Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[NH:13][C:14]1[N:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([NH:28][NH2:29])=[O:27].C(=O)([O-])O.[Na+]>O>[NH2:1][C:2]1[O:27][C:26]([C:25]2[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=2[C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]3[C:14]=2[NH:13][C:7]2[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=2[CH3:5])=[N:28][N:29]=1
Reactant: N#CBr
Reactant: Cc1cccc(C)c1Nc1c(-c2ccccc2C(=O)NN)nc2ccc(F)cn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Nc1c(-c2ccccc2-c2nnc(N)o2)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
2.4 16.9 mg (0.160 mmol) of cyanogen bromide are added to a solution of 60 mg (0.141 mmol) of 2-[3-(2,6-dimethylphenylamino)-6-fluoro-imidazo[1,2-a]pyridin-2-yl]benzohydrazide hydrochloride and 29.4 mg (0.350 mmol) of sodium hydrogencarbonate in 10 ml of water, and the mixture is stirred at RT for 2 hours. The precipitated product is filtered off with suction, dried and purified by preparative thin-layer chromatography, giving 10 mg (17%) of {2-[2-(5-amino-1,3,4-oxadiazol-2-yl)phenyl]-6-fluoroimidazo[1,2-a]pyridin-3-yl}-(2,6-dimethylphenyl)amine (“B1”) as solid; MS-FAB (M+H+)=415.8; Rf (HPLC, polar method): 1.07 min.;
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[O:12][CH:13]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:25][C:13]1[O:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(-c2coc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(-c2c(Br)oc3ccccc23)cc1
Yield: 90.3 %

Procedure:
A solution of the product of Step 2 (100 mg), NBS (90 mg) and benzoyl peroxide in CCl4 (5 mL) was heated to reflux under a spotlight for 30 min. The mixture was cooled, diluted with Et2O (3 ml) and filtered. The filtrate was concentrated and the residue was purified by flash chromatography, eluted with 15:1 hexane/EtOAc to give the title compound (120 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.CC1N=C(N2CCN(C3C=CC(N)=CC=3)CC2)C=CC=1>>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[N:18][CH:19]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: Cc1cccc(N2CCN(c3ccc(N)cc3)CC2)n1
Product: Cc1ccc(N2CCN(c3ccc(N)cc3)CC2)nc1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloro-5-methylpyridine, in the same manner as the preparation of 4-[4-(6-methyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH2:15])[C:7]([C:16]([O:18]CC)=O)=[CH:6]2.Cl.[C:22]([C:27](=[NH:31])OCC)([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.C(O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:27]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:31][C:16](=[O:18])[C:7]1=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2nc1N
Reactant: CCOC(=N)C(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1

Procedure:
An alternative route to this product comprises heating a mixture of ethyl 6,7-dimethoxy-2-aminoquinoline-3-carboxylate (1.38 g., 5.0 mM), ethyl 1-carbethoxyformimidate hydrochloride (1.82 g., 10 mM), triethylamine (5.1 g., 5.0 mM), ethanol (50 ml.) and N,N-dimethylformamide (20 ml.) on a steam bath for 17 hours. The reaction mixture is cooled and the solid which separates filtered off, triturated with hot chloroform and then recrystallized from chloroform to give 0.170 g. of product. M.P. 273°-274° C. (dec.).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[C:11]([CH3:20])=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([OH:19])[O:14][CH2:13]2.N1C=CN=C1>C(Cl)Cl>[Br:9][C:10]1[C:11]([CH3:20])=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([O:19][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:14][CH2:13]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(Br)ccc2c1COC2O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1c(Br)ccc2c1COC2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of TBS-Cl (3.63 g, 24.10 mmol) in methylene chloride (15 mL) was added to a solution of 5-bromo-4-methyl-1,3-dihydroisobenzofuran-1-ol (2.76 g, 12.1 mmol) and imidazole (1.72 g, 25.3 mmol) in methylene chloride (80 mL) at 0° C., the resulting solution was stirred at rt overnight. The mixture was partitioned between DCM and water, the water phase was extracted with methylene chloride and the combined organic phase was dried over sodium sulfate then concentrated, and the residue was purified on silica gel column using ethyl acetate/hexane to give the title compound. LC/MS: (M−131)+: 210.91; 212.91.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[S:31]([O-])(=O)(=O)[CH3:32].C[S-].[Na+]>>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][S:31][CH3:32])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CO)cc1
Reactant: CS(=O)(=O)[O-]
Agent: C[S-]
Agent: [Na+]
Product: CSCc1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Yield: 64 %

