Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH:11]1[CH2:13][CH2:12]1)=[N+:2]=[N-:3].O=[C:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].C[O-].[Na+]>CO.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[C:15]([CH3:21])=[C:16]([C:17]([OH:19])=[O:18])[N:3]=[N:2]2)=[C:5]([CH:11]2[CH2:13][CH2:12]2)[CH:6]=1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1C1CC1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)nnn1-c1ccc(Cl)cc1C1CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-azido-4-chloro-2-cyclopropylbenzene (204 mg, 1.054 mmol) and methyl 3-oxobutanoate (0.341 ml, 3.16 mmol) in MeOH (2 ml) was added sodium methoxide (5M in MeOH) (1.264 ml, 6.32 mmol) dropwise and the mixture was stirred at RT for 2.5 h. The mixture was heated at 50° C. for 5 hrs and then left to stir at RT for 16 hrs. The resulting mixture was diluted with water, extracted with diethylether (×2) and the organic extracts were discarded. To the aqueous layer was added 6M HCl (aq) until acidic and this was extracted with diethyl ether. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as an orange oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.Cl[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]=O>[C:16]([C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)([OH:18])=[O:17]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1-n1nc(C(=O)O)c2ccccc21
Yield: 30.3 %

Procedure:
3-Indazolecarboxylic acid (4.10 g), 3.90 g of 2-chlorobenzoic acid, 3.90 g of potassium carbonate and 0.18 g of copper(II) oxide were stirred in 150 ml of nitrobenzene at 170° to 180° C. for 3 hours. After cooling, 100 ml of water was added to the reaction mixture, and the insoluble substance was removed by filtration. The resulting solution was washed with chloroform, and the aqueous layer was decolored with active charcoal and then filtered. The filtrate was made acidic with 50 ml of 1N hydrochloric acid and then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from methanol-chloroform-ether to obtain 2.13 g (30.2%) of 1-(2-carboxyphenyl)-3-indazolecarboxylic acid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[Na+].O>CO>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(I)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1I
Temperature: 65 °C

Procedure:
A mixture of methyl 4-iodo-3-(methyloxy)benzoate (3.25 g, 0.011 mol), sodium hydroxide (0.48 g, 0.012 mol) and water (30 mL) in methanol (30 mL) was heated in an oil bath at 65° C. for 3 hr. The mixture was concentrated in vacuo to remove the methanol and the aqueous residue was chilled in an ice bath. Concentrated aqueous hydrogen chloride was added until the pH was acidic and the mixture was stirred at ice bath temperature. The resulting solid was filtered, washed with water and dried to give 4-iodo-3-(methyloxy)benzoic acid as a white solid, used without further purification. LC/MS (method A) tR 2.35 min; m/z 279 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)[CH3:10])[CH:6]=[CH:5][N:4]=1.[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH2:40])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:21]([O:25][C:26]([N:28]1[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]2[C:30](=[CH:31][C:32]([NH:40][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[NH:11][CH:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=3)[CH3:10])=[CH:33][CH:34]=2)[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CNc1nccc(C(C)Nc2ccccc2C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[1-(2-methylamino-pyrimidin-4-yl)-ethylamino]-benzoic acid (Step B, 800 mg, 2.94 mmol) in CH2Cl2 (40 mL) was added 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butylester (812 mg, 2.94 mmol), TBTU (1.0 g, 3.23 mmol), and DIEA (1.5 mL, 8.81 mmol). The reaction was stirred at RT under N2 for 20 h. The reaction was quenched with sat. NH4Cl, washed with water, brine, dried over MgSO4, and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with Hexanes:acetone mixture (80:20) gave final compound. MS m/z: 531.2 (M+H). Calc'd. for C30H37N6O3-531.66.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1)[CH2:28][NH:29][CH3:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:38]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([CH:27]([OH:26])[CH2:28][N:29]([CH2:20][C:18]2[S:19][C:12]3[C:11](=[O:23])[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=4)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=3[C:17]=2[CH3:22])[CH3:30])=[CH:32][CH:33]=1)(=[O:40])[CH3:39]
Reactant: CNCC(O)c1ccc(NC(C)=O)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 78.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), N-{4-[1-hydroxy-2-(methylamino)ethyl]phenyl}acetamide (Preparation 56)(42 mg, 0.20 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/DMF/water (5 mL/2 drops/1 mL, dissolved with warming, added water and then cooled to 0° C. overnight) gave the title compound (58 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]1([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:13]1([C:19]2[CH:20]=[N:21][N:22]([C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][N:12]=3)[CH:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-n1cc(-c2ccccc2)cn1
Temperature: 130 °C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
A mixture of 3.6 g of ethyl 2-chloronicotinate (19.4 mmol), 1.3 g of 4-phenylpyrazole (8.12 mmol), 4.4 g of K2CO3, 40 mg of 18-crown-6 and 30 mg of KI in 30 ml of N,N-dimethylformamide was stirred at 130° C. for 6 hours. For workup, H2O was added and, after extraction with ethyl acetate, the organic phase was washed with H2O and sat. NaCl solution. The crude product obtained after drying and concentration of the solution was purified by chromatography on silica gel (eluent: CH2Cl2/methanol 1-10%). In total, 1.9 g of an oil were obtained, which crystallized completely on standing in a refrigerator.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].C(OO)(=O)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]C=C)=[CH:14][CH:13]=1.O>ClCCl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:1]2[O:4][CH2:2]2)=[CH:14][CH:13]=1
Reactant: CC(=O)[O-]
Reactant: C=CCCc1ccc(Br)cc1
Agent: CC(=O)OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(CCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 156 %

