Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:20]=[N:19][CH:18]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:43][CH:44]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:25]3)[CH:20]=[N:19][CH:18]=2)[CH:42]=[N:43][CH:44]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cncc(-c2ccc3c(c2)c(-c2cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n2)nn3C2CCCCO2)c1
Temperature: 120 °C
Yield: 59.2 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl (3R)-3-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.100 g, 0.179 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (0.084 g, 0.358 mmol, Sigma-Aldrich), trans-dichlorobis(triphenyl-phosphine)palladium (II) (10.05 mg, 0.014 mmol) and Na2CO3 (0.095 g, 0.895 mmol) in dioxane (0.7 mL) and Water (0.175 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 20 min. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl (3R)-3-((6-(5-(5-methoxy-3-pyridinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.062 g, 0.106 mmol, 59.0% yield) as a brown oil. MS (ESI, pos. ion) m/z: 587.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[Br:22][CH2:23][C:24]([N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:25]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CN[C@@H](C)CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)CBr)[C@@H](C)CO)cc1
Temperature: -21 °C

Procedure:
Into a 20000 mL 4-necked, round bottomed flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (S)-2-(4-methoxybenzylamino)propan-1-ol (300 g, 1.54 mol) in dichloromethane (12000 mL) and triethylamine (155.8 g, 1.54 mol). 2-Bromoacetyl bromide (310.8 g, 1.54 mol) was added dropwise, while cooling to a temperature of −17 to −25° C. and maintained at this temperature for 4 hours. The reaction mixture was warmed to room temperature and washed three times with 2000 mL of water, dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[CH3:21].C1(C)C=CC=CC=1>[Pt].CC(O)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]=1[NH:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OCCNc1c(C)c(C)n2nnnc2c1[N+](=O)[O-]
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(=O)OCCNc1c(C)c(C)n2nnnc2c1N
Yield: 91.3 %

Procedure:
A Parr vessel was charged with acetic acid 2-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]ethyl ester (50.0 g, 170 mmol), 5% platinum on carbon (5.00 g), toluene (600 mL), and 2-propanol (50 mL) and purged with nitrogen. The vessel was then placed under hydrogen pressure (20 psi, ) for 20 hours at room temperature. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with 90:10 dichloromethane:methanol. The filtrate was concentrated under reduced pressure to provide a dark gray solid, which was triturated with diethyl ether, isolated by filtration, and dried to provide 41.0 g of acetic acid 2-[(8-amino-5,6-dimethyltetrazolo[1,5-a]pyridin-7-yl)amino]ethyl ester as a light gray solid.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH3+:10])=[CH:5][CH:4]=1.[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCCC1.O.[Cl-].[Na+].O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: [NH3+]Cc1ccc(Br)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(Br)cc1)OCc1ccccc1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
In a 500 mL round bottomed flask, equipped with a magnetic stir bar, (4-bromophenyl)methanaminium chloride (10.0 g, 44.9 mmol) and sodium hydroxide (4.00 g, 100 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL). The solution was cooled in an ice water bath, and benzyl chloroformate (7.06 mL, 49.4 mmol) was added dropwise. The reaction was allowed to stir for 1 hour. The reaction was poured into a brine solution and extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound as a white solid (14.8 g, 102%): 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J=6.0 Hz, 1H), 7.64-7.53 (m, 2H), 7.47-7.33 (m, 5H), 7.32-7.20 (m, 2H), 5.10 (s, 2H), 4.23 (d, J=6.2 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 156.33, 139.20, 137.05, 131.10, 129.22, 128.33, 127.72, 119.77, 65.42, 43.19; ESIMS m/z 320, 322 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.C(O)C.[OH-].[Na+]>CC(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 68.1 %

Procedure:
To a solution of ethyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.54 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.074 g, 0.50 mmol) in 2-propanol (2.5 mL), 2M hydrochloric acid in ethanol (0.25 mL, 0.50 mmol) was added at ambient temperature then refluxed for 24 h. Cooled with ice bath, aqueous 2M sodium hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to neutralize and the mixture was refluxed for 1 h. The precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.14 g, y. 69%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[O:35][CH3:36])[C:8](=[O:11])[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[F:1][C:2]([F:44])([F:45])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([C:29](=[O:34])[C:30]([F:31])([F:32])[F:33])[CH:26]=[CH:25][C:24]=1[O:35][CH3:36])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(O)C(F)(F)F)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(=O)C(F)(F)F)ccc1OC

