Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([NH:18][CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1.04 mL (1.0 mmol) of cyclohexanone and 1.6 g (1.0 mmol) of N-(2-t-butoxycarbonylaminoeth-1-yl)amine in 24 mL of tetrahydrofuran were added 0.71 mL (1.2 mmol) of acetic acid and 2.97 g (1.4 mmol) of sodium triacetoxyborohydride. The reaction stirred at room temperature for 20 hr then saturated sodium bicarbonate (12 mL) was added and the mixture extracted with ethyl acetate (12 mL). The organic phase was washed with more saturated sodium bicarbonate (12 mL) and brine (12 mL). At this point a crystalline precipitate formed which was filtered off and washed with water and ethyl acetate to leave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14](=O)[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][NH2:15])([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(CN)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 5.7 %

Procedure:
A 1M solution of borane complex in THF (2.25 mL, 2.25 mmol) was added to a cooled solution (0° C.) of 4-tert-butoxycarbonylamino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (107 mg, 0.3 mmol) in THF (4.3 mL). After stirring for 5 minutes at 0° C. the reaction mixture was allowed to warm to room temperature. The reaction mixture was further warmed to 60° C. and stirred overnight. The reaction mixture was cooled to room temperature and methanol (5.1 mL) was added. After stirring for 30 minutes, the solvents were removed by evaporation. The reaction mixture was partitioned between an aqueous saturated solution of ammonium chloride (10 mL) and dichloromethane (10 mL). After further extraction of the aqueous phase with dichloromethane (20 mL), the combined organic phases were dried (Mg2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 5% methanol in dichloromethane, gave 4-aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (5.5 mg, 0.017 mmol, 6%). LC-MS (LCT2) m/z 352 [M+Na+], Rt 7.16 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]([CH3:13])[CH:3]1[CH3:14].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:13])=[C:3]1[CH3:14]
Reactant: CC1c2cc(C=O)ccc2N(C)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1c(C)n(C)c2ccc(C=O)cc12
Yield: 12.1 %

Procedure:
1,2,3-Trimethylindoline (21.5 g) was formylated in a similar manner to that described in Step 2 of Example 1 to obtain 20.1 g of 1,2,3-trimethylindoline-5-carbaldehyde. The obtained aldehyde (7.5 g) was dissolved in 200 ml of 1,4-dioxane, followed by the addition of 18 g of DDQ. The obtained mixture was heated under reflux for 2.5 hours, followed by the addition of 100 ml of toluene. Insolubles were filtered out and the organic phase was concentrated in a vacuum. The obtained residue was purified by flash column chromatography to give 900 mg of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:22][O-:23].[Na+]>C(O)C>[CH3:22][O:23][CH2:2][C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1cccc(-c2ccc3nnc(CCl)n3n2)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 2.1 g. of 3-(chloromethyl)-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine and 0.40 g. of sodium methoxide in 50 ml. of ethanol is refluxed for 24 hours. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane. The solution is filtered through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 1.4 g. of the product of the Example as crystals, m.p. 149°-150° C. Recrystallization from dichloromethane-hexane gives 0.6 g. of white crystals, m.p. 149°-151° C.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][Br:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>C(Cl)(Cl)Cl>[Br:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([Cl:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: BrCCCOc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(OCCCBr)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
20 ml of a chloroform solution containing 5.8 g of 3-phenoxypropyl bromide was cooled to -10° C., and 3.6 ml of chlorosulfuric acid was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was poured onto ice, and extraction was performed with 100 ml of chloroform. Water washing, drying and concentration were successively carried out to obtain 3.4 g (yield: 40%)of 4-(3-bromopropoxy)benzenesulfonic acid chloride in an oily state.
Reaction SMILES: [P:1]([O-:12])([O:7][C:8](C)(C)[CH3:9])[O:2][C:3](C)(C)[CH3:4].[CH:13]([N:16](C(C)C)P(Cl)(N)=O)(C)C.[O-]P(OP([O-])([O-])=O)(=O)[O-].C(OP([O-])(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>>[CH2:3]([O:2][P:1]([C:13]#[N:16])(=[O:12])[O:7][CH2:8][CH3:9])[CH3:4]
Reactant: CC(C)N(C(C)C)P(N)(=O)Cl
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Agent: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: CCOP(=O)(C#N)OCC

Procedure:
In order to try different protecting groups on the phosphate, several other methods of phosphorylation were attempted. These included the use of alkylamidophosphines, which have been shown to readily phosphorylate alcohols and phenols in high yield. For example, di-tert-butyloxy (N,N-diisopropylamido)phosphine, prepared from dichloro(N,N-diisopropylamido)phosphine and tert-butanol was allowed to react with diphenol 1 in the presence of 1H-tetrazole. After phosphorylating diphenol 1, subsequent in situ oxidation of the trivalent phosphorous to the pentavalent species with meta-chloroperoxybenzoic acid did not result in the desired phosphate. Perhaps this unpromising result arose from the steric crowding involved with four tert-butyl groups in the 2′- and 3′- positions, or from the oxidation step which may have effected the stilbene olefin. Interestingly, the use of dibenzyloxy(N,N-diisopropylamido)phosphine under the reaction conditions just described did afford phosphate 10 but only in 10% yield. Two other phosphorylation methods were attempted using di-tert-butyl phosphite with an in situ generation of the appropriate halide (Br, Cl), and N,N-diisopropylphosphorodiamidic chloride. Neither method led to the corresponding diphosphate analog of dibenzylphosphate 10. Diphosphorylation of 1 was also achieved in good yield with diethylcyano-phosphonate. However, this method proved to be problematic due to harsh conditions needed to remove an ethyl group.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][S:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Sc1ccccn1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2nc(CCSc3ccccn3)cs2)c(C(=O)C2CCCC2)c1
Yield: 46.8 %

Procedure:
1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-{4-[2-(pyridin-2-ylsulfanyl)-ethyl]-thiazol-2-yl}-urea (24 mg, 467%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.05 g, 0.11 mmol) and 2-mercapto pyridine (0.012 g, 0.11 mmol) following the general procedure Z.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].[Cl-].[Al+3].[Cl-].[Cl-].[OH:22][C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=1[C:30]1[N:35]=[C:34](C2C=CC(C)=CC=2C)[N:33]=[C:32]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:45]=2[CH3:51])[N:31]=1.CC1C=C(C)C=CC=1C1N=C(C2C=CC(C)=CC=2C)N=C(C2C=CC(C)=CC=2C)N=1>ClC1C=CC=CC=1.C1(C)C=CC=C(C)C=1>[OH:11][C:10]1[CH:12]=[C:13]([OH:14])[CH:15]=[CH:16][C:17]=1[C:34]1[N:35]=[C:30]([C:24]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=2[OH:22])[N:31]=[C:32]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:45]=2[CH3:51])[N:33]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Agent: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(C)c1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: Cc1cccc(C)c1
Product: Cc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of 1.84 g of cyanuric chloride, 1.1 gm of resorcinol, 2.5 mL of m-xylene and 25 mL of chlorobenzene was added 3.35 g of aluminum chloride (2.5 eq. based on cyanuric chloride) at 5° C. The reaction mixture was stirred at 5° C. for 2 h, then at 15° C. for 4 hr and finally at room temperature for 24 hr. The reaction mixture was analyzed by TLC and HPLC. The HPLC analysis confirmed the formation of 2-(2,4-dihydroxyphenyl)-4,6-(2,4-dimethylphenyl)-1,3,5-triazine (4) and 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine as the only two major products. The bisresorcinol based product, 2,4-bis(2,4-dihydroxyphenyl)-6-(2,4-dimethylphenyl)-1,3,5-triazine (3), was formed only as a minor component and the ratio of 4:3 was 97:3. The 2-chloro-4,6-bis(2,4-dihydroxyphenyl)s-triazine (2) was only 0.36% and 2,4,6-tris-(2,4-dihydroxyphenyl)-s-triazine (1) was 0.5%. The experiment demonstrated the preferential formation of monoresorcinol based product 4 by reacting cyanuric chloride, resorcinol, m-xylene and aluminum chloride simultaneously with higher charge of aluminum chloride.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH2:41][OH:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH:41]=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: OCc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Compound 2 (206 g) was dissolved in DCM (11 l) under continuous stirring. Manganese dioxide (450 g) was added in 100-g portions and the resulting reaction mixture was stirred for 1 hour. The mixture was filtered over dicalite and the filtrate was evaporated. The residue was stirred in ACN, filtered off and dried, yielding 170 g (83%) of 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde (compound 4, mp. 193.5° C.).
Reaction SMILES: [CH3:1][C@@:2]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[Br-].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN1CCCC1=O>[OH:10][C:8]1[CH:9]=[C:4]([CH2:3][C@@:2]([CH3:1])([C:12]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])[NH2:15])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: BrCc1ccccc1
Reactant: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 85 %

