Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[CH2:2]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:14]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])[CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CNc2ccccc2C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1Cc2ccccc2N(Cc2ccccc2)C1

Procedure:
5.6 g of 1,2,3,4-tetrahydroquinoline-3(R,S)-carboxylic acid (Example 1t)) are stirred in 100 ml of dimethylformamide, with the addition of 12.7 ml of benzyl bromide and 25.1 g of caesium carbonate, at room temperature for 24 h. The concentrated crude product is then purified by means of FC over 250 g of silica gel with a 1:1 mixture of methylene chloride and hexane as the mobile phase. The title compound is obtained: Rf (1:1 mixture of methylene chloride and hexane)=0.31.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[N:33]4)[CH:27]=3)[CH2:24][C:23](=[O:38])[NH:22][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3cccc(F)c3F)cc2N1
Yield: 81 %

Procedure:
Prepared from {2′,3′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K95) (118 mg, 0.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (74 mg). mp 230° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:41]1([CH3:50])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:50][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: OCc1cc2ccccc2nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Cc1ccccc1-c1nc2ccccc2cc1CO
Temperature: 120 °C
Yield: 37 %

Procedure:
A mixture of (2-chloro-3-quinolinyl)methanol (500 mg, 2.60 mmol), potassium phosphate tribasic (770 mg, 3.60 mmol), Pd(OAc)2 (30 mg, 0.13 mmol), PPh3 (136 mg, 0.52 mmol) and o-tolylboronic acid (530 mg, 3.90 mmol) in water (4.0 mL) was degassed. DME (13 mL) was added and the mixture was degassed further, then heated at 120° C. for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between EtOAc and 10% aqueous potassium carbonate solution. The aqueous phase was extracted with further EtOAc and the combined organic fractions were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO2, 10-40% EtOAc in heptane) then by preparative HPLC (Method 2). The product obtained was partitioned between DCM and 10% aqueous K2CO3 solution. The organic phase was dried (MgSO4) and evaporated in vacuo to give the title compound (240 mg, 37%) as a clear gum. δH (CDCl3) 8.34 (s, 1H), 8.12-8.17 (m, 1H), 7.86-7.91 (m, 1H), 7.69-7.76 (m, 1H), 7.54-7.62 (m, 1H), 7.18-7.37 (m, 4H), 4.52 (br. d, J 4.3 Hz, 2H), 2.40 (br. t, J 5.1 Hz, 1H), 2.07 (s, 3H). LCMS (ES+) 250.1 (M+H)+, RT 3.17 minutes (Method 4).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].[BrH:23]>>[Br:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: OCCCCCCCCCCCCCCCCCCCCO
Reactant: Br
Product: OCCCCCCCCCCCCCCCCCCCCBr

Procedure:
20-Bromo-icosan-1-ol was synthesized according to Uneyama et al, Tetrahedron Letters, 1991, 32(11), 1459-1462. Briefly, 400 ml petrolether were heated before 240 ml petrolether, 20.34 g icosane-1,20-diol and 280 ml HBr (48% in H2O) were added. The mixture was refluxed over night and incubated at room temperature for another day. The precipitate was then removed by filtration and dissolved in 300 ml dichloromethane. The solution was dried over Na2SO4 and filtered through silica gel. The solvent was removed and the crude product finally recrystallized from petrolether. Purity of the product was judged by 1H-NMR.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([CH:30]=[O:31])[CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:32][Li]>O1CCCC1>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:18][CH2:19][C:20]([C:24]5[CH:25]=[N:26][CH:27]=[C:28]([CH:30]([OH:31])[CH3:32])[CH:29]=5)([OH:23])[CH2:21][CH2:22]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]C
Reactant: O=Cc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Solvent: C1CCOC1
Product: CC(O)c1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
A suspension of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(5-formyl-3-pyridyl)piperidin-4-ol (0.350 g, 0.852 mmol) in tetrahydrofuran (20 mL) under nitrogen was cooled to 0° C. Methyl lithium (1.0M in diethyl ether, 1.72 mL, 2 eq) was added dropwise with dissolution of the suspension as addition proceeded. The solution became a golden brown color. The reaction was warmed to 10° C. and stirred at this temperature for 2.5 h. At the end of this time period, the reaction was quenched with water (25 mL) and the aqueous phase extracted with ethyl acetate (3×20 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (30 mL, eluent: 10% methanol in diethyl ether) to yield 0.280 g (77%) of the title compound as a white solid. TLC analysis (Rf 0.17, 10% methanol in diethyl ether). 1H NMR (CDCl3, 300 MHz) 8.65 (d, J=2.2 Hz, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.83 (t, J=2.1 Hz, 1H), 7.24 (m, 2H), 7.18 (m, 2H), 6.95 (m, 4H), 4.95 (q, J=6.5 Hz, 1H), 4.28 (br s, 1H), 3.49 (br s, 2H), 2.94 (m, 2H), 2.74 (m, 2H), 2.63 (br s, 2H), 2.13 (m, 2H), 1.76 (m, 2H), 1.59 (m, 3H) MS (CI, CH4) m/z 427 (M+1,100), 455 (M+29,17), 409 (62), 235 (11), 221 (22), 206 (17), 169 (28). The free base was dissolved in methylene chloride containing small amounts of methanol and acidified with ethereal HCl. The hydrochloride salt was precipitated by ether dilution, filtered, rinsed with fresh ether, and dried in vacuo (60° C., 10 pascal, 18 h) to yield a white solid, mp 177°-183° C. The analysis for dihydrochloride was not in agreement with calculated; 1H NMR and MS of salt were completely consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)CCN(CCCC(=O)O)CC4)no2)cc1Cl
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 87.6 %