Procedure:
Methyl [3,5-bis(trifluoromethyl)benzyl]{[2′-methoxy-5′-(2,2,2-trifluoro-1-hydroxyethyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 139, 29 mg, 0.048 mmol) was dissolved in methylene chloride, and Dess-Martin periodinane (31 mg, 0.072 mmol) was added. Once the reaction was complete, the solution was diluted in diethyl ether and washed sequentially with saturated sodium thiosulfate, saturated sodium bicarbonate and water. The aqueous extracts were combined and back extracted with diethyl ether, then recombined with the previous organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 1:3 acetone:hexane.
Reaction SMILES: C(O[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14]([CH:5]=[CH:6][CH2:7][CH:8]2[CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CCC2OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(CCNC(C)=O)CC=C2
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the compound obtained in Step D (261 mg, 0.86 mmol) in a mixture of methanol/water (2/0.2 mL) at ambient temperature there is added sodium hydroxide (86 mg, 2.14 mmol). The mixture is stirred for 1 hour under reflux, and the solution is then cooled. Hydrochloric acid (2.6 mL, 2.6 mmol, 1N) is added and the mixture is stirred overnight. The aqueous phase is extracted with dichloromethane, and the organic phases are washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated. The title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then ethyl acetate-methanol: 90-10) in the form of an oil in a yield of 61%.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16](Cl)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]1[CH2:34][O:33][CH:32]2[CH:27]([CH2:28][CH2:29][NH:30][CH2:31]2)[O:26]1>C(OCC)(=O)C>[CH2:25]1[CH2:34][O:33][CH:32]2[CH:27]([CH2:28][CH2:29][N:30]([C:16]([CH:6]3[C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=4[CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]3=4)=[O:17])[CH2:31]2)[O:26]1
Reactant: C1CC2OCCOC2CN1
Reactant: O=C(Cl)C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(C1c2ccccc2CCc2ccccc21)N1CCC2OCCOC2C1
Reaction time: 8 h

Procedure:
To a stirred solution of 10.9 parts of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carboxylic acid chloride is added 4 parts of anhydrous sodium carbonate and then 6.1 parts of 4-(ethylenedioxy)piperidine. The mixture is stirred overnight and then diluted with ethyl acetate. Sodium carbonate is removed by filtration, the filtrate is washed with 1.2 N hydrochloric acid, 15% aqueous sodium hydroxide, and brine, dried with magnesium sulfate and concentrated to give 4-(ethylenedioxy)-1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)carbonyl]piperidine, as a white solid melting at about 148.5°-149.5° C. after recrystallization from cyclohexane. This compound has the following structural formula ##STR23##
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([CH3:17])(O)[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=2[CH2:6]1.S(=O)(=O)(O)O.[OH-].[K+]>C(Cl)Cl>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[CH2:17])[C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]=2[CH2:6]1
Reactant: CN(C)CCC1Cc2ccccc2C(C)(O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: C=C1c2ccccc2CC(CCN(C)C)c2ccccc21

Procedure:
A mixture of 8 g. (0.027 mole) of 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol and 250 ml. 2M-sulfuric acid is refluxed for 2 hours. The mixture is cooled in ice and made basic by the addition of solid potassium hydroxide. The mixture is extraced with methylene chloride. The methylene chloride is washed with water, dried over anhydrous magnesium sulfate and evapored in vacuo. The oily residue is distilled at 140° C/0.5 mm and the distillate is dissolved in ethanol. The resulting precipitate is filtered and recrystallized from diethylether-ethanol 1:1 to give the product 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene, m.p. 171° to 172 C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:27])[F:28])=[CH:21][CH:22]=2)[N:3]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Solvent: CCCCO
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCOC2)cc1
Yield: 23.4 %

Procedure:
The operation is carried out as in Stage 2 of Example 2 starting from 200 mg (0.77 mmoles) of the product obtained in Stage 1 of Example 2 and 3 ml of butanol and using 0.130 ml of 4-(trifluoromethoxy)-benzenamine (0.96 mmoles) in place of the benzylamine. In this way 72 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[F:27][C:24]([F:25])([F:26])[O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by hydrolysis of 23f using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH2:12][CH2:11]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NCC1CCC(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dimethylsulfamoyl chloride (one mol-equivalent, ClSO2N(CH3)2) was added to a stirred solution of 1,4-bis-aminomethylcyclohexane (3 mol-equivalents) and diisopropylethylamine (1 mol-equivalent) in dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 24 hours, concentrated under reduced pressure and chromatographed (silica) to give the desired product as viscous oils. (Scheme 1A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16](Cl)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1.CN(C)C=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[N:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:14]=2[CH:26]=1
Reactant: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccc(C)cc3)c2c1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCOc1ccc2nc(N3CCCCC3)n(-c3ccc(C)cc3)c2c1
Temperature: 110 °C
Reaction time: 7.5 h