Procedure:
In a manner similar to that described in Example I, 1.05 grams (0.005 mole) of α-methyldopa, 0.88 gram (0.010 mole) of lithium bromide, 0.5 gram of powdered 4A sieves, 0.98 gram (0.0057 mole) of benzyl bromide and 5.0 grams of N-methylpyrrolidinone were stirred for 65 hours at 25° C. At the end of this period, high pressure liquid chromatographic assay showed an 85 percent yield of the desired benzyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate product.
Reaction SMILES: [O:1]([CH:8]([P:13](=[O:16])([OH:15])[OH:14])[P:9](=[O:12])([OH:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.[C:17]([O:23][CH2:24]I)(=[O:22])[C:18](C)(C)C>>[CH2:2]([O:1][CH:8]([P:13](=[O:16])([O:14][CH2:24][O:23][C:17](=[O:22])[CH3:18])[O:15][CH2:24][O:23][C:17](=[O:22])[CH3:18])[P:9](=[O:12])([O:10][CH2:24][O:23][C:17](=[O:22])[CH3:18])[O:11][CH2:24][O:23][C:17](=[O:22])[CH3:18])[CH2:7][CH2:6][CH3:5]
Reactant: O=P(O)(O)C(Oc1ccccc1)P(=O)(O)O
Reactant: CC(C)(C)C(=O)OCI
Product: CCCCOC(P(=O)(OCOC(C)=O)OCOC(C)=O)P(=O)(OCOC(C)=O)OCOC(C)=O

Procedure:
This compound was prepared as described in Example 51 by substituting (n-butoxymethylene)-bisphosphonic acid for (phenoxymethylene)-bisphosphonic acid and by substituting iodomethyl acetate for iodomethyl pivalate.
Reaction SMILES: Br[CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].[Cl:23]CI>>[Cl:23][CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5]
Reactant: ClCI
Reactant: O=C(Cc1ccccc1C(=O)OCBr)OCc1ccccc1
Product: O=C(Cc1ccccc1C(=O)OCCl)OCc1ccccc1

Procedure:
In like manner benzyl 2-(bromomethoxycarbonyl)-phenylacetate is prepared by substituting bromoiodomethane for chloroiodomethane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](Cl)[O:31][CH3:32]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:30][O:31][CH3:32])[C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(Cl)nc4[nH]3)nc12
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
0.3 g 5-Chloro-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (0.74 mmol) was dissolved in dry DMF (10.0 ml) and treated with 0.033 g NaH (65% in oil, 0.9 mmol) at 0° C. After stirring at ambient temperature for 1 h, 68 μl MOMCl (0.9 mmol) and 0.011 g tetrabutyl ammonium iodide (0.03 mmol) were added and the reaction mixture was stirred for 16 h. The suspension was filtered and the residue triturated in ether. Upon drying in vacuo, one obtained 0.29 g of 5-chloro-3-methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (87%) as a yellow solid; M.p.: 167–170° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35]([OH:37])=[O:36]>CN(C)C=O.O1CCCC1>[CH3:42][C:38]1[C:34]([C:35]([OH:37])=[O:36])=[C:33]([NH:32][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:41]=[CH:40][CH:39]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(C)c1C(=O)O
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
After a tetrahydrofuran solution (12.4 ml) of N-tert-butoxycarbonyl-L-methionine (1.24 g) was cooled to -15° C., N-methylmorpholine (0.55 ml) and isobutyl chloroformate (0.60 ml) were added to the solution, and the mixture was stirred for 20 minutes. Subsequently, an N,N-dimethylformamide solution (8.27 ml) containing 2-amino-6-methylbenzoic acid (0.50 g) and N-methylmorpholine (0.44 ml) was added dropwise, and the mixture was stirred at -15° C. for 0.5 hour and then at room temperature overnight. The reaction mixture was treated by the same procedures as in item (c) of Example 1 to obtain 6-methyl-2-[(N-tert-butoxycarbonyl-L-methionyl)amino]benzoic acid (348 mg).
Reaction SMILES: CNC.N(CC#CC[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([O:17][CH2:18][C:19]2[C:27]3[O:26][CH:25]=[CH:24][C:23]=3[CH:22]=[C:21]([C:28]3[N:32]([CH3:33])[N:31]=[N:30][CH:29]=3)[CH:20]=2)[C@@H:12]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N+]=[N-]>O1CCOCC1>[C:34]1([CH:12]2[CH:13]([O:17][CH2:18][C:19]3[C:27]4[O:26][CH:25]=[CH:24][C:23]=4[CH:22]=[C:21]([C:28]4[N:32]([CH3:33])[N:31]=[N:30][CH:29]=4)[CH:20]=3)[CH2:14][CH2:15][CH2:16][NH:11]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)c2occc2c1
Agent: CNC
Solvent: C1COCCO1
Product: Cn1nncc1-c1cc(COC2CCCNC2c2ccccc2)c2occc2c1
Temperature: 80 °C
Yield: 48.6 %