Procedure:
By a method similar to that in Example 395, 3-acetyl-6-bromo-2-(4-hydroxymethylbenzyl)-4-phenyl-2H-isoquinolin-1-one was converted to mesylate and reacted with sodium thiomethoxide to give the title compound (239 mg, 64%).
Reaction SMILES: CS(C1C=CC([C:9](=O)[CH2:10][CH:11]([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=CC=1)(=O)=O.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](OO)=O)[CH:24]=1.[S:33]([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:29][C:25]1[CH:24]=[CH:23][C:28]([C:9](=[S:33])[CH2:10][CH:11]([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:27][CH:26]=1
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CC(=S)c1ccc(C)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
43(ii) Methyl 2-(4-methylsulfonylphenacyl)acetoacetate 4.42 g (15.8 mmol) of methyl 2-(4-methylthiophenacyl) acetoacetate [prepared as described in step (i) above] were dissolved in 150 ml of methylene chloride, and 7.77 g (31.5 mmol) of 70% m-chloroperbenzoic acid were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour. 30 ml of a 10% w/v aqueous solution of sodium thiosulfate were added to the mixture, and the mixture was vigorously shaken, after which it separated into liquid phases. The organic layer was separated and washed with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate and the solvent was then removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 1:1 by volume mixture of ethyl acetate and hexane, to give 3.65 g (yield 74%) of the title compound as a slightly yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]C)=[O:12])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H]1c1cccc(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC1c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford 2-(3-bromophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]\[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2\[C:11]([CH:13]=[CH:14][CH:15]=[CH:16]\2)=[O:12])/[CH:2]=1.O>C(O)(=O)C>[CH:4](=[N:5][CH2:6][CH2:7][N:8]=[CH:9][C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12])[C:3]1[C:17](=[CH:19][CH:20]=[CH:1][CH:2]=1)[OH:18]
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1/C=CC=CC1=O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O

Procedure:
Approximately 1 mmol of SALEN ligand dissolved in acetic acid solution was loaded into each reactor tube of the Multiclave™, and 5 ml of 4:1 (weight ratio) water/EO was added at 100° C. The results are shown in Table 3.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:20])[N:13]([CH2:17][CH2:18][CH3:19])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:21])[CH:4]=1.[CH:24]1(C=O)CC1>>[F:23][C:2]([F:1])([F:22])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH:12]([CH3:20])[N:13]([CH2:17][CH:18]4[CH2:24][CH2:19]4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:21])[CH:4]=1
Reactant: O=CC1CC1
Reactant: CCCN1c2cc3c(C(F)(F)F)cc(=O)[nH]c3cc2CCC1C
Product: CC1CCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2N1CC1CC1

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 187 (Structure 33 of Scheme VI, where R1=methyl, n=1) and cyclopropanecarboxaldehyde. 1H NMR (400 MHz, CDCl3) 10.91 (br. s, 1H), 7.14 (s, 1H), 7.01 (s, 1H), 6.94 (s, 1H), 3.65 (m, 1H), 3.35 (dd, 1H, J=15.0, 5.5), 3.09 (dd, 1H, J=15.0, 6.2), 2.97–2.82 (m, 2H), 2.00–1.94 (m, 1H), 1.84–1.79 (m, 1H), 1.17 (d, 3H, J=6.5), 0.88–0.85 (m, 1H), 0.58 (m, 2H), 0.28 (dd, 2H, J=10.3, 5.0).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14].OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([CH2:10][NH:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:3]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)NCC1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCC(=O)NCC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
N-Indan-2-ylmethyl-propionamide (4.00 g, 19.7 mmol) was dissolved in nitromethane (60 mL) and added to a mixture of concentrated H2SO4 (19 mL), concentrated nitric acid (1.4 mL) and water (3.2 mL) cooled to 5° C. After stirring for 45 min, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (4.67 g, 96%).
Reaction SMILES: CN1CCOCC1.OC1C2N=NNC=2C=CC=1.[NH2:18][C@H:19]([CH2:27][OH:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:29]([N:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]([CH2:44][C:45](O)=[O:46])[C:34](=[O:48])[CH:33]1[CH:49]([CH3:51])[CH3:50])(=[O:31])[CH3:30].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[C:29]([N:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]([CH2:44][C:45]([NH:18][C@@H:19]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:27][OH:28])=[O:46])[C:34](=[O:48])[CH:33]1[CH:49]([CH3:51])[CH3:50])(=[O:31])[CH3:30]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)O)C(=O)C1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@H](CO)Cc2ccccc2)C(=O)C1C(C)C
Reaction time: 72 h

