonitrile (139.5 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60%) (38.0 mg). After the mixture was stirred at room temperature for 10 minutes, 2-chlorotriethylamine hydrochloride (89.4 mg) and triethylamine (0.120 ml) were added, and the mixture was stirred with heating at 70° C. for 1.5 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (181 mg, quantitative yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CCCC([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[C:36]([C:46]#[N:47])[CH:35]=2)=O)=CC=1>>[C:46]([C:36]1[CH:35]=[C:34]([NH:33][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([B:5]3[O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:7][O:6]3)=[CH:13][CH:12]=2)[CH:39]=[CH:38][C:37]=1[S:40]([CH:43]([CH3:44])[CH3:45])(=[O:42])=[O:41])#[N:47]
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B3OCC(C)(C)CO3)cc2)cc1C#N
Yield: 97 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 9C (600 mg, 1.34 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 9D (625 mg, 97%) as a brown foam. MS (ESI) m/z 413.1 (M−H)− for free boronic acid.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[OH:6][C@@:7]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]([NH:41][CH3:42])=[O:40])[CH:35]=2)[CH:30]=1)([C:14]1[N:15]=[CH:16][N:17]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=1)[CH2:8][C:9](OCC)=[O:10].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.O.C(OCC)(=O)C>[OH:6][C@@:7]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C:39]([NH:41][CH3:42])=[O:40])[CH:33]=[CH:32]2)([C:14]1[N:15]=[CH:16][N:17]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:21])=[O:20])[CH:18]=1)[CH2:8][CH2:9][OH:10]
Reactant: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
To a solution of anhydrous calcium chloride (1.86 g, 16.3 mmol) in ethanol (32 mL) were added sodium borohydride (1.27 g, 33.6 mmol) and ethanol (5 mL) at −10° C., and the mixture was stirred at −10° C. for 30 min. To the reaction mixture were added dropwise a solution of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate (2.5 g, 5.6 mmol) in tetrahydrofuran (73 mL)/ethanol (10 mL), and tetrahydrofuran (5 mL) at −10° C. The obtained reaction mixture was stirred at 5° C. for 6 hr, and to the obtained reaction mixture were added dropwise water (100 mL), 1 mol/L hydrochloric acid (40 mL) and ethyl acetate (200 mL) at 10° C. or below, and the mixture was stirred. To the separated organic layer was added 0.2 mol/L hydrochloric acid (14 mL) at 5° C., and the mixture was stirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To the separated organic layer was added again 0.2 mol/L hydrochloric acid (14 mL) at 5° C., and the mixture was stirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To the separated organic layer was added water (10 mL), and the mixture was adjusted to pH 9.5 with 0.5 mol/L aqueous sodium hydroxide solution. To the separated organic layer was added water (120 mL), and the mixture was heated to 60° C., and stirred for 3 hr. The separated organic layer was concentrated at 60° C. under reduced pressure to give 6-[(1S)-1,3-dihydroxy-1-(1-tosyl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (2.9 g, 6.1 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([OH:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:22][S:19]([O:18][CH:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:17])(=[O:21])=[O:20]
Reactant: CC(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(OS(C)(=O)=O)c1cc(Br)ccc1OCc1ccccc1
Temperature: -10 °C

Procedure:
1-(2-Benzyloxy-5-bromophenyl)-ethanol (3.74 g) was dissolved in pyridine (15 mL) and cooled to -10° C. under argon. Mesyl chloride (0.95 mL) was added dropwise over ten minutes and the mixture stirred allowing to come to ambient temperature over seventeen hours. The mixture was diluted with ethyl acetate (100 mL) and then washed with hydrochloric acid (1M, 3×70 mL) until the organic phase tested to pH 1. The ethyl acetate fraction was then washed with saturated sodium hydrogen carbonate solution (50 mL) and dried (MgSO4). After removal of solvent the oily residue was purified by MPLC (eluting 75% dichloromethane, 25% hexane, silica) to give 1-(2-benzyloxy-5-bromophenyl)ethanol methanesulphonate which was used rapidly without further purification, yield 1.19 g.