Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]1(B(O)O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+].ClCCl>C(OCCO)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>[C:21]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]3)[C:22]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2cc(-c3cccc4ccccc34)ccc2n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
6-Bromo-2-methylquinoline (32.5; 0.145 mole) was dissolved in 2-ethoxy ethanol (200 ml) and to the magnetically stirred solution under nitrogen was added tetrakis(triphenyl phosphine) palladium (5.1 g; 0.0044 mole) followed by 2-ethoxy ethanol (25 ml). After 5 minutes stirring at room temperature 1-naphthaleneboronic acid (25.0 g; 0.145 mole) was added followed by 2-ethoxyethanol (75 ml). Sodium hydrogencarbonate (35 g; 0.42 mole) in water (200 ml) was added all at once and the reaction mixture was stirred and heated under nitrogen atmosphere at 90° C. for 20 h. After 1 h, the reaction mixture became orange in colour. The reaction mixture was allowed to cool, dichloromethane (100 ml) was added and the reaction mixture was filtered off under suction using celite, with a layer of silica gel on the top. To the filtrate further dichloromethane (250 ml) was added, extracted with de-ionised water (2×300 ml) and finally with brine (250 ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent removed to give a thick liquid. Trituration with diethyl ether and cooling in the refrigerator gave a light yellow solid. The product was dried under vacuum at 80° C., (22 g; 56%). Mp 111° C. (DSC, onset). Elemental analysis: Found C, 89.16; H, 5.58; N, 5.15; C20H15N requires C, 89.19; H, 5.61; and N, 5.20%.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH3:13])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>[OH-].[Na+].C(OCC)(=O)C>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][CH:23]=[N:22][CH:21]=3)[CH:15]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cnc[nH]2)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(-c2cnc[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 3-hexyl-6-[3-(1H-imidazol-5-yl)phenyl]-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 75, 21 mg, 62.3 μmol) in tetrahydrofuiran (1.5 ml) at room temperature was added lithium aluminium hydride (1.0 M in tetrahydrofuran, 0.12 ml, 0.12 mmol) over 2 min. The reaction mixture was stirred at room temperature for 30 min and then heated under reflux for 2 h before cooling to room temperature. Aqueous sodium hydroxide solution (1 M, a few drops) and excess ethyl acetate were added followed by solid sodium hydrogen carbonate. The reaction mixture was stirred rapidly for 1 h before filtering. The mother liquor was concentrated in vacuo and the crude residue was chromatographed on silica gel eluting with ethyl acetate and then ethyl acetate:methanol (80:20) to give the product as a colourless semi-solid (15 mg, 75%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([O:7]C)=[O:6])[CH3:4].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C(Cl)Cl.O>[C:16]([NH:2][CH:3]([CH3:4])[C:5]([OH:7])=[O:6])(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)C(C)N
Reactant: CCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(=O)NC(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 g (291 mmol) of methyl D,L-alaninate hydrochloride and 64.77 g (640 mmol) of triethylamine are initially charged in 300 ml of dry methylene chloride, at 0° C. 43.24 g (291 mmol) of heptanoyl chloride in 50 ml of methylene chloride are added dropwise. The mixture is allowed to warm to room temperature and stirred at this temperature for 2 h. The precipitate is filtered off, and the methylene chloride phase is extracted with saturated sodium bicarbonate solution and with saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed under reduced pressure and the residue is dissolved in 300 ml of methanol. 300 ml of water, in which 46.55 g (1164 mmol) of sodium hydroxide are dissolved, is added to this solution, and the mixture is stirred at RT for 2 h. The mixture is filtered, the methanol is removed using a rotary evaporator and the aqueous phase that remains is acidified with conc. Hcl to pH 1-2. The precipitated product is filtered off and dried. A second product fraction is obtained by extracting the aqueous phase with ethyl acetate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc3[nH]ccc3n2)cc(OC)c1OC
Temperature: 110 °C
Yield: 88.5 %

Procedure:
A flask was charged with 2-bromo-5H-pyrrolo[2,3-b]pyrazine (9.5 g, 48 mmol), 3,4,5-trimethoxyphenylboronic acid (13.22, 62 mmol), and K2CO3 (19.9, 144 mmol). Dioxane (213 ml) and water (71 ml) were added, and the solution was vacuum degassed under argon. [1,1′-bis(Diphenylphosphino)ferrocene]dichloro-palladium(ll) (3.92 g, 4.8 mmol) was added, and the reaction mixture was refluxed (110° C.) overnight. The reaction mixture was filtered through a plug of celite using dichloromethane, and the filtrate was concentrated giving a black oil. The oil was purified by silica gel chromatography using 5%-60% EtOAc in hexanes as eluant to provide 12.12 g (89%) of 2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4].Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[C:3]([C:5]1[CH:20]=[C:19]([CH2:21][O:22][C:24]2[CH:25]=[C:26]3[N:33]([CH3:34])[CH2:32][CH2:31][N:27]3[C:28](=[O:30])[N:29]=2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=1)#[N:4]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2C#N)cc1F
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(F)c3)c(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-fluorobenzonitrile (41.9 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimi-din-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccc(F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
To a solution of 4-fluoroaniline (3.85 g, 34.7 mmol) in tetrahydrofuran (100 mL) were added 2,4-dimethoxybenzaldehyde (6.34 g, 38.2 mmol) and acetic acid (11.9 mL, 208 mmol). After stirring at room temperature for 15 min, sodium triacetoxyborohydride (22.1 g, 104 mmol) was added thereto and the mixture was stirred at the same temperature for 15 hr. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, and then washed with 2 mol/L aqueous sodium hydroxide solution and brine successively. The organic layer was dried over anhydrous sodium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the title compound as a pale yellow solid (7.37 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2C=CC=CC=2)=[CH:4][CH:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][C:28]([OH:30])=O>ClCCl.C(N(CC)CC)C.O.C(=O)(O)[O-].[Na+]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:28](=[O:30])[CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:3][CH:4]=1)(=[O:15])[CH3:9]
Reactant: O=C(O)COc1ccc2ccccc2c1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 121.7 %

Procedure:
A stirred mixture of para-aminobenzophenone (6.75 g) in dichloromethane (75 mL) and triethylamine (20 mL) was chilled to -78° C. and treated with the acid chloride prepared from 2-naphthoxyacetic acid (10.1 g). The mixture was stirred for 30 minutes at -78° C. and for 1 hour at room temperature. The mixture was diluted with water and sodium bicarbonate solution and the solids were recovered by filtration and washed with water and dichloromethane to give 13.3 g of N-(4-acetylphenyl)-2-naphthoxyacetamide, 208°-210° C.
Reaction SMILES: O.[OH-].[Na+].[N:4]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:33][CH2:32][CH2:31][C@H:5]1[C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([O:29]C)=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].Cl>CO>[N:4]1([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:33][CH2:32][CH2:31][C@H:5]1[C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([OH:29])=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
35 ml of water and 5.0 ml of 1N sodium hydroxide solution are added to 1.92 g of Z-Pro-Phe-His-OMe (H. Derwald et al., J. Med. Chem. 7, 50 [1964]) dissolved in 50 ml of methanol. The solution is stirred for 45 minutes at 25° and then neutralised with 5.0 ml of 1N hydrochloric acid. The solvent is removed and the residue is flash-chromatographed over 10 g of silica gel (eluant: chloroform/methanol/concentrated aqueous ammonia solution [5:3:1]; fractions of approximately 15 ml). Fractions 6-13 are combined, concentrated by evaporation and the residue is dissolved in 70 ml of water. After neutralisation to a pH value of 5.0 by the addition of dilute hydrochloric acid, extraction is carried out twice with n-butanol and the combined butanol phases are washed with water and concentrated by evaporation. After drying the residue in a high vacuum, Z-Pro-Phe-His-OH is obtained in the form of a colourless powder; Rf (I)=0.23.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.O>O1CCCC1>[CH:11]1([CH2:14][NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC1CC1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccnc1NCC1CC1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
3 g (18.9 mM) of 2-chloro-3-nitropyridine and 5 g (70.3 mM) of cyclopropylmethylamine in 12 ml of tetrahydrofurane were refluxed under stirring for 1 h. Water was added and the aqueous layer was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 3.5 g of N-(cyclopropylmethyl)-3-nitropyridin-2-amine as a yellow oil. Yield: 95%.
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[C:13]3[CH:19]=[CH:20][CH:21]=[N:22][C:12]2=3)(=O)=O)=CC=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[N:22]1[C:12]2[NH:11][CH2:17][CH2:16][CH2:15][C:14](=[O:18])[C:13]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=O)c3cccnc32)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1CCCNc2ncccc21
Temperature: 0 °C
Yield: 78 %

Procedure:
A solution of 5.00 g of 6,7,8,9-tetrahydro-9-[(4-methylphenyl)sulfonyl]-5H-pyrido[2,3-b]azepin-5-one in 60 ml of 40% (v/v) sulfuric acid in acetic acid is heated at 60° C. for 11 hours. The mixture is chilled and poured into 350 ml of ice water (cooled in an ice bath) with thorough stirring. To the cold mixture is added solid NaOH until the pH is 8 while keeping the temperature below 30° C. The mixture is filtered and the solid washed with ethyl acetate. The organic layer of the filtrate is separated and the aqueous layer extracted with ethyl acetate. The organic layer and extracts are combined and treated with activated carbon. The mixture is filtered through MgSO4 and the solvent removed under vacuum to give 2.0 g of yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C:3](=[CH2:6])[CH:4]=[O:5].[CH2:9]([O:11][C:12](=[O:16])[CH2:13][N+:14]#[C-:15])[CH3:10]>>[CH2:9]([O:11][C:12]([CH:13]1[CH:4]([C:3]([C:2]([CH3:8])([CH3:7])[CH3:1])=[CH2:6])[O:5][CH:15]=[N:14]1)=[O:16])[CH3:10]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)C(C)(C)C
Product: C=C(C1OC=NC1C(=O)OCC)C(C)(C)C

Procedure:
The starting material is manufactured as follows: Reaction of 3,3-dimethyl-2-methylene-butanal with isocyanoacetic acid ethyl ester in amanner analogous to that described in Example 1 yields 5-(3,3-dimethylbuten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 17 to 2-formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. Subsequent reaction with thionyl bromide followed by treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[S:4][C:3]=1[CH2:15]O.C([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:38])[CH2:32]C(OCC)=O)=[CH:27][C:26]=1[CH3:39])C1C=CC=CC=1>>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:38])[CH2:32][CH2:15][C:3]2[S:4][C:5]3[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[CH:27][C:26]=1[CH3:39]
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: Cc1c(CO)sc2cc(C(F)(F)F)ccc12
Product: Cc1cc(C(=O)CCc2sc3cc(C(F)(F)F)ccc3c2C)ccc1O

Procedure:
The titled compound was prepared from the above-mentioned 3-methyl-6-(trifluoromethyl)benzothiophen-2-ylmethanol [WO 2005077926] (906 mg, 3.68 mmol) and Ethyl 3-(4-benzyloxy-3-methylphenyl)-3-oxopropionate (1.14 g, 3.65 mmol) in a procedure similar to that of Example 1 (1) as a brown powder (680 mg, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
630 mg (1.88 mmol) of ethyl rac-2-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionate from Example 85A are placed in 8 ml methanol, treated with 4 ml 20% aqueous potassium hydroxide and stirred for 2 hours at room temperature. The methanol is removed in vacuo, the aqueous residue acidified with 2 N hydrochloric acid, extracted with dichloromethane, and the organic phase dried over sodium sulphate and evaporated in vacuo. 463 mg (80% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=3)[CH:25]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:13]=1.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH3:41][O:40][C:38](=[O:39])[CH2:37][NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=3)[CH:25]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc2cc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc([N+](=O)[O-])cc3)ccc2c1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc3cc(OC)ccc3c2)cc1