Procedure:
N-Methylmorpholine (525 μl), hydroxybenzotriazole (647 mg) and L-phenylalaninol (491 mg) are added to a solution of {(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetic acid (1.01 g, Reference compound No. 51-1) in methylene chloride (25 ml). The mixture is cooled with ice, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added to the mixture, and the whole is stirred for three days. Ethyl acetate is added to the reaction mixture, and the whole is washed with a 0.1 N aqueous sodium hydroxide solution, saturated brine, 1 N hydrochloric acid and saturated brine successively. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (1.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.N[C:11](N)=[S:12].ClC1C=CC(Cl)=CC=1S.ClC[C:25]([OH:27])=[O:26]>S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[CH:11]([SH:12])[C:25]([OH:27])=[O:26]
Reactant: NC(N)=S
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=C(O)CCl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: Sc1cc(Cl)ccc1Cl
Product: O=C(O)C(S)c1cc(Cl)ccc1Cl

Procedure:
the method in which 2,5-dichloroaniline is diazotized and then reacted with thiourea in the presence of copper sulfate and subsequently hydrolyzed to 2,5-dichlorothiophenol, followed by reaction with monochloroacetic acid to yield 2,5-dichlorophenylthioglycolic acid (Ger. Offen. DE3715508),
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](OC)(=[O:12])[CH:10]=[CH2:11].BrC1C=CC(OC(C)C(O)=O)=CC=1>CO.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH2:11][CH2:10][C:9]2=[O:12]
Reactant: Oc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: CC(Oc1ccc(Br)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C1CCOc2ccc(Br)cc21

Procedure:
The title compound was prepared by the method of Canalini et al.2 by the reaction of 4-bromophenol (40 g, 0.23 mole) and methyl acrylate (100 ml) in the presence of Triton B (6 ml of a 40% solution in methanol); followed by dilute acid hydrolysis of the resulting ester and cyclisation of the (4-bromophenoxy)propionic acid in concentrated sulphuric acid. The product was recrystallised from petroleum ether (60°-80° C.) to give a white crystalline solid (6.80 g, 13%). M.p. 78°-80° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[NH:3][C:4](=[O:9])[C:5](C)([CH3:7])[CH3:6].CN(C)N.C(N(CC)CC)C.C(Cl)(=O)C(C)C>C(OCC)C>[CH3:1][N:2]([CH3:10])[NH:3][C:4](=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: CN(C)NC(=O)C(C)(C)C
Agent: CC(C)C(=O)Cl
Agent: CN(C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NN(C)C

Procedure:
In a fashion similar to the preparation of LtBu,NMe2H, treatment of a diethyl ether (250 mL) solution of 1,1-dimethylhydrazine (3.88 mL, 50 mmol) and triethylamine (7.52 mL, 53 mmol) with isobutyryl chloride (5.39 mL, 50 mmol) afforded LiPr,NMe2H as colorless crystals upon crystallization from Et2O and subsequent sublimation at 60° C./0.05 Torr (6.12 g, 94%): mp 94-96° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7](O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.Cl.[CH2:35]([O:42][C:43](=[O:61])[C@@H:44]([NH2:60])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[Cl:59])=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.[F:69][C:70]([F:85])([F:84])[S:71]([O:74][C@H:75]([CH3:83])[C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])(=[O:73])=[O:72]>C(Cl)Cl>[F:84][C:70]([F:69])([F:85])[S:71]([O:74][C@H:75]([CH3:83])[C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77])(=[O:72])=[O:73].[CH2:35]([O:42][C:43](=[O:61])[C@@H:44]([NH:60][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[Cl:59])=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1
Agent: C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Step 3′: t-Butyl (R)-2-(trifluoromethylsulfonyloxy)propionate was prepared from (R)-2-hydroxy-propionic acid tert-butyl ester (602 mg, 4.12 mmol), triflic anhydride (0.696 mL, 4.12 mmol) and 2,6-lutidine (0.480 mL, 4.12 mmol) in DCM (5 mL). To a suspension of ((S)-2-amino-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester hydrochloride (600 mg, 1.38 mmol) in dichloromethane (10 mL) was added triethylamine (0.574 mL, 4.12 mmol) at 0° C. After stirred for 10 min, a half amount of the freshly prepared t-butyl (R)-2-(trifluoromethylsulfonyloxy)propionate was added at room temperature and stirred for 1 hour. Additional triethylamine (0.574 mL, 4.12 mmol) and the rest of t-butyl (R)-2-(trifluoromethylsulfonyloxy)propionate were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-2-((S)-1-tert-butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester (580 mg). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=6.8 Hz), 1.41 (s, 9H), 3.00-3.07 (m, 2H), 3.26 (dd, 1H, J=7.1, 13.9 Hz), 3.70 (dd, 1H, J=7.1, 7.1 Hz), 5.09 (s, 2H), 7.20-7.42 (m, 12H); MS: m/z (MH+) 528.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:31][CH:32]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(1-methyl-piperidin-4-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (47.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.042 g, 38%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=8.2 Hz. 1H), 7.85 (d, J=6.7 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.46 (m, 3H), 7.20 (d, J=8.5 Hz, 2H), 6.69 (t, J=7.4 Hz, 1H), 6.37 (s, 1H), 6.42 (d, J=7.6 Hz, 1H), 5.29 (t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.16 (s, 3H), 3.01-2.94 (m, 2H), 2.50-2.39 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.86-1.73 (m, 4H). MS=491 (MH)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5].C(Cl)Cl.C(N(CC)CC)C.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>O>[CH3:27][Si:28]([CH3:30])([CH3:29])[O:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5]
Reactant: CCCCCCCCCCC[C@@H](O)CC#N
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC#N)O[Si](C)(C)C
Temperature: 0 °C
Yield: 100 %