Procedure:
Dimethylamine (approximately 10 ml) was condensed at -80° C. in a pressure tube and to this was added a solution of (2S,3S]-1-(4-azidobut-2-yn-1-yl)-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine (120 mg) in dioxan (5 ml). The tube was sealed and the solution was heated at 80° C. for 14 hours. The solvent was evaporated under reduced pressure to dryness and the residue was purified by MPLC [5% methanol in dichloromethane containing 0.25% ammonia (SG. 0.88)] to give [2S,3S]-1-[(5-dimethylaminomethyl)-1H[1,2,3]-triazol-4-yl)methyl]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine as a clear oil (47 mg). To a solution of this residue in diethyl ether was added 5M-HCl in ethanol. The solution was evaporated to dryness and the residue recrystallised from ether/ethanol to give [2S,3S]-1-[(5-(Dimethylaminomethyl)-1H-[1,2,3]triazol-4-yl)methyl]-2-phenyl-3-[(5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl)methyloxy]piperidine hydrochloride (57 mg) mp 136-138° C. 1H NMR (360 MHz,D2O)δ1.64 (1H, m), 1.87 (1H, m), 2.34 (2H, m), 2.65 (6H, s), 3.27 (1H, d, J=14.0 Hz), 3.71-3.78 (3H, m), 3.85 (1H, br s), 3.93 (3H, s), 4.24 (1H, s), 4.33 (1H, d, J=16.0 Hz), 4.38 (1H, d, J=16.0 Hz), 4.69 (1H, d, J=14.0 Hz), 5.00 (1H, d, J=14.0 Hz), 6.79 (1H, s), 6.92 (1H, d, J=1.0 Hz), 7.16 (5H, m), 7.63 (1H, s), 7.74 (1H, s), 7.81 (1H, d, J=1.0 Hz); m/z (CI+) 527 (M+H+).
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1.[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.[CH:60]1([C:63]2[NH:64][C:65](I)=[C:66]([CH3:68])[N:67]=2)[CH2:62][CH2:61]1.IC1NC(C)=NC=1C>>[CH:60]1([C:63]2[NH:64][C:65]([C:27]3[C:28]([CH3:30])=[CH:29][C:20]([CH3:19])=[C:21]([CH:26]=3)[C:22]([O:24][CH3:25])=[O:23])=[C:66]([CH3:68])[N:67]=2)[CH2:62][CH2:61]1
Reactant: Cc1nc(C2CC2)[nH]c1I
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1cc(-c2[nH]c(C3CC3)nc2C)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 2-cyclopropyl-5-iodo-4-methyl-1H-imidazole (compound 160.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 285 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[OH:13])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nccc1C(O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of 6.60 g of 1-methylpyrazole in 150 mL of tetrahydrofuran was cooled to −60° C., and 60 mL of a 1.6-M n-butyllithium/n-hexane solution was added dropwise to the solution under a nitrogen atmosphere. After the mixture was stirred for one hour, a solution of 11.288 g of 4-chlorobenzaldehyde in 50 mL of tetrahydrofuran was added dropwise to the mixture. It took 7 hours to bring back a temperature of the mixture to a room temperature, and then to the mixture, 125 mL of a 1-N ammonium chloride aqueous solution was added. The extraction with ethyl acetate was performed twice, and the extract was washed with a saturated saline solution. After the washed solution was dried over sodium sulfate, the solvent was distilled off. The raw product was purified by silica gel column chromatography (hexane/ethyl acetate (volume ratio)=1:2 to 1:3) to give the title compound (7.898 g (44%)).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13](#[N:17])[CH2:14][C:15]#[N:16].[CH3:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:21][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[CH3:18][C:19]1[CH:32]=[CH:31][C:22]([C:23](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: N#CCC#N
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=C(C#N)C#N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To a solution of 0.85 mL (6 mmol) of diisopropylamine in 11.3 mL of dry tetrahydrofuran, cooled to -78° C., was added 3.5 mL (5.6 mmol) of BuLi and the resulting mixture was stirred for 10 min. Next, 0.34 g (5.1 mmol) of malononitrile dissolved in 1.7 mL of tetrahydrofuran was carefully added and the resulting mixture was stirred for 30 min more. Finally, 1 g (5.1 mmol) of 4-methylbenzophenone in 1.7 mL of tetrahydrofuran was added. The mixture was allowed to warm up to room temperature and then it was heated at reflux for 2 days. Ethyl acetate was added and the resulting solution was washed with water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried and the solvent was removed to yield 1.3 g of the desired product as a reddish oil (yield: quantitative).