Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[C:15](OC([O-])=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C.[OH-].[Na+]>[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Temperature: 10 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution is prepared of 41 g (0.17 M) of 4,4′-bipiperidine dihydrochloride in 250 ml of ethanol and 250 ml of 2N sodium hydroxide. A solution of 18.5 g (0.085 M) of t-butyl dicarbonate in 100 ml of ethanol are added slowly, at 0° C. The reaction mixture is agitated for 1 hour at 10° C. and the ethanol is then removed by an evaporator, under reduced pressure. The residual aqueous phase is saturated with sodium chloride and extracted with ethyl acetate. The organic phase obtained is dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a dichloromehane/methanol/aqueous ammonia mixture (8/2/0.4; v/v/v). 16.5 g of the compound sought after are thus obtained as a white solid (yield=72%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][CH:11]([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][CH:11]([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCCc1ccccc1OC(F)F
Reactant: Nc1ccccc1C=O
Product: Nc1nc2ccccc2cc1Cc1ccccc1OC(F)F

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-difluoromethoxyphenyl)propionitrile.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[N:7]3[N:8]=2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(Br)n3n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)n3n2)cc1

Procedure:
5-Bromo-2-(4-tert-butyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (20 mg, 60 μM) and piperazine (21 mg, 244 μM) in DMSO was heated at 80° C. for 8 h. The reaction was cooled and diluted with ethyl acetate (25 mL) and water (25 mL). After partitioning the ethyl acetate layer was washed with water (3×) and dried over magnesium sulfate. After filtering and concentration the title compound was obtained in 80% yield. LC/MS (Method A): r.t.=1.26 min. calculated mass=335 [M+H]+=336.
Reaction SMILES: [Br:1]Br.C([O:6][CH2:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=O)C.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CC(=O)OCC>[Br:1][C:14]1[CH:13]=[C:12]([S:9]([CH2:8][CH2:7][OH:6])(=[O:11])=[O:10])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)CCOC(C)=O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)CCO)cc1Br
Temperature: 50 °C
Yield: 29.5 %

Procedure:
Br2 (25 g, 155.0 mmol) was added dropwise over 30 min to the title compound of step 2 (8.0 g, 31.0 mmol) in acetic acid (100 mL) at 0° C. The mixture was heated at 50° C. for 12 h. Aqueous Na2SO3 (200 mL) was added and the pH was adjusted to 8 with sat. aq. NaHCO3. The mixture was subjected to EA extractive work up and silica gel chromatography (PE:EA=1:0-1:1) to give the title compound (2.7 g, 27.3%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H), 7.87 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 4.05-4.00 (m, 5H), 3.34-3.67 (m, 3H). LCMS: 316.9, 318.9 (M+Na)+
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)=[CH:19][C:18]=1[CH3:33])CC1C=CC(C(OC)=O)=CC=1.[OH-:36].[Na+].[CH2:38]1[CH2:42][O:41][CH2:40][CH2:39]1.Cl>CO>[F:34][C:2]([F:1])([F:35])[CH2:3][CH2:4][CH:5]([NH:24][C:23]1[CH:20]=[CH:19][C:39]([C:40]([OH:36])=[O:41])=[CH:38][CH:42]=1)[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][N:24]=2)=[CH:19][C:18]=1[CH3:33]
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(CC(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A reaction mixture of methyl 4-(5,5,5-trifluoro-2-(2-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)pentyl)benzoate (13.6 g), 1M aqueous sodium hydroxide solution (82 mL), THF (82 mL) and methanol (82 mL) was stirred at 70° C. for 7 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C. and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step 1 without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C1C=NC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([NH:24][N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:6][CH:7]=1
Reactant: NN1CCCCCC1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NN1CCCCCC1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Part A: To a solution of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid (0.50 gram, 1.30 mmol) in dichloromethane (10 mL) is successively added 1-aminohexahydro(1H)azepine (0.15 gram, 1.30 mmol), 7-aza-1-hydroxybenzotriazole (0.18 gram, 1.30 mmol), 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) (0.68 gram, 1.30 mmol) and diisopropylethylamine (0.34 mL, 1.95 mmol) and the resulting solution is stirred for 1 hour at room temperature. Concentration In vacuo gives a crude oil (2.01 gram) which is purified by flash chromatography (ethyl acetate/petroleum ether=1/3 (v/v)) to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-(hexahydro(1 H)azepin-1-yl)thiazole-2-carboxamide (0.350 gram, 56% yield). Melting point: 185-186° C. (after recrystallisation from diisopropyl ether).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH2:14]([N:16](CC)CC)[CH3:15].FC(F)(F)C([O-])=O.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]N.[C:50](=[Re+:52](=[C:55]=[O:56])=[C:53]=[O:54])=[O:51]>C(#N)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:15][CH2:14][NH:16][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1.[C:50](=[Re+:52](=[C:55]=[O:56])=[C:53]=[O:54])=[O:51]
Reactant: CCN(CC)CC
Reactant: NCCCCCCN(Cc1ccccn1)Cc1ccccn1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Agent: O=C=[Re+](=C=O)=C=O
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)NCCCCCCCCN(Cc2ccccn2)Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a suspension of 4-isothiocyanatobenzenesulfonamide (11 mg, 0.05 mmol) in dry acetonitrile (1 mL) and triethylamine (15 μL, 0.11 mmol) was added tricarbonyl rhenium(I) 6-(bis(pyridin-2-ylmethyl)amino)hexylamine trifluoroacetate (40 mg, 0.48 mmol). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated and the resulting solid recrystallized from methanol/water to afford MIP-1140 as an off-white solid (38 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ 9.83 (br, 1H), 8.80 (d, J=5.4 Hz, 2H), 8.11 (br, 1H), 7.96 (m, 2H), 7.86-7.25 (m, 10H), 4.90 (m, 4H) 3.72 (m, 2H), 3.47 (br, 2H), 1.83 (br, 2H), 1.57 (m, 2H), 1.37 (bm, 8H); (M+H)+ (811).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:35][CH2:34][CH2:33][N:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCN(C)CC2)cc1
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Yield: 48.9 %

Procedure:
A mixture of 0.037 g (0.1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 0.062 g (0.2 mmole) of toluene-4-sulfonic acid 3-(4-methyl-piperazin-1-yl)-propyl ester, 1 mL of dimethylformamide and 0.160 g (0.5 mmole) of cesium carbonate was heated at 100 degrees for 20 minutes. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 40:60-100:0) to give 0.025 g of 4-(3-chloro-phenyl)-2-{6-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.33) as a white powder. MH+/Z=511
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br.CCCCCCC>COC>[Br:26][C:10]1[C:11]([CH3:25])=[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1cc(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Agent: COC
Solvent: CCCCCCC
Product: Cc1c(C)c(OCc2ccccc2)c(Br)c(C)c1OCc1ccccc1
Reaction time: 8 h

Procedure:
In 100 mL dimethyl ether (DME) was dissolved 1,4-bis(benzyloxy)-3,5,6-trimethylbenzene prepared as in step 1(5 g, 15.0 mmol) which was treated with a solution of Br2 (0.85 mL, 16.5 mmol, 1.1 equiv.) in 10 mL DME (1.6 M) over ten minutes via a dropping funnel. The reaction was judged incomplete by HPLC. Additional Br2 in DME (0.42 mL, 1.31 g, 8.19 mmol, 0.55 equiv.) was added and stirred overnight. A white solid precipitated from the solution during the night. The reaction was treated with 200 mL EtOAc, which dissolved the solid, and washed with H2O until the aqueous washings were colorless (3×100 mL). The combined aqueous layers were back extracted with EtOAc (3×50 mL) and the combined organics washed 2×100 mL saturated NaCl, dried over Na2SO4 and concentrated to a brown solid. The solid was adsorbed onto silica and purified by flash chromatography (gradient elution 2-20% EtOAc/heptane) to give a yellow solid. The solid was suspended into heptane, stirred overnight, filtered and the filter cake rinsed with heptane. The resulting white powder was dried in vacuo and yielded 3.31 g of 2-bromo-1,4-bis(benzyloxy)-3,5,6-trimethylbenzene as a white powder. HPLC 97.8% at 215 nm, did not ionize; 1H NMR (400 MHz, CDCl3) d=7.57 (d, 2H), 7.48 (d, 2H), 7.44-7.36 (m, 6H), 4.87 (s, 2H), 4.74 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].Br[CH:9]([CH3:15])[C:10]([CH:12]1[CH2:14][CH2:13]1)=O.C(N(CC)CC)C>C(O)C>[CH:12]1([C:10]2[N:6]=[CH:5][NH:7][C:9]=2[CH3:15])[CH2:14][CH2:13]1
Reactant: CC(Br)C(=O)C1CC1
Reactant: N=CN
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]cnc1C1CC1
Temperature: 60 °C

Procedure:
4-Cyclopropyl-5-methyl-1H-imidazole was synthesized according to the following procedure: Under nitrogen with stirring formamidine acetate (15.62 g, 150 mmol) was suspended in 40 ml anhydrous ethanol. 2-bromo-1-cyclopropylpropan-1-one (2.64 g, 15 mmol) was added via syringe and the mixture was heated to 60° C. for 2 hours. Triethylamine (21 ml, 155 mmol) was then added and the reaction was heated for an additional 12 hours at 60° C. The solvent was removed under reduced pressure, and the residue was dissolved in 50 ml of water. An aqueous solution of saturated sodium bicarbonate (20 ml) was added, followed by sodium chloride until the solution became saturated. The mixture was placed in a separatory funnel and extracted with ethyl acetate (3×50 ml), the organic extracts combined, dried over magnesium sulfate, filtered and then the solvent removed under reduced pressure. The oily residue was washed with hexanes (2×100 ml) to remove any residual triethylamine, leaving an oily residue which was >90% pure by 1H-NMR, which was further purified by loading onto a silica gel column in ethyl acetate and eluting with 0 to 10% methanol in ethyl acetate. Yield 0.607 g, 33%
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.Cl[CH:10]([CH3:18])[CH2:11][CH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1.[OH-].[Na+].C1COCC1>CN(C=O)C.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:10]([CH3:18])[CH2:11][CH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1
Reactant: CC(Cl)CCc1nnn[nH]1
Reactant: Oc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCc1nnn[nH]1)Oc1cccc(O)c1

Procedure:
A mixture of 1.43 g (0.013 mol) 1,3-dihyroxybenzene, 2.1 g (0.013 mol) 5-(3-chlorobutyl)tetrazole and 15 ml (2N, NaOH) in 15 ml DMF and 50 ml THF are stirred overnight at 60° C. bath temperature. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gives the tetrazole product which is used directly in the next step.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[NH2:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][NH:42][CH2:43][CH2:44][NH2:45].[OH-:46].[Na+]>O1CCOCC1.O>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:36][CH2:37][CH2:38][N:39]([C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]3)[OH:14])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]3[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]3)[OH:1])[N:6]=2)[CH2:40][CH2:41][N:42]([C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]3)[OH:14])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]3[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]3)[OH:1])[N:6]=2)[CH2:43][CH2:44][NH:45][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:23])([CH3:24])[CH2:16]3)[OH:46])[N:10]=[C:5]([NH:4][CH2:3][CH:2]([CH:26]3[CH2:27][C:28]([CH3:35])([CH3:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH2:31]3)[OH:1])[N:6]=2)[N:6]=1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: [OH-]
Reactant: NCCNCCNCCN
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(C(O)CNc2nc(NCCN(CCN(CCNc3nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)n3)c3nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)n3)c3nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)nc(NCC(O)C4CC(C)(C)NC(C)(C)C4)n3)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (8.0 g) and triethylenetetramine (0.5 g) were dissolved in dioxane (100 ml) and to the solution was added an aqueous solution of sodium hydroxide (0.7 g) in water (10 ml). The mixture was heated to reflux for 6 hours. Dioxane was distilled off from the reaction mixture and the residue was extracted with benzene. The extract was treated with silica gel column chromatography (eluent=ethyl acetate:benzene:ethanol:triethylamine=20:4:2:1) to give the desired product as white crystals melting at 158° C.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.O>O1CCCC1.CO>[OH:3][CH:4]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2CC(=O)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2CC(O)c2ccccc2)CC1
Temperature: 5 °C
Yield: 76.1 %

Procedure:
NaBH4 (0.034 mol) was added portionwise at 5° C. to a mixture of (±)-1,1-dimethylethyl 4-[[1-(2-oxo-2-phenylethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (0.034 mol) in tetrahydrofuran (250 ml) and methanol (250 ml). The mixture was stirred at 5° C. and then hydrolyzed cold with H2O. The solvent was evaporated and the residue was taken up in H2O. The precipitate was filtered off, washed with diisopropylether and dried, yielding 11.3 g of (±)-1,1-dimethylethyl 4-[[1-(2-hydroxy-2-phenylethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (76%) (interm. 3).
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)C(=O)O
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of Boc-Phe(3-F)—OH (0.20 g, 0.706 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.578 mmol) and CMPI (0.20 g, 0.783 mmol) in THF (6 ml), TEA (0.30 ml, 2.15 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=60:1:0.05) to give Boc-Phe(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH3:11][C:12]1[C:17]([CH:18]=O)=[CH:16][N:15]=[C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[N:13]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(N(CC)CC)C>[OH-].[Na+].ClCCl.CN(C=O)C>[CH3:1][C:2]1[C:3]2[N:10]=[C:18]([C:17]3[C:12]([CH3:11])=[N:13][C:14]([NH:20][CH2:21][CH2:22][CH2:23][CH:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[N:15][CH:16]=3)[NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1

Procedure:
To a 4 mL vial were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (69 mg, 0.33 mmol), 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (92 mg, 0.33 mmol), 2,3-dichloro-5,6-dicyano-p-benzoquinone (75 mg, 0.33 mmol), and DMF (2 mL). After addition of triethylamine (0.09 mL, 0.66 mmol), the resultant mixture was stirred for 5 hours at room temperature. The resultant mixture was then diluted with 1N NaOH (7.5 mL) and dichloromethane (7.5 mL). The organic layer was concentrated and purified by flash chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].CC(C)([O-])C.[K+].[CH2:29]([O:31][P:32]([CH3:37])([CH2:34][CH:35]=O)=[O:33])[CH3:30]>C(Cl)Cl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:35]\[CH2:34][P:32]([O:31][CH2:29][CH3:30])([CH3:37])=[O:33])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CCOP(C)(=O)CC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOP(C)(=O)C/C=C(\NC(=O)OCc1ccccc1)C(=O)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
After 214 mg of N-(benzyloxycarbonyl)-alpha-phosphonoglycine trimethyl ester was dissolved in 5 ml of methylene chloride, 74 mg of potassium t-butoxide was added, followed by stirring at −78° C. for 30 minutes. 76.5 mg of 2-(ethoxy(methyl)phosphinyl)-acetaldehyde in methylene chloride solution (1 ml) was gradually added dropwise into this reaction solution, which was stirred for 1 hour. After the reaction temperature was gradually raised up to room temperature, further the reaction solution was stirred for 3 hours. Consuming of ingredients was confirmed by using TLC, and the solvent was removed off under reduced pressure. The residual was purified by silica gel column chromatography (chloroform-methanol (100:1-50:1)), 168 mg of an objective compound was obtained (93% yield).