Procedure:
To a sample of sodium acetate (2.50 g, 30.48 mmol, 0.63 equiv) under a N2 atmosphere was added a 32% solution (in dilute aqueous acetic acid) of peracetic acid (50 mL, 18.08 g, 237.74 mmol, 4.92 equiv). The mixture was stirred at rt for 10 min to completely dissolve the NaOAc. This peroxide solution was then added dropwise over a period of 5 min to a solution of alkene 11a (10.20 g, 4832 mmol, 1 equiv) in dichloromethane (100 mL) at rt. The mixture was heated at reflux temperature with stirring for 3 h. Monitoring by TLC (silica gel, hexanes) confirmed the completion of the reaction. Water (100 mL) was added and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (3×100 mL), and the combined organic extracts were washed sequentially with a saturated solution of sodium hydrogencarbonate (2×), and brine, dried over anhydrous Na2SO4, and then concentrated. High-vacuum drying afforded the epoxide 12a (10.80 g, 47.56 mmol, 98%) as a clear oil: Rf˜0.2 (hexanes); 1H NMR (400 MHz, CDCl3): δ 1.73-1.92 (m, 2H), 2.45-2.49 (4-tet, 1H), 2.66-2.82 (m, 3H), 2.90-2.96 (m, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 31.8, 34.2, 47.3, 51.7, 119.9, 130.3, 131.6, 140.3; HRMS (EI) Calcd. for C10H11BrO: 225.9993 (M+). Found: 225.9996.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([O:22][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(-c2nc(OCC(=O)N(C)C)nn2-c2ccc(OC)cc2)cc1
Yield: 72.6 %

Procedure:
2-{[1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl]oxy}-N,N-dimethylacetamide (467 mg, 72.6% yield) was prepared from 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol and 2-chloro-N,N-dimethylacetamide by the similar manner described for Example 18.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)C=CC=CC=1.[Cl:31][CH2:32][CH2:33][O:34][CH2:35]Cl>CN(C=O)C>[Cl:31][CH2:32][CH2:33][O:34][CH2:35][N:15]1[C:14]2[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]=2[N:8]=[CH:16]1
Reactant: ClCCOCCl
Reactant: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Nc1nc2ncn(COCCCl)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 6 (1.77 g, 4.49 mmol) in DMF (30 mL) was added (2-chloroethoxy)methyl chloride (0.65 g, 5.0 mmol). The reaction mixture was stirred at 25° C. for 8.0 h. The solution was then partitioned between EtOAc (100 mL) and water (100 mL). The EtOAc solution was washed with water (4×100 mL); then it was dried over MgSO4 (s) and filtered. Evaporation under reduced pressure and purification of the residue by use of column chromatography (EtOAc) afforded 7 (1.07 g, 4.39 mmol) in 88%: mp>280° C. (dec.); Rf(hexanes/EtOAc=1:2) 0.20; UV (EtOH) λmax 288 (ε 15,100); 1H NMR (DMSO-d6) δ 3.67 (t, J=6.10 Hz, 2 H, CH2Cl), 3.75 (t, J=6.10 Hz, 2 H, OCH2), 5.62 (s, 2 H, H2C1′), 6.15 (s, 2 H, NH2), 7.58 (s, 1 H, NH), 8.16 (s, 1 H, HC8); 13C NMR (DMSO-d6) δ 43.39 (CH2Cl), 68.50 (OCH2) 74.71 (C1′), 107.71 (C5), 143.87 (C8), 153.15 (C4), 154.37 (C2), 159.12 (C6); MS m/z 243 (M+, Cl-cluster). Anal (C8H10ClN5O2) C, H, N, Cl; calcd (%): 39.43, 4.14, 28.74, 14.56; found (%): 39.38, 4.13, 28.70, 14.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C:7](=[NH:15])[CH:8](OCC)OCC.S(=O)(=O)(O)O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:16]([CH:8]=[C:7]([NH2:15])[N:6]=[CH:5]2)=[CH:17][CH:18]=1.[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]2[C:3]=1[CH:8]=[C:7]([NH2:15])[N:6]=[CH:5]2
Reactant: CCOC(OCC)C(=N)NCc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cc2c(Cl)cccc2cn1
Product: Nc1cc2ccc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a flask was placed N-(3-chlorobenzyl)-2,2-diethoxyacetimidamide (1.9 g, 7.02 mmol) and sulfuric acid (14 mL, 263 mmol). This was stirred at room temperature for 24 hours. The reaction was then neutralized to pH 9 using 10 N NaOH. The resulting precipitate was dissolved in dichloromethane and the water layer was washed with dichloromethane. The organic layers were combined and concentrated to give the above regioisomers (1.1 grams, 6.1 mmol, 88%) in a 2:1 ratio of 7-chloroisoquinolin-3-amine to 5-chloroisoquinolin-3-amine. This regioisomer mixture is carried on without further separation. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (s, 1H) 8.81 (s, 2H) 7.90 (d, J=2.26 Hz, 2H) 7.82 (d, J=8.28 Hz, 1H) 7.65 (dd, J=7.28, 1.00 Hz, 1H) 7.58 (d, J=9.03 Hz, 2H) 7.44 (dd, J=9.03, 2.26 Hz, 2H) 7.07-7.19 (m, 1H) 6.83 (s, 1H) 6.64 (s, 2H) 6.28 (s, 2H) 6.05 (s, 4H) LC/MS R.T=0.955 mins, [M+H]=181.03
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].Cl>C(Cl)Cl>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])=[O:25]
Reactant: O=C(Cl)CCCl
Reactant: NC(=O)c1c(N)sc2c1CCCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 2 h
Yield: 78.9 %

