Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[CH2:23]([NH2:29])[CH:24]1[O:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.O.C1C=CC=CC=1>[CH2:23]([NH:29][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([CH3:12])=[CH:11][C:3]=1[O:2][CH3:1])[CH:24]1[O:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(C)c([N+](=O)[O-])cc1C(=O)Cl
Reactant: NCC1CCCO1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(C)c([N+](=O)[O-])cc1C(=O)NCC1CCCO1
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
To a solution of 2-methoxy-4-methyl-5-nitrobenzoyl chloride (7.0 g), methylene chloride (35 ml) and triethylamine (7.68 g) is added a mixture of tetrahydrofurfurylamine (4.33 g) and dry benzene (11 ml) with ice cooling and stirring. The resultant mixture is allowed to stand at room temperature for 20 minutes, mixed with water and shaken with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to remove the solvent. The residue is washed with ethyl acetate/isopropyl ether and recrystallized from methylene chloride/ethyl acetate to give N-tetrahydrofurfuryl-2-methoxy-4-methyl-5-nitrobenzamide (7.1 g) as crystals melting at 178° to 179.5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:8])=[CH:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O>[CH3:1][N:2]1[C:3]2[C:12](=[O:14])[CH2:11][CH2:10][NH:9][C:7](=[O:8])[C:4]=2[CH:5]=[CH:6]1
Reactant: Cn1ccc(C(=O)NCCC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cn1ccc2c1C(=O)CCNC2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A mixture of Compound 4 (348 mg, 1.5 mmole) and polyphosphoric acid (80%, 17.5 g) was stirred at 100° C. for 1 hour. Water (150 ml) was added to the reaction mixture, followed by the addition of potassium carbonate to adjust the pH to 5. The resulting mixture was saturated with sodium chloride and then extracted with THF (3 times). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was fractionated and purified by chromatography on a silica gel column (eluent: 3%-methanol/chloroform), whereby Compound 5 (161 mg) was obtained (yield: 50%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](Cl)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:22]1[N:23]=[CH:24][O:25][C:21]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:27]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ncoc1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ncoc1-c1ccccc1
Yield: 39.9 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0452 g, 0.192 mmol), 5-phenyl-1,3-oxazole-4-carbonyl chloride (0.041 g; 0.192 mmol), and triethylamine (0.0672 mL; 0.479 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.028 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenyloxazole-4-carboxamide as a solid.
Reaction SMILES: ClCCl.[O:4]1[C@@:21]2([CH3:22])[C@@H:5]1[CH2:6][C@@H:7]1[C:12]([C:13](O)=[O:14])=[CH:11][O:10][C@@H:9]([O:16][C:17](=[O:20])[NH:18][CH3:19])[C@H:8]12.[N-]=[N+]=[N-].C1(OP([O-])(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.[CH3:44][NH2:45]>ClCCl.CO.C(N(CC)CC)C>[CH3:44][NH:45][C:13]([C:12]1[C@H:7]2[CH2:6][C@@H:5]3[O:4][C@:21]3([CH3:22])[C@@H:8]2[C@H:9]([O:16][C:17](=[O:20])[NH:18][CH3:19])[O:10][CH:11]=1)=[O:14]
Reactant: CN
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Agent: Cl
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)O[C@@H]1OC=C(C(=O)NC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
A dichloromethane solution containing 395 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid described in Example 1 was cooled with ice followed by addition of 0.49 ml of triethylamine, 0.38 ml of diphenylphosphate azide and 118 mg of methylamine hydrochloride and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain colorless needles from the dichloromethane-methanol eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid methylamide (194 mg, yield: 47%). The physicochemical properties of this compound are described in Table 3, Compound No. 15.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[CH:17]=[O:18].S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[C:17]1[O:18][CH:31]=[N:30][CH:29]=1
Reactant: CN1C2CCC1C(C=O)=C(Cl)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CN1C2CCC1C(c1cnco1)=C(Cl)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate (0.55 g, 2 mmol) in 20 ml methanol powdered potassium carbonate (1.5 g) and tosylmethylisocyanide (0.4 g, 2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Upon evaporation in vacuo water (30 ml) was added to the residue and the water solution extracted with methylenechloride (3×20 ml). The combined methylenechloride extracts were dried and evaporated in vacuo. The residue was dissolved in ethanol, and the title compound precipitated with a 1M oxalic acid ether solution. The compound was filtered and dried. M.p. 69°-71° C. decomposes.
