Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43](C(OC(C)(C)C)=O)[CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([C:40]5[CH:41]=[N:42][NH:43][CH:44]=5)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(-c2cn[nH]c2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 120 °C
Yield: 34.8 %

Procedure:
To a 25 mL microwave reactor pressure tube was charged 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodothieno[3,2-c]pyridin-4-amine (129 mg, 0.236 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (69.3 mg, 0.236 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex 9.62 mg, 0.012 mmol), and saturated aqueous sodium carbonate (0.707 mL, 0.707 mmol) followed by dioxane (5 mL). The reaction was heated at 120° C. for 40 min in microwave reactor. The reaction was cooled to room temperature, the mixture was transfered into a 100 mL Erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube, total 100 mL of EtOAc was added to the mixture. The EtOAc solution was evaporated to dryness, and re-dissolved with CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallizaton in CH3CN to give the title compound 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-amine (40 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24-3.29 (m, 2H), 3.97 (s, 2H), 4.32 (t, J=8.46 Hz, 2H), 5.40 (s, 2H), 7.18-7.21 (m, 1H), 7.23-7.29 (m, 3H), 7.38 (s, 1H), 7.49 (s, 1H), 7.96 (s, 1H), 8.07 (s, 1H), 8.12 (d, J=8.34 Hz, 2H), 13.09 (s, 1H)
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH3:15])[CH2:3]1.[N:16]1[NH:17][N:18]=[C:19]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:25][C:24]=2[F:34])[CH:20]=1>>[F:34][C:24]1[CH:25]=[C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:19]1[CH:20]=[N:16][N:17]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:4]([CH3:15])[CH2:3]2)[N:18]=1
Reactant: CC1CC(O)CCN1C(=O)OC(C)(C)C
Reactant: Fc1cc(-n2cnnn2)ccc1OCc1cn[nH]n1
Product: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate and 1-(4-((2H-1,2,3-triazol-4-yl)methoxy)-3-fluorophenyl)-1H-tetrazole (Intermediate 16) in a manner similar to that described in Example 48, Step 4. The title compound was isolated as a mixture of four stereoisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: COc1cc(C(=O)O)n(C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 91.7 %

Procedure:
In the same manner as in Example 18-4 and using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (201 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (265 mg, 92%) was obtained as a white solid.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1C2C=CC(O)=CC=2OC1.[Br:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1>>[Br:51][C:52]1[CH:53]=[CH:54][C:55]([OH:58])=[C:56]([C:26]2([OH:33])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]([CH:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]2=[O:34])[CH:57]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (90%) as an orange solid: MS (ES+) m/z 486.2 (M+1), 488.2 (M+1).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:15][O:14][C:13](=[O:16])[NH:12]3)[CH2:7][CH2:6]2)[O:4]CC1>C(#N)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:15][O:14][C:13](=[O:16])[NH:12]2)[CH2:7][CH2:6]1
Reactant: O=C1NC(C2CCC3(CC2)OCCO3)CO1
Solvent: CC#N
Product: O=C1CCC(C2COC(=O)N2)CC1

Procedure:
A solution of 4-(1,4-dioxaspiro[4.5]decan-8-yl)oxazolidin-2-one (880 mg, 3.87 mmol) and acetonitrile (65 mL).), prepared in the previous step, was deprotected as described in example 1, step C to afford the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:24]1([N:21]2[CH2:20][CH2:19][CH:18]([O:17][C:15]3[S:16][C:10]4[CH2:9][NH:8][CH2:13][CH2:12][C:11]=4[N:14]=3)[CH2:23][CH2:22]2)[CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC(N2CCC(Oc3nc4c(s3)CNCC4)CC2)C1
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A solution of 2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (2.0 grams, 5 mmol, obtained in above step) in dichloromethane (30 mL) was treated with trifluroacetic acid (5.0 mL, 50 mmol) at 0° C. Reaction mass was stirred for 4 hours. After completion of reaction, the reaction mass was quenched into ice cold water and adjust pH to 10, by using 40% aqueous sodium hydroxide solution. The product was extracted with dichloromethane (3×50 mL), combined organics were washed with water followed by brine and dried over anhydrous sodium sulphate. Organic volatiles were evaporated under vacuum to obtain the title compound (1.3 grams).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][C:10]1[C:11]([CH2:16]Br)=[CH:12][CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[CH3:3][S:4]([N:7]1[CH:16]=[C:11]2[C:10]([CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9]1)(=[O:6])=[O:5]
Reactant: BrCc1ccccc1CBr
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1cc2ccccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.88 g) was suspended in 3 ml dimethyl formamide. To this stirred solution was added methanesulfonamide (0.95 g, 10 mmol) in 5 ml dimethyl formamide dropwise under nitrogen. After stirring at 60° C. for 0.5 hours, a solution of 2.64 g (10 mmol) α,α'-dibromo-o-xylene in 7 ml DMF was added at a rate appropriate to maintain the temperature at 60-70° C. The mixture was stirred at room temperature for another hour, then quenched by pouring into water. The resulting precipitate was collected and washed with water, petroleum ether and ether successively. Weight 1.57 g (80%). 1H-NMR 62.37 (s, 3H, --CH3), 4.709 (s, 4H, 2CH2). 7.25~7.35 (m. 4H, ArH).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>C(O)(C)C.C1COCC1.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a stirring solution of 4-benzylpiperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester (31.6 mmol, 11.01 g) in isopropyl alcohol (50 mL) and THF (50 mL) was added 3N NaOH (63.4 mmol, 21.1 mL) and the biphasic solution was heated to reflux. The reaction was heated for 8 h. and then left stirring at room temperature overnight. The reaction was then diluted with water (200 mL) and acidified to pH=4 with glacial acetic acid. The aqueous mixture was then extracted with ethyl acetate (2×500 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting solid was triturated with diethyl ether to give 6.7 g of a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:29]1[CH:34]=[C:33]([C:7]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:32]=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2cccc(C#N)c2)CCC1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}-1-cyclopentene-1-carboxylate (1.2 g, 4.16 mmol) in 10 ml anhydrous dioxane was added potassium phosphate (1.32 g, 6.2 mmol), 3-cyanophenyl boronic acid (0.612 g, 4.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl 2-(3-cyanophenyl)-1-cyclopentene-1-carboxylate (0.7 g, 71%) as a light yellow oil after drying. ES-MS (M+H+): 242.15. H1NMR (CDCl3) δ: 1.09-1.13 (t, 3H); 1.96-2.01 (m, 2H); 2.80-2.84 (m, 4H); 7.39-7.59 (m, 4H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([OH:5])=[O:3]
Reactant: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCCCCCC(=O)O

Procedure:
1-(7-Ethoxycarbonylheptyl)-2-heptyl-4,5-diphenyl-imidazole (1 g) was reacted with sodium hydroxide in a method similar to Example 10 to give, after colnmn chromatography on silica gel (dichloromethane/methanol) and recrystallisation from hexane, 1-(7-carboxyheptyl)-2-heptyl-4,5-diphenylimidazole (0.26 g, 28%) as a white solid, m.p. 75°-6°. Found: C, 78.04; H, 8.85; N, 6.10%; C30H40N2O2 requires: C, 78.22; H, 8.75; N, 6.08%;
Reaction SMILES: [CH2:1]([O:8][C:9](=[C:19]([OH:21])C)[CH:10](C(OC)=O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl.[CH:26]([NH2:28])=[NH:27]>CO>[CH2:1]([O:8][C:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:27][CH:26]=[N:28][C:19]=1[OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C(=O)OC)C(OCc1ccccc1)=C(C)O
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncnc(O)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
To a solution of dimethyl 2-benzyloxy-3-hydroxy-2-butenedicarboxylate (3.0 g) in methanol (60 ml) were added sodium methoxide (1.28 g) and formamidine hydrochloride (953 mg) under ice-cooling, and the mixture was stirred at 70° C. for 1.5 hr. The reaction solvent was evaporated under reduced pressure, and water was added to dissolve the residue. 5% Aqueous potassium hydrogen sulfate solution was added, and the precipitated solid was collected by filtration, washed with water and dried to give methyl 5-benzyloxy-6-hydroxypyrimidine-4-carboxylate (1.1 g).
Reaction SMILES: [CH3:1][N:2]([CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[C:9](=O)[CH3:10])[N:3]=C(C)C.Cl>C(O)C.O>[CH3:1][N:2]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[C:9]([CH3:10])=[N:3]1
Reactant: CC(=O)C(=CN(C)N=C(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)c1cn(C)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-((1-methyl-2-(propan-2-ylidene)hydrazinyl)methylene)pentane-2,4-dione (Preparation 3, 9.1 g) was dissolved in Ethanol (20 mL) and treated with 1M Hydrogen chloride in Water (20 mL). the reaction solution was stirred at room temperature for 15 minutes. The reaction solution was then concentrated under vacuum with a rotavap to approximately 20 mL total volume. The reaction solution was then treated with saturated aqueous sodium bicarbonate (45 mL), and extracted with methylene chloride (4×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo afford the title compound as a light orange solid. (6.2 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:17][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: Cc1cc(O)cc(C)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)c(C)c1
Yield: 112.1 %