Procedure:
A suspension of ethyl 4-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]butanoate (Preparation 97) (185 mg, 0.371 mmol) in ethanol (3 ml), was treated with 2M sodium hydroxide (0.556 ml, 1.11 mmol) at room temperature overnight to give a colourless precipitate. A further 1-2 mls of ethanol was added and the temperature was raised to 50° C. to complete the reaction. Acetic acid (0.07 ml, 1.22 mmol) was added to the solution and the mixture concentrated. The resultant oily residue was treated with water (ca 3 ml) then stirred at room temperature for 1-2 hr and filtered. The solid was washed with water, then dissolved in methanol and the solvent evaporated. The resultant solid was dried overnight in vacuo at ca 60° C. to give the title compound (153 mgs).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:35](I)[CH3:36].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:35][CH3:36])=[CH:29][CH:30]=1)[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOc1ccc(CC(C(=O)OC(C)(C)C)N(CC(=O)OC(C)(C)C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
13.2 g (30 mmol) of N-benzyl-2-(4-hydroxybenzyl)-3-azaglutaric acid-di-tert-butyl ester (Example j) is dissolved in 50 ml of anhydrous N,N-dimethylformamide and mixed at 0° C. under argon with 1.31 g (33 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 15 minutes, then 8.05 g (51.7 mmol) of ethyl iodide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another three hours. For working-up, the batch is taken up in toluene and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11](CC([O-])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:18].[Na+].O.C1(C)C=CC=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C([O-])C[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1

Procedure:
The mixture (208.5 g) of the compound (X1) and the compound (X11) obtained in Step E was dissolved in ethanol (460 ml), and a solution of NaOH (28 g) and water (30 ml) was added and the mixture was heated, followed by reflux for one hour. After cooling, toluene (500 ml) and water (500 ml) were added, and the resulting toluene layer was washed with 2 N--NaOH aqueous solution and further with water till the layer became neutral. After removing toluene by concentration of the layer, the resulting raw crystals were recrystallized from ethyl acetate (130 ml) to obtain trans-4-(p-bromophenyl)-cyclohexanol (X11) (130 g) having a melting point of 109.5°~111.0° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:17][C:18]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)C4CCCCN4C(=O)OC(C)(C)C)cc(S(C)(=O)=O)c3)nc21
Yield: 15 %

Procedure:
Starting from piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (176 mg; 0.768 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (200 mg; 0.512 mmol), 45 mg (0.074 mmol; 15% yield) of the desired compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][C:23]([OH:25])=O)[CH2:20][O:21][CH:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][C:23]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:25])[CH2:20][O:21][CH:13]2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CC(=O)O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CC(=O)N1CCC2(CC2)[C@H](O)C1
Yield: 96.5 %

Procedure:
-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added to a solution of (3S,6S)-3-carboxymethyl-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester (84 mg, 0.24 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (39 mg, 0.24 mmol) and 4-methylmorpholine (73 mg, 0.73 mmol) in DMF(1 mL), then after 16 h the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (106 mg, 96%). Colourless gum, MS: 458.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Product: COC(=O)COc1cc(C(=O)OC)nc2cc(Cl)ccc12

Procedure:
The purified methyl 7-chloro-4-hydroxy-2-quinoline-carboxylate was alkylated with methyl bromoacetate as described in example 2 to produce methyl 7-chloro-4-methoxycarbonylmethyloxy-2-quinolinecarboxylate as a white solid having a melting point of 153.5°-154.5° C.
Reaction SMILES: FC1C=C(CN)C=NC=1.[CH3:10][C:11]1[N:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[N:13][CH:12]=1.[CH2:19]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=2)[C:24]1=[O:37])[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[S:29][C:30]([C:34]([NH:18][CH2:17][C:15]3[CH:14]=[N:13][CH:12]=[C:11]([CH3:10])[N:16]=3)=[O:35])=[C:31]([CH3:33])[N:32]=2)[C:24]1=[O:37])[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1cncc(CN)n1
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1cncc(CNC(=O)c2sc(N3CCN(CC(C)C)C3=O)nc2C)n1
Yield: 46 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (6-methylpyrazin-2-yl)methanamine to react with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 46% yield: mp 139-142° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.38 (s, 1H), 6.75-6.72 (m, 1H), 4.69 (d, J=5.0 Hz, 2H), 4.14-4.08 (m, 2H), 3.62-3.56 (m, 2H), 3.13 (d, J=7.4 Hz, 2H), 2.62 (s, 3H), 2.56 (s, 3H), 1.98-1.88 (m, 1H), 0.94 (d, J=6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.6, 157.7, 155.7, 153.1, 152.5, 148.7, 143.4, 142.7, 117.1, 51.5, 42.9, 42.3, 42.0, 26.8, 21.2, 19.9, 17.2; MS (ES+) m/z 388.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:17]1[CH2:25][O:24][C:23]2[C:19](=[C:20]([CH:26]=[O:27])[S:21][CH:22]=2)[O:18]1.CCOC(C)=O>C1COCC1.O>[Br:8][C:4]1[CH:3]=[C:2]([CH2:1][CH:26]([C:20]2[S:21][CH:22]=[C:23]3[O:24][CH2:25][CH2:17][O:18][C:19]=23)[OH:27])[CH:7]=[CH:6][N:5]=1
Reactant: O=Cc1scc2c1OCCO2
Reactant: Cc1ccnc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC(Cc1ccnc(Br)c1)c1scc2c1OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
4-Methyl-2-bromopyridine (450 mg, 2.62 mmol) was dissolved in anhyd THF (10 mL) and the resulting mixture was cooled to −78° C. LDA (1.76 mL, 1.8 M solution in THF, 3.17 mmol) was added dropwise and the resulting mixture was stirred for 1 h at the same temperature. A solution of 3,4-ethylenedioxythiophene-2-carboxaldehyde (500 mg, 2.94 mmol) in THF (20 mL) was added and the resulting mixture was stirred for 30 min at room temperature. AcOEt (120 mL) and water (120 mL) were added and the layers were separated. The organic layer was washed with water (2×150 mL), dried (Na2SO4) and the solvent was removed by rotary evaporation. Flash chromatography of the residue (silica gel, petroleum ether/AcOEt 1:1) afforded (9) as a yellow oil (850 mg, 2.48 mmol, 95%). 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J=5.0 Hz, 1H), 7.38 (s, 1H), 7.10 (d, J=5.0 Hz, 1H), 6.29 (s, 1H), 5.18 (t, J=6.7 Hz, 1H), 4.20-4.05 (m, 4H), 3.20-2.95 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[C:8]([F:10])[CH:9]=1)[CH3:2].[I-:14].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1>C1COCC1.O>[F:10][C:8]1[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[C:6]([I:14])[CH:7]=1
Reactant: [I-]
Reactant: CCOc1cc(F)cc(B(O)O)c1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(F)cc(I)c1
Reaction time: 20 h

Procedure:
(3-Ethoxy-5-fluorophenyl)boronic acid (2.5 g, 0.014 mol) was dissolved in THF (30 mL) and a solution of sodium iodide (4.1 g, 0.028 mol) in H2O (15 mL) was added followed by a solution of chloramine T (7.8 g, 0.1 mol) in H2O (15 mL). After 20 h stirring, the reaction mixture was extracted with diethylether (3×50 mL). The organic layers were combined and the solvent was evaporated. The resulting residue was triturated with hexanes (3×) and the hexanes layers were combined. The solvent was evaporated to yield 1-fluoro-3-iodo-5-ethoxybenzene as an orange oil. The product was used in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]2[C:11]([CH3:17])=[C:12]([C:14]([NH2:16])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH2:29]([O:28][C:26]([C:25]1[N:16]=[C:14]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:10]=3[C:11]=2[CH3:17])[O:15][CH:24]=1)=[O:27])[CH3:30]
Reactant: C=CCOc1cccc2oc(C(N)=O)c(C)c12
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCOc1cccc2oc(-c3nc(C(=O)OCC)co3)c(C)c12

Procedure:
4-Allyloxy-3-methyl-benzofuran-2-carboxylic acid amide (3370 mg) in tetrahydrofuran (60 ml) was treated with sodium bicarbonate (5.58 g) and ethyl bromopyruvate (2.20 ml) followed by trifluoroacetic anhydride (5.63 ml) to give 2-(4-allyloxy-3-methyl-benzofuran-2-yl)-oxazole-4-carboxylic acid ethyl ester as a white solid [2443 mg, EI-MS: m/z 327 (M+)] as mentioned in Example 77.
Reaction SMILES: [F:1][C:2]([F:18])=[C:3]([C:8]1[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[CH:13]=O)[C:4]([F:7])([F:6])[F:5].[NH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([NH:19][CH2:13][C:12]2[CH:15]=[C:8]([C:3]([C:4]([F:7])([F:6])[F:5])=[C:2]([F:18])[F:1])[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[C@@H:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Reactant: COc1ccc(C(=C(F)F)C(F)(F)F)cc1C=O
Product: COc1ccc(C(=C(F)F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 79 and Compound 12 in the same manner of Compound 13.
Reaction SMILES: [CH3:1][CH:2]([CH:4]([NH:8][C:9]([CH:11]1[N:15]([C:16]([CH:18]([NH:24][C:25]([CH2:27][NH:28][C:29]([CH:31]([NH:42][C:43]([CH:45]([NH:53][C:54]([CH:56]([NH:64][C:65]([CH:67]([NH:74][C:75]([CH:77]([NH:83][C:84]([CH:86]([NH:91][C:92]([CH:94]([NH:97][C:98]([CH:100]([NH:109][C:110]([CH:112]([NH:115][C:116]([CH3:118])=[O:117])[CH2:113][OH:114])=[O:111])[CH2:101][C:102]2[CH:107]=[CH:106][C:105]([OH:108])=[CH:104][CH:103]=2)=[O:99])[CH2:95][OH:96])=[O:93])[CH2:87][CH2:88][S:89][CH3:90])=[O:85])[CH2:78][CH2:79][C:80]([OH:82])=[O:81])=[O:76])[CH2:68][C:69]2[NH:73][CH:72]=[N:71][CH:70]=2)=[O:66])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[CH2:46][CH2:47][CH2:48][NH:49][C:50]([NH2:52])=[NH:51])=[O:44])[CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[O:30])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:17])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH3:3]>[Na+].[Cl-]>[CH3:3][CH:2]([C@H:4]([NH:8][C:9]([C@H:11]1[N:15]([C:16]([C@@H:18]([NH:24][C:25]([CH2:27][NH:28][C:29]([C@@H:31]([NH:42][C:43]([C@@H:45]([NH:53][C:54]([C@@H:56]([NH:64][C:65]([CH:67]([NH:74][C:75]([C@@H:77]([NH:83][C:84]([C@@H:86]([NH:91][C:92]([C@@H:94]([NH:97][C:98]([C@@H:100]([NH:109][C:110]([C@@H:112]([NH:115][C:116]([CH3:118])=[O:117])[CH2:113][OH:114])=[O:111])[CH2:101][C:102]2[CH:107]=[CH:106][C:105]([OH:108])=[CH:104][CH:103]=2)=[O:99])[CH2:95][OH:96])=[O:93])[CH2:87][CH2:88][S:89][CH3:90])=[O:85])[CH2:78][CH2:79][C:80]([OH:82])=[O:81])=[O:76])[CH2:68][C:69]2[NH:73][CH:72]=[N:71][CH:70]=2)=[O:66])[CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:55])[CH2:46][CH2:47][CH2:48][NH:49][C:50]([NH2:52])=[NH:51])=[O:44])[CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[O:30])=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:17])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:5]([NH2:7])=[O:6])[CH3:1]
Reactant: CSCCC(NC(=O)C(CO)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(C)=O)C(=O)NC(CCC(=O)O)C(=O)NC(Cc1cnc[nH]1)C(=O)NC(Cc1ccccc1)C(=O)NC(CCCNC(=N)N)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCC(=O)NC(CCCCN)C(=O)N1CCCC1C(=O)NC(C(N)=O)C(C)C
Agent: [Cl-]
Agent: [Na+]
Product: CSCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(=O)O)C(=O)NC(Cc1cnc[nH]1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(N)=O)C(C)C

Procedure:
200 μg or 1000 μg α-melanocyte stimulating hormone/kg b.w. in 0.5 ml 150 mM NaCl.