Reaction SMILES: [CH:1]1[C:6](C(N[C@H](C(O)=O)CCC(O)=O)=O)=[CH:5][CH:4]=[C:3]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]3[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([NH2:32])[C:25]=3[N:26]=2)[CH:2]=1.[OH-].[Na+].C[C:36]([OH:38])=[O:37]>CC([O-])=O.[Na+].[Cl-].[Cl-].[Zn+2]>[CH:5]1[C:6]([C:36]([OH:38])=[O:37])=[CH:1][CH:2]=[C:3]([NH:19][CH2:20][C:21]2[N:26]=[C:25]3[C:27]([NH2:32])=[N:28][C:29]([NH2:31])=[N:30][C:24]3=[N:23][CH:22]=2)[CH:4]=1
Reactant: Nc1nc(N)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Product: Nc1nc(N)c2nc(CNc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 5 °C
Yield: 86 %

Procedure:
Aminopterin (2.4 g, 0.005 mol) is suspended in 1M NaOAc (500 ml) containing ZnCl2 (0.1 g), and 2N NaOH is added dropwise with stirring until a clear solution forms. Glacial AcOH is then added dropwise to bring the pH to 7.5, and 5 μl of carboxypeptidase G1 (4000 units/ml) is added. The mixture is shaken at 37° C. for 1 day, cooled to 5° C., and suction filtered. The solid is washed thoroughly with H2O, and dried in vacuo on a freeze-drying apparatus to obtain 4-amino-4-deoxypteroic acid (APA) (1.43 g, 86%) as an orange-yellow solid. The analytical sample is prepared by passing a small amount of this material through a microcrystalline cellulose column, with 0.1M glycine, pH 10, as the eluent. Appropriate fractions are pooled and acidified with AcOH, and the precipitate is collected, washed with H2O, and dried in vacuo over P2O5 ; Rf 0.1 (cellulose, pH 7.4 phosphate), dark absorbing spot; UVλmax (0.1N HCl) 243 nm (ε 18,500), 297 (23,900), 337 infl (13,700); UVλmax (0.1N NaOH) 261 nm (ε 30,400), 371 (9,100). Analysis for C, H, and N confirms the composition of APA.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:35])=[N:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:35])=[N:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Reactant: C#Cc1ccc(COC)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(-c2cc(Cc3ccc(Cc4ccc(Cl)o4)cc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Manufacturing Example 62-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine (11 mg, 0.069 mmol) described in Manufacturing Example 26-1-7 and triethylamine (19 μL, 0.014 mmol), which was stirred for 1 hour at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound as a crude product. This product was then purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (7.5 mg, 27%).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[CH:11]=O.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].C(=O)=O>N1C=CC=CC=1.O>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[CH:11]=[CH:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])cc1C=CC(=O)O

Procedure:
Piperidine (1 ml) was added to a mixture of 2-methoxy-5-nitrobenzaldehyde (24 g) and malonic acid (30 g) in pyridine (about 60 ml). The mixture was warmed on a steam bath for 3 hours (slow evolution of carbon dioxide) and then poured into water (500 ml) when a yellow solid precipitated. The solid was removed by filtration and crystallized from ethanol (1 liter). The weight of the product was 20 grams.
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:20])=[CH:13][C:14]([OH:19])=[C:15]([CH:18]=3)[CH:16]=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>>[C:1]12([C:11]3[C:12]([O:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:13][C:14]([O:19][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])=[C:15]([CH:18]=3)[CH:16]=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COCCOCCl
Reactant: O=Cc1cc(C23CC4CC(CC(C4)C2)C3)c(O)cc1O
Product: COCCOCOc1cc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)cc1C=O
Yield: 75.2 %

Procedure:
In a manner analogous to that of Example 17(a), 25 g (91.9 mmol) of 5-(1-adamantyl)-2,4-dihydroxybenzaldehyde were reacted with 26.2 ml (0.23 mol) of 2-methoxyethoxymethyl chloride and 31 g (75%) of the expected compound were recovered in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8](C(=O)C2C=CC=CC=2Br)[CH:9]=[C:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]([F:27])([F:26])[F:25])[N:11]=[CH:12]/1)=[O:5].[Li+].[OH-].CCO.CCOC(C)=O>O>[Br:1][C:2]1[CH:40]=[CH:39][CH:38]=[CH:37][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[N:11][C:10]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]([F:25])([F:26])[F:27])=[CH:9][N:8]=1)=[O:5]
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cn(C(=O)c2ccccc2Br)/c(=N/C(=O)c2ccccc2Br)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2ccccc2Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Into a 50 mL round bottom flask was placed (E)-2-bromo-N-[1-(2-bromo-benzoyl)-5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-1H-pyrazin-2-ylidene]-benzamide (vi) (50 mg, 0.07 mmol). To this was added LiOH (100 mg), followed by EtOH (25 mL). The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the resulting solution was diluted with 15 mL of H2O and extracted two times with 10 mL of EtOAc. The organic layers were combined and dried over Na2SO4. After removal of the solvent and volatile components under vacuum, the residue was purified by eluting through a silica gel column with a 1:6 EtOAc/PE solvent system. This resulted in 10 mg (27%) of the final product 2-bromo-N-[5-(5-methoxy-2-trifluoromethyl-benzoimidazol-1-yl)-pyrazin-2-yl]-benzamide (Compound 85) as a white solid.
Reaction SMILES: [Br-].[Si]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:11]=1[O:36][CH2:37][CH3:38])(C(C)(C)C)(C)C.[Li]CCCC.[CH:44]([C:47]1[CH:48]=[C:49]([CH:53]([CH3:57])[CH2:54][CH:55]=O)[CH:50]=[CH:51][CH:52]=1)([CH3:46])[CH3:45].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:37]([O:36][C:11]1[CH:12]=[C:13]([CH:16]=[CH:55][CH2:54][CH:53]([C:49]2[CH:50]=[CH:51][CH:52]=[C:47]([CH:44]([CH3:45])[CH3:46])[CH:48]=2)[CH3:57])[CH:14]=[CH:15][C:10]=1[OH:9])[CH3:38]
Reactant: CCOc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C=CCC(C)c2cccc(C(C)C)c2)ccc1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
(4-(tert-Butyldimethylsilyloxy)-3-ethoxyphenyl)methyltriphenylphosphonium bromide (1.15 g, 1.89 mmol, 1.0 equiv.) in THF (8 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 1.2 mL, 1.89 mmol, 1.0 equiv.) at 0° C., the red solution was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 3-(3-isopropylphenyl)butanal (541 mg, 2.84 mmol, 1.5 equiv.) in THF (3 mL) was added, and the mixture was stirred at 65° C. for 18 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 98:2) to yield a colorless oil which was dissolved in THF (10 mL). n-Bu4NF (1.0 M in THF, 2.3 mL, 2.27 mmol, 1.2 equiv.) was added, and the mixture was stirred at 25° C. for 1 h. After addition of H2O, the aqueous layer was extracted with EtOAc (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 19:1→9:1) to yield 0.33 g (54% over 2 steps) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[Cl-].[NH4+:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:27])=[N:13]2)[CH:7]=1
Reactant: CC1(c2cc(Br)ccc2F)COCC(=O)N1
Reactant: [NH4+]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Product: CC1(c2cc(Br)ccc2F)COCC(N)=N1

Procedure:
In analogy to step a) in the synthesis of building block D, the treatment of (RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one with trimethyloxonium tetrafluoroborate followed by the nucleophilic substitution with ammonium chloride yielded the title compound; its hydrochloride was obtained as a white solid. Mass (calculated) C11H12BrFN2O [287.13]; (found) [M+H]+=287, [M+2+H]+=289.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([OH:6])=[O:5].[CH2:10]([C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=2)=[N:22][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClCCl>[CH3:1][C@@H:2]([CH2:8][CH3:9])[C@H:3]([Cl:7])[C:4]([O:6][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[CH:19][C:18]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][N:22]=2)=[CH:29][CH:28]=1)=[O:5]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CC[C@H](C)[C@H](Cl)C(=O)O
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(OC(=O)[C@@H](Cl)[C@@H](C)CC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8 g of (S,S)-3-methyl-2-chloropentanoic acid, 16 g of p-(5-n-octylpyrimidin-2-yl)phenol, 11.6 g of N,N-dicyclohexylcarbodiimide, 0.6 g of 4-N,N-dimethylamino-pyridine and 300 ml of dichloromethane is stirred overnight at room temperature. After filtering off the precipitated urea derivative, the filtrate is washed with dilute hydrochloric acid and water, and the organic phase is worked up in the usual manner. p-(5-n-Octylpyrimidin-2-yl)-phenyl (S,S)-3-methyl-2-chloropentanoate is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.O>[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[N:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=3[CH:20]=2)=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A suspension of methyl 8-bromo-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (700 mg), 4-(2-butoxyethoxy)phenylboric acid (640 g), and potassium carbonate (744 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) was stirred for 30 minutes under an argon atmosphere. After addition of tetrakis(triphenyl)phosphine palladium (120 mg), the solution was heated at 100° C. for 3 hours under an argon atmosphere. The solution was allowed to cool, followed by addition of water and extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain yellow oil of methyl 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (294 mg). The oil was redissolved in THF (21 ml) and methanol (21 ml), and after addition of 1N sodium hydroxide (7 ml), the mixture was heated at 70° C. for 2 hours. The mixture was cooled to 0° C., followed by addition of water, neutralized with 1N hydrochloric acid, and then extraction with ethyl acetate. The organic layer was washed with saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from hexane-ethyl acetate to yield yellow crystals of 8-[4-(2-butoxyethoxy)phenyl]-1-propyl-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (200 mg).
Reaction SMILES: [OH:1][C@H:2]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([C:17]([OH:19])=O)[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4].Cl.[CH2:28]([NH2:30])[CH3:29].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.Cl.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.CO>[CH2:28]([NH:30][C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:7][CH2:6][NH:5][C@@H:3]([CH3:4])[C@H:2]([OH:1])[C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:19])[CH3:29]
Reactant: CCN
Reactant: C[C@H](NCCc1c[nH]c2c(C(=O)O)cccc12)[C@H](O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cccc2c(CCN[C@@H](C)[C@H](O)c3ccc(O)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 24 %

Procedure:
To a solution of 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-(methyl)ethylamino]ethyl}-1H-indole-7-carboxylic acid (29.1 mg, 0.0821 mmol) in N,N-dimethylformamide (3 mL) are added ethylamine hydrochloride (67 mg, 0.822 mmol), triethylamine (171 μL, 1.23 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSCI) hydrochloride (78.7 mg, 0.411 mmol) and 1-hydroxybenzotriazole (HOBt, 55.5 mg, 0.411 mmol), and the mixture is stirred at room temperature for 17 hours. The reaction solution is poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture is separated into chloroform. The organic layer is washed with a saturated brine and dried over anhydrous sodium sulfate. The solvent is removed by distillation, and the resulting crude product is purified by preparative TLC (a saturated ammonia solution in chloroform:methanol=20:1) to give 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-(methyl)ethyl-amino]ethyl}-1H-indole-7-carboxylic acid ethylamide (7.5mg, 0.0197 mmol, 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([O:28]CC)=O)=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.O.[NH2:32][NH2:33]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26]([NH:32][NH2:33])=[O:28])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)NN)c2)cc1

Procedure:
A solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-carboxylate (2.04 g) and hydrazine monohydrate (4.82 mL) in ethanol (20 mL) was stirred at 95° C. for 12 days. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.43 g) as a white solid.