Procedure:
A mixture of 11.3 g (49.6 mmol) of 3,5-dimethyl-4-(phenylmethoxy)phenol (Example G), 13.3 g (1.2×49.6 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 8.2 g (1.2×49.6 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed. A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine, dried and evaporated leaving 20.6 g of the product as a pale yellow oil. Distillation through a short path apparatus affords 15.4 g of the title compound; bp 190°-194° C./0.1 mm (230°-240° C).
Reaction SMILES: [CH3:1][SiH:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([O:7][SiH](C)C)=[CH:5][CH:4]=1.C[O-].[Na+]>C(OCC)C.CO>[CH3:1][SiH:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: C[SiH](C)Oc1ccc([SiH](C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: C[SiH](C)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a cold solution (~9° C.) of 26.0 g of 4-dimethylsilylphenoxydimethylsilane in 250 ml of diethylether was added 10 ml of a solution of sodium methoxide (0.4N) in methanol and the mixture stirred overnight. Solvents were removed by evaporation on a rotary evaporator at room temperature to yield 15.6 g (83.0%) of crude product, m.p. 59°-60° C. After recrystallization from hexane, the phenol was obtained as needles, m.p. 61° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].IC.[C:25]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:25])=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCOc1ccc(OC)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.69 g, 2.34 mmol), iodomethane (0.58 mL, 9.34 mmol) and K2CO3 (1.61 g, 11.68 mmol) in acetone (20 mL) was stirred, and refluxed for 3 hours, cooled. The solution was filtered, dried with silica gel powder (10 g). 30% Ethyl acetate in hexanes (2 L) was used to run flash chromatography. The title compound was obtained (377 mg, 52%). MS (APCI) m/z 310 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([O:26][C:27]([N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C:35]([OH:37])=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCOCC1>[CH2:19]([O:26][C:27]([N:29]1[C:33](=[O:34])[CH2:32][CH2:31][C@H:30]1[C:35]([N:2]([CH3:1])[C@H:3]([C:10]([OH:12])=[O:11])[CH2:4][C:5]1[N:9]=[CH:8][NH:7][CH:6]=1)=[O:37])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)[C@@H](Cc1c[nH]cn1)C(=O)O
Reaction time: 15 h

Procedure:
Nα -Methyl-L-histidine (428 mg) and sodium carbonate (288 mg) was dissolved in water (5 ml) and the solution adjusted to pH 8.5. Benzyloxycarbonyl-L-pyroglutamic acid N-hydroxsuccinimido ester (933 mg) in dioxane (5 ml) was added and the solution stirred for 15 hrs at 22°. The solution was evaporated and the residue chromatographed on a silica gel column (15 × 330 mm) using isopropanol-ethyl acetate - acetic acid - water (3 : 1 : 1 : 1) as eluant to give, after evaporation of the appropriate fraction, the product (615 mg) as a white solid m.p. 192°-195° RF 3A 0.21 RF 3B 0.69 [α]D22 - 1.3° (c = 1, dimethylformamide)
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:2][CH3:1])[N:8]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1cccc(CCO)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cccc(CCOS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A mixture of 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (300 mg, 1.9 mmol), triethylamine (0.3 ml, 2.2 mmol), methanesulfonyl chloride (0.17 ml, 2.2 mmol), and dichloromethane (15 ml) was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried with sodium sulfate, filtered, and evaporated under vacuum to give a yellow oil. The crude product was chromatographed over silica gel to yield 300 mg (69%) of 2-[6-(Methylamino)-2-pyridyl]ethyl methylsulfonate. NMR 1H Cl3CD δ: 7.45 (dd, 1H, J=7.2, 8.4 Hz), 6.51 (d, 1H, J=7.2 Hz), 6.33 (d, 1H, J=8.4 Hz), 4.65 (t, 2H, J=6.4 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.92 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[C:17]([C:16]1[CH:22]=[N:1][C:2]2[C:7]([C:15]=1[OH:14])=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=2)([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(OC)c(OC)cc2c1O
Temperature: 165 °C

Procedure:
A mixture of 30.6 g of 4-aminoveratrole and 43.2 g of diethyl ethoxymethylenemalonate was heated at 100 for 2 h and at 165° C. for 0.75 h. The intermediate thus obtained was dissolved in 600 ml of diphenyl ether, and the resulting solution was heated at reflux temperature for 2 h, cooled, and diluted with hexane. The resulting solid was filtered, washed with hexane followed by ether, and dried to provide the tide compound as a brown solid, mp 275-285° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:30][CH3:31])[CH3:29])[CH:22]=3)[O:18][N:17]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])(C)(C)C>Cl>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:30][CH3:31])[CH3:29])[CH:22]=3)[O:18][N:17]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH3:33]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)CC)c3)n2)cc(C)c1CCC(=O)OC(C)(C)C
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)CC)c3)n2)cc(C)c1CCC(=O)O
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(ethyl-methyl-amino)-6-methyl-isonicotinic acid (106 mg, 0.459 mmol) and DIPEA (178 mg, 1.38 mmol) in DMF (2 mL) is added PyBOP (253 mg, 0.486 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (140 mg, 0.459 mmol) is added. Stirring is continued for 1 h at 0° C. The reaction mixture is diluted with water (2 mL) and sat. aq. NaHCO3-solution and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxyamidine ester intermediate; LC-MS: tR=0.92 min; [M+1]+=483.22. This material is dissolved in dioxane and then stirred at 80° C. for 15 h. The solvent is removed in vacuo to give crude 3-(2-ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid tert-butyl ester; LC-MS: tR=1.03 min; [M+1]+=463.31. The crude ester is dissolved in 6 N aq. HCl (10 mL) and stirred at 65° C. for 18 h. The mixture is concentrated and the crude product is purified by prep. TLC using DCM containing 11% of methanol as eluent to give 3-(2-ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (5 mg) as a yellow resin; LC-MS: tR=0.89 min; [M+1]+=409.19.