Procedure:
4-(2,4-Dichloro-phenyl)-1-(4-nitro-phenyl)-2-(6-methoxy-naphthalen-2-ylmethyl)-1H-imidazole (252 mg, 0.5 mmol) was reduced to amine and was reacted with methyl bromoacetate following general procedures D & E to give {4-[4-(2,4-dichloro-phenyl)-2-(6-methoxy-naphthalen-2-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:9])[CH:15]=2)=[CH:7][N:6]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Brc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cnc(Br)cn2)ccn1
Temperature: 70 °C
Yield: 84.1 %

Procedure:
A mixture of 2,5-dibromopyrazine (2.42 g, 10.2 mmol), 2-chloro-4-hydroxy pyridine (1.2 g, 9.3 mmol) and Cs2CO3 (3.02 g, 9.26 mmol) in DMF (15 mL) was heated at 70° C. for 16 h with stirring. The mixture was poured into water (150 mL) and stirred for 15 min. The resultant precipitate was collected by filtration, washed with water (4×4 mL) and dried in vacuo to provide 2-bromo-5-((2-chloropyridin-4-yl)oxy)pyrazine (2.24 g, 84%) as an off-white solid. MS (ESI) m/z: 285.9/287.9 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:4].Cl>CO>[CH3:33][N:2]([CH3:1])[C:3](=[O:4])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])[CH:7]=1
Reactant: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: COCCOC1(C(=O)Nc2cccc(OC(=O)N(C)C)c2)CCNCC1

Procedure:
tert-Butyl 4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)-4-(2-methoxyethoxy)piperidine-1-carboxylate from step C (2.1 g, 4.4 mmol) was treated with HCl (4.0 N in dioxane, 5.5 mL, 22 mmol) in methanol (20 mL) at 50° C. for 30 minutes. The mixture was concentrated to give the title compound as the hydrochloride salt in quantitative yield. MS (ES+) [M+H]+=380.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:29]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: O=C(O)CCCCCCCCCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCBr
Reaction time: 0.07 h
Yield: 50 %

Procedure:
To a solution of (4) (2.60 g., 11 mM) and 11-bromoundecanoic acid (2.65 g., 10 mM) in anhydrous methylene chloride (90 mL) is added 4-(dimethylamino)pyridine (1.22 g., 10 mM) followed by N,N'-dicyclohexylcarbodiimide (2.3 g., 11 mM) (4×5 mL of methylenechloride rinses). Precipitation of dicyclohexylurea (DCU) begins within 4 minutes. When TLC analysis indicates the reaction is complete, the mixture is filtered, the filtrate concentrated in vacuo and the residue extracted with ether. The combined ether extracts are washed 1× with 1N hydrochloric acid, 1× saturated sodium chloride solution, dried (Na2SO4) and concentrated to a residue which is stirred, filtered, and concentrated alternately with ether and methylene chloride until all DCU is removed. Concentration of the final solution yields the title product (32) (2.35 g.) as an oil that goes readily to a waxy solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(CC)=O)C>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:15][CH2:16][CH:17]([C:9]#[N:10])[CH2:5][CH3:6])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(=O)CC
Product: CCC(C#N)CCOc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Yield: 145.6 %

Procedure:
A mixture of the phenol prepared in example 91 (0.90 g, 2.2 mmol), 4-bromocaproonitrile (0.6 mL, 5.0 mmol), potassium carbonate (0.97 g, 7.0 mmol), potassium iodide (0.1 g) and ethyl ethyl ketone (30 mL) was heated at reflux for 10 h. The reaction was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (3x). The combined organic layers were washed with water (3x), brine, dried (MgSO4), and concentrated in vacuo to a light pink oil, The material was purified by flash chromatography over silica gel eluting with 5% MeOH/CHCl3 to provide 0.80 g (72%) of a clear oil. MS (FD+) 500.78 (MH+). NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:8]1[CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]3[O:13][CH2:14][O:15][C:11]=3[C:10]=2[CH2:9]1)=[O:23])([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: COc1cc2c(c3c1OCO3)CNCC2
Product: COc1cc2c(c3c1OCO3)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 4-methoxy-6,7,8,9-tetrahydro-[1,3]dioxolo[4,5-h]isoquinoline (CA [110103-21-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 448.3 (M+H+).