Procedure:
5 g of (R)-3-hydroxy-tetradecanenitrile and 35 ml of methylene chloride were placed in a reactor and stirred. The mixture was cooled to 0° C., and 3.87 ml of triethylamine was added thereto, to which 3.38 ml of trimethylsilyl chloride was added over about 30 minutes, and stirred for about 1 hour. Subsequently, the resulting mixture was slowly heated to room temperature and stirred for about 1 hour, 50 ml of water was added thereto, and stirred vigorously for 5 minutes. The aqueous layer was removed. The organic layer was combined with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure, to give 6.66 g of the title compound (yield: 100%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=C[CH:6]=[N:7]2.[C:12]([O:16][K])(C)([CH3:14])[CH3:13].C(C1OC1)Cl.C[N:24](C=O)C>>[O:16]1[CH2:14][CH:12]1[CH2:13][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:24][CH:6]=[N:7]2
Reactant: CC(C)(C)O[K]
Reactant: Oc1cccc2ncccc12
Reactant: CN(C)C=O
Solvent: ClCC1CO1
Product: c1cc(OCC2CO2)c2cncnc2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 30 ml of dried DMF was dissolved 2 g of 5-hydroxyquinoline, and 1.5 g of t-butoxypotassium was added thereto, followed by heating and stirring at 50° C. for 1 hour. To the reaction liquid was added 4 g of epichlorohydrin, and the liquid was then heated with stirring at 90° C. for 3 hours. The solvent was distilled off under reduced pressure, and the resultant residue was then purified by the use of a silica gel column chromatograph. On allowing an effluent solvent of chloroform:methanol=100:1 to flow therethrough, 5-(2,3-epoxypropoxy)quinazoline was obtained in an oily state in an amount of 0.84 g. In 20 ml of ethanol were dissolved 0.84 g of this epoxy compound and 1.05 g of N-diphenylmethylpiperazine, and the liquid was then heated under reflux for 3 hours. After the reaction, the solvent was distilled off, and the resultant residue was then purified through the silica gel column chromatograph. On allowing the effluent solvent of chloroform:methanol=50:1 to flow therethrough, the intended product 5-[3-(4-diphenylmethylpiperazine-1-yl)-2-hydroxypropoxy]quinazoline was obtained in a powdery state in an amount of 0.48 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10](=[O:21])[N:11]([CH3:20])[C:12]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:13]=2[CH3:14])=[CH:5][CH:4]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][CH2:14][C:13]1[C:12]2([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[N:11]([CH3:20])[C:10](=[O:21])[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C2=C(C)C3(CCCCC3)N(C)C2=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C2=C(CBr)C3(CCCCC3)N(C)C2=O)cc1
Temperature: 25 °C

Procedure:
3-(4-Methoxyphenyl)-1,4-dimethyl-1-azaspiro[4.5]dec-3-ene-2-one (881 mg, 3.09 mmol) and N-bromosuccinimide (1.2 eq.) were stirred in 40 mL CCl4 with a catalytic amount of benzoyl peroxide for 3 h at 85° C. After cooling to room temperature the mixture was diluted with CH2Cl2, washed with water, dried (Na2SO4) and evaporated. The 4-bromomethyl-3-(4-methoxyphenyl)-1-methyl-1-azaspiro[4.5]dec-3-ene-2-one thus obtained was dissolved in ethanol (100 mL), CH2Cl2 (20 mL), and ethylamine (70% solution in water, 2 mL), the mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl.