Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[C:4]([NH:6][C:7](=[S:10])[SH-]C)=[S:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>C1(C)C=CC=CC=1>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1)=[S:10])=[S:5]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C[SH-]C(=S)NC(=S)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: S=C(NC(=S)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
3.0 g of N-(2,6-dichlorothiobenzoyl)-S-methyldithiocarbamate and 1.6 g of 3,4-dichloroaniline are dissolved in 25 ml of toluene and subsequently heated while refluxing for 5 hours. The resulting yellow precipitate is worked up in the usual manner. Yield 2.1 g. Melting point 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]#[N:14])[CH2:8][CH2:7][CH2:6]2.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1.CCOC(C)=O>[C:13]([CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[C:4]([NH:15][S:17]([CH3:16])(=[O:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]1=2)#[N:14]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1N)CCCC2C#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1NS(C)(=O)=O)CCCC2C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 445.9 %

Procedure:
To a solution of 6-methoxy-5-amino-1, 2,3,4 -tetrahydronaphthalene-1-carbonitrile (1.7 g, 8.3 mmol) in 20 ml of anhydrous pyridine was added methanesulfonyl chloride (1.9 ml, 1.2 mmol). The resulting solution was stirred for 2 h at 25° C. The reaction mixture was concentrated in vacuo to yield an oily residue which was redissolved in EtOAc and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo to provide an oily residue which was purified by column chromatography (EtOAc, neat) to yield 1.5 g (65%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 6 1.82 (m, 1H), 1.94 (m, 1H), 2.14 (m, 2H), 2.96 (s, 3H), 3.03 (q, 2H, J=8.8 Hz), 3.84 (s, 3H), 3.96 (t, 1H, J=6.3 Hz), 6.85 (d, 1H, J=8.9 Hz), 7.39 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH3:19])=[O:4].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19][Br:20])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1CBr
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 5-bromo-2-methyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.51 g, 7.8 mmol), N-bromosuccinimide (1.53 g, 8.6 mmol), and benzoyl peroxide (189 mg, 0.78 mmol) in CCl4 (60 mL) was refluxed for 16 h. After cooling to r.t., the solvent was evaporated in vacuo, and the residue was chromatographed (0-20% EtOAc/hexanes) to give 2.82 g of the title compound. MS: (+) m/z 402.06 (M+1)
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Reactant: C1CNCCN1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)NCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine (prepared in Example 80) 150.0 mg in chloroform 5.0 ml is treated with m-chloroperbenzoic acid (80%) 85.6 mg at 0° C. for 30 minites. Piperazine 0.263 g is added thereto and the mixture is stirred at room temperature overnight. To the reaction mixture is added ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution, and the organic layer is separated. The organic layer is washed with an aqueous saturated sodium hydrogen carbonate solution, water and a saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo. The residue is purified with silica gel chromatography (solvent; ethyl acetate) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine as a colorless amorphous solid, 128.4 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:19]3[CH2:20][CH2:21][CH2:22][C:23](=O)[C:18]=3[O:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C(O)C.[BH4-].[Na+]>C1COCC1>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][CH:23]2[C:18]3[O:17][N:16]=[C:15]([C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[C:19]=3[CH2:20][CH2:21][CH2:22]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc(-c2noc3c2CCCC3=O)ccc1-n1cnc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2noc3c2CCCC3Nc2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a mixture of 3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6-dihydrobenzo[d]isoxazol-7(4H)-one (850 mg, 2.6 mmol) and 4-fluoroaniline (877 mg, 7.89 mmol) in THF (10 mL) was added Ti(OPr-i)4 (823 mg, 2.9 mmol) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to 0° C., and 10.0 mL of dry ethanol was added, followed by NaBH4 (149 mg, 3.4 mmol). The mixture was stirred for 1 hr, precipitate was removed by filtration and washed with ethyl acetate. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography using a gradient of 0-7% of MeOH in DCM to afford the 660 mg of the title product.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]([CH3:24])[CH2:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9]>[Pd].CO>[CH3:25][N:2]([CH3:1])[CH:3]([CH3:24])[CH2:4][C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=CC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of methyl 6-dimethylamino-4,4-diphenyl-2-heptenoate (60 mg), 10% Pd/C (10 mg), and methanol was hydrogenated at room temperature for 18 hours. The mixture was filtered through a short pad of celite, and the filtrate was rotary evaporated to give methyl 6-dimethylamino-4,4-diphenyl-heptanoate, as a crude material which was then dried in vacuo.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C=O)C>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:15]
Reactant: CCI
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (2.0 g, 14.1 mmol) in DMF (30 mL) was added NaH (60% suspension in mineral oil, 0.81 g, 20.3 mmol, 1.4 eq) at 0° C. The mixture was stirred at 0° C. for 30 min before EtI (1.35 mL, 16.9 mmol, 1.2 eq) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with H2O then extracted by Et2O (3×40 mL). The combined organic layers were washed with H2O (50 mL) then dried over Na2SO4. The solvent was removed to afford crude product (2.57 g, ca. 14.1 mmol) which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(OCCCCCCO)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 129.2 %

Procedure:
Ethyl p-hydroxybenzoate (33.2 g), 6-bromohexanol (54.3 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and dissolved in water (1 L). Concentrated hydrochloric acid (25.7 mL) was added thereto, and the precipitated crystal was collected through filtration under reduced pressure, and washed with water. This was dried to give 4-(6-hydroxyhexyloxy)benzoic acid (61.5 g, 86%). 4-(6-Hydroxyhexyloxy)benzoic acid (9.53 g), N,N-dimethylaniline (5.33 g) and dioxane (100 mL) were put into a 300-mL three-neck flask, and acrylic acid chloride (3.98 g) was gradually and dropwise added thereto at 60° C. and stirred for 6 hours. After cooled, this was poured into water with ice (200 mL), and the precipitated crystal was collected through filtration under suction, washed with hexane and dried to give TP-55C (9.4 g, 80%). Production of 2,3,6,7,10,11-hexa(4-(6-acryloyloxyhexyloxy)benzoyloxy)triphenylene (TP-55):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:24])=[C:14]([O:16]CC3C=CC=CC=3)[CH:15]=2)=[CH:6][CH:5]=1>CCO.O.[Pd]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:24])=[C:14]([OH:16])[CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc(N)c(O)c2)cc1
Reaction time: 22 h
Yield: 31 %

Procedure:
To a stirring solution of 4-(6-amino-5-benzyloxy-pyridin-3-yl)-benzoic acid methyl ester (10.0 g, 0.03 mol) in EtOH:H2O (95:5, 600 mL) was added Pd/C (15.9 g, 0.015 mol) (the reaction was de-gassed under vacuum). The solution was allowed to stir under an H2 atmosphere for 22 hr. The solution was filtered through wet celite and the celite washed with EtOH. The filtrate was concentrated under vacuum to yield 4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoic acid methyl ester (2.3 g, 9.3 mmol, 31%). 1H NMR (MeOD, 300 MHz) δ 3.90 (s, 3H), 7.21 (d, 1H, J, 1.9 Hz), 7.62 (d, 2H, J, 8.5 Hz), 7.76 (d, 1H, J, 1.9 Hz), 8.04(d, 2H, J, 8.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH2:4].[C:14](Cl)(Cl)=[O:15]>O1CCOCC1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[N:4]=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Solvent: C1COCCO1
Product: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (133 mg, 0.60 mmol; Preparation 2) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture is stirred for 60 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: CNCCC#Cc1ccccn1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)N(C)CCC#Cc1ccccn1
Yield: 77.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2-methoxybenzoyl chloride (69 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 71 mg of 2-methoxy-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a green-brown oil (Yield: 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Li]CCCC>C1COCC1>[CH2:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([N:10]([CH3:12])[CH3:11])[N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCBr
Reactant: COc1cc(C)nc(N(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cc(OC)nc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution containing 1.06 g (6.34 mmol) of 4-methoxy-N,N,6-trimethylpyrimidin-2-amine and 1.32 g (6.34 mmol) of 1-bromononane in 20 mL of anhydrous THF were added 5.15 mL (8.34 mmol) of 1.6 M n-BuLi in hexanes. The reaction mixture was stirred at 23° C. for 20 min. The reaction mixture was quenched with saturated aqueous ammonium chloride and poured into 100 mL of water. The compound was extracted with two 80-mL portions of ethyl acetate. The combined organic layer was washed with one 80-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 9:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 1.22 g (66%); silica gel TLC Rf 0.7 (9:1 hexanes-ethyl acetate); 1H-NMR (CDCl3) δ 0.85 (t, 3H, J=6.8 Hz), 1.28-1.23 (br m, 14H), 1.82 (quint, 2H, J=7.2 Hz), 2.46 (dd, 2H, J=7.6, 7.6 Hz), 3.14 (s, 6H), 3.85 (s, 3H) and 5.77 (s, 1H); 13C NMR (CDCl3) δ 14.09, 22.66, 28.46, 29.31, 29.32, 29.48, 29.54, 29.59, 31.88, 36.78, 37.83, 37.83, 52.75, 93.03, 162.29, 170.25 and 173.93.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][NH2:43])[CH3:39]>O1CCCC1>[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][NH:43][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:39]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN(CC)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran (3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1-hydroxy benzotriazole (0.306 Kg) and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30° C. After addition, the reaction mixture was stirred for 16 hours at 25-30° C. and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCO3, saturated solution of NaCl and DM water. Organic layer was separated and ¾th of the solvent distilled under diminished pressure. The product was cooled to 0-5° C. and stirred for 2 hours, filtered and washed with chilled ethyl acetate (70 mL). The product was dried at 60° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: C1CNCCNC1
Reactant: COc1cc2c(nc(CCl)n2C)c(OC)c1OC
Product: COc1cc2c(nc(CN3CCCN(Cc4nc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-4,5,6-trimethoxybenzimidazole (75 mg) and homopiperazine (11 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:27]1[C:28]2[C:35]([CH3:36])=[CH:34][S:33][C:29]=2[N:30]=[CH:31][N:32]=1>C(O)C>[O:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([NH:2][C:27]1[C:28]3[C:35]([CH3:36])=[CH:34][S:33][C:29]=3[N:30]=[CH:31][N:32]=1)[CH2:11]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1Cc2ccc(Oc3ccccc3)cc2C1
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccc(Oc5ccccc5)cc4C3)c12
Yield: 39.4 %

Procedure:
using 2-amino-5-phenoxyindan hydrochloride (99 mg, 0.36 mmol), ethanol (3 ml), triethylamine (92 μl, 0.66 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (61 mg, 0.33 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (51 mg, 0.13 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:28][CH:29]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:30])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:30][CH:29]([NH:31][C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH3:28])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-(4-Benzyloxyphenoxy)phenol (1.948 g, 6.66 mmol), 2-tert-butoxycarbonylaminopropyl methanesulfonate (2.0 g, 6.66 mmol) and cesium carbonate (5.43 g, 16.66 mmol) were stirred in 75 ml of DMF at 80° C. for 3 h. Following addition of 2 g of 2-tert-butoxycarbonylaminopropyl methanesulfonate the reaction mixture was stirred at 80° C. for a further 4 h. The reaction mixture was concentrated in vacuo and the residue is taken up in ethyl acetate and water. The organic phase was separated off, concentrated and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 837 mg (28%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:15].[CH2:16](O)[CH3:17]>>[ClH:15].[CH2:16]([O:13][C:12](=[O:14])[C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH2:11])[CH3:17]
Reactant: CCO
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of O-benzyl-L-serine (9.75 g, 50 mmol) in ethanol (200 mL) is saturated with HCl gas for 8 minutes. The mixture is stirred overnight at room temperature, and then concentrated in vacuo. The solid is washed with diethyl ether and collected by filtration to yield O-benzyl-L-serine ethyl ester hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH:27]=[C:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]=2[CH2:32][O:31][C:30]2[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]1=2>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:6][CH2:7][N:8]([CH2:25][CH2:26][CH:27]=[C:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:33]=3[CH2:32][O:31][C:30]3[CH:39]=[CH:40][C:41]([C:43]([OH:46])([CH3:45])[CH3:44])=[CH:42][C:29]2=3)[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporate from the combined dried (MgSO4) organic extracts. Purification on silica gel chromatography using dichloromethane-methanol (9.6:0.4) afforded the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:3]([OH:11])[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[C:19]([S:23]([CH2:26][C@@H:27]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:28]([NH:30][C@H:31]([C:50](O)=[O:51])[CH2:32][C:33]1[N:37](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:36]=[N:35][CH:34]=1)=[O:29])(=[O:25])=[O:24])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([S:23]([CH2:26][C@@H:27]([CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:28]([NH:30][C@@H:31]([CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1)[C:50]([NH:1][C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@@H:3]([OH:11])[CH:4]([OH:5])[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:51])=[O:29])(=[O:25])=[O:24])([CH3:22])([CH3:20])[CH3:21]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)c1ccco1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(O)c1ccco1

Procedure:
In an analogous manner to that described in Example 13, by reacting (1RS,2R,3S)-3-amino-4-cyclohexyl-1-(2-furyl)-1,2-butanediol with N-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there was obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-(2-furyl)propyl]imidazole-4-propionamide (1:1 mixture of epimers) as a pale yellow solid, MS: 657 (M+H)+. The more polar epimer, (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3-(2-furyl)propyl]imidazole-4-Propionamide, MS: 657 (M+H) can be separated from the above mixture by chromatography.