Procedure:
240 mg of 6-[[2-chloro-1-(4-methylphenyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 0.2 ml of N,N-dimethylformamide and 0.75 ml of piperidine, and the mixture was stirred for 7.5 hours at 110° C. Another 0.75 ml of piperidine was added, and it was heated for another 4 hours at 110° C. It was mixed with water, extracted with ethyl acetate, the organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 16 mg was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][CH:30]=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([CH:19]([CH3:20])[CH3:21])=[CH:23][CH:24]=3)[S:29][CH:30]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CC(C)c1ccc(-c2nc(CCO)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(C(C)C)cc3)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethanol in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-isopropyl-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[O:26][C:27]([CH3:30])=[CH:28][CH:29]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(C)NCC3)o1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1ccc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Br)cn4n2)CC3)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: ClCCCl.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:19]([N:26]1[CH2:29][CH:28]([C:30](O)=O)[CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[SH:40]>C(Cl)Cl>[C:22]([O:21][C:19]([N:26]1[CH2:29][CH:28]([C:30]2[S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=2)[CH2:27]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1ccccc1S
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3s2)C1
Temperature: 80 °C

Procedure:
To 10 mL DCE was added 533 mg (3.7 mmol) phosphorus pentoxide and 1.57 mL (7.36 mmol) bis-trimethylsilyl ether and the mixture was heated at 80° C. for 15 minutes. 0.19 g (0.92 mmol) N-boc-azetidine-3-carboxylic acid and 108 μL (1.01 mmol) 2-aminothiophenol were added and the mixture heated at 85° C. for 20 minutes. After cooling to room temperature the mixture was diluted with 20 mL DCM and washed with 1 M Na2CO3 (2×10 mL). The organic layer was dried with Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[C:18]([Br:19])=[C:17]([N+:20]([O-:22])=[O:21])[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[C:23](Cl)=[O:24]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:23]([C:10]2[C:11]3[O:16][CH2:15][CH2:14][O:13][C:12]=3[C:17]([N+:20]([O-:22])=[O:21])=[C:18]([Br:19])[C:9]=2[Br:8])=[O:24])[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2c(Br)c(Br)c([N+](=O)[O-])c3c2OCCO3)CC1
Temperature: 10 °C
Yield: 69.5 %

Procedure:
400 ml of methylethylcetone and 11 g of methylpiperazine were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 10° C. and then 41 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were added in portions with the temperature being maintained below 20° C. After agitation of the mixture, the crystals were dried off, washed with methylethylcetone and dried and then dissolved in water and reprecipitated by addition of 50 ml of 20% ammonia. The crystals were dried off, washed with water and dried. 33 g of 5-[(4-methyl-1-piperazinyl)-carbonyl]-6,7-dibromo-8-nitro-1,4-benzodioxane were obtained (M.P.: 164° C.; yield: 69.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=[O:8].[CH2:12](Cl)Cl.CO.C[Si](C=[N+]=[N-])(C)C>CCOCC>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([O:9][CH3:12])=[O:8]
Reactant: ClCCl
Reactant: Cc1c(Br)cncc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cncc(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 5-bromo-4-methylnicotinic acid (223.4 mg, 1.034 mmol) in methylene chloride (3.0 mL, 47 mmol) and methanol (3.0 mL, 74 mmol) was added 2.0 M of trimethylsilyldiazomethane in ether (0.70 mL). The reaction mixture was stirred at room temperature for one hour, and then 2.0 M of trimethylsilyldiazomethane in ether (0.50 mL) was added. After an additional two hours, the crude reaction mixture was evaporated in vacuo to yield 237.2 mg (100%) of methyl 5-bromo-4-methylnicotinate which was carried forward without further purification. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.82 (s, 1H), 3.89 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[CH2:40][C:41]([NH:43][C@@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42]>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:40][C:41]([NH:43][C@@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reactant: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CN)C(N)=O
Product: CSCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 59 %

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (Example 1, 0.93 g.) and HGly-DLeu-MetNH2 (0.63 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-DLeu-MetNH2 in 59% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-DLeu-MetNH2 (0.88 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-DLeu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt in 59% yield.