Procedure:
2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (250 mg, 1.28 mmol) and triethylamine (0.18 mL, 1.28 mmol) were stirred in DCM (5 mL). 3-chloropropionylchloride (162 mg, 1.28 mmol) was added dropwise under a nitrogen atmosphere. Stirring was continued for 2 h. 2 M HCl (20 mL) was added and the reaction mixture extracted into DCM (3×50 mL). The combined DCM layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to give the desired product as a yellow solid (290 mg, 1.01 mmol, 79%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][O:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CO)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(COS(C)(=O)=O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 124.9 %

Procedure:
To a solution of {4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methanol (971 mg, 2.72 mmol) in DCM (40 mL), DIPEA (526 mg, 4.07 mmol) and methanesulfonyl chloride (373 mg, 3.26 mmol) is added. The reaction mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM. The combined organic extracts are dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (1.48 g) as an orange solid containing {5-[3-(4-chloromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine; LC-MS: tR=0.58 min; [M+1]+=436.11. b) A solution of the above crude methanesulfonic acid 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzyl ester (248 mg, 0.569 mmol) in 7 N NH3 in methanol (10 mL) is stirred in a sealed vial at 80° C. for 16 h. The solvent is removed in vacuo and the residue is dissolved in EA and washed with brine and water. The organic extract is dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 5% of 7N NH3 in methanol to give the title compound (137 mg) as a pale yellow oil; LC-MS: tR=0.38 min; [M+1]+=357.30; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.0 Hz, 4H), 3.73 (s, 2H), 3.98 (s, 2H), 7.47 (d, J=7.8 Hz, 2H), 7.67 (s, 1H), 8.13 (d, J=7.5 Hz, 2H).
Reaction SMILES: [Al](Cl)(Cl)Cl.[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>ClCCl.C(OCC)C>[F:12][C:13]1[CH:18]=[C:17]([C:5](=[O:11])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Fc1ccccc1F
Reactant: O=C1C=CC(=O)O1
Agent: Cl[Al](Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)/C=C/C(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
Aluminum chloride anhydrous (32.6 g, 0.245 mol.) was added at room temperature and under dry nitrogen atmosphere, to a solution of maleic anhydride (9.6 g, 0.098 mol.) and difluorobenzene (20 ml, 0.195 mol.) in dry dichloromethane. The reaction mixture was heated to reflux for 4 hours; then cooled and quenched with ice/37% hydrochloric acid (100 g/100 mL). Dichloromethane (200 mL) was added, the phases separated and the aqueous layer was extracted twice with dichloromethane (50 mL), the collected organic extracts were washed with 2N HCl and then with brine. The resulting solution was dried (Na2SO4) and evaporated in vacuo to provide the crude product, as deep yellow oily material, which was dissolved in diethyl ether (60 mL). The organic phase was extracted with saturated sodium bicarbonate solution (150 mL), the collected aqueous layers were washed with diethyl ether and cooled at 0° C., then to the alkaline aqueous solution, 37% hydrochloric acid was added on stirring until the pH was 2. The obtained suspension was extracted with ethyl acetate (3×100 mL); the collected organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to provide a yellow solid (11 g). Crystallisation from toluene provided the pure titled compound (7.6 g, 40%) melting at 107-108° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:11]3[CH:12]=[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3cccnc3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
In EtOH (15 ml), pyridine-3-aldehyde (0.63 g, 5.89 mmol) and methyl 4-amino-3-hydroxyphenylacetate (1.06 g, 5.85 mmol) were stirred at room temperature for 20 hours. To the reaction mixture was added iodobenzene diacetate (2.26 g, 7.02 mmol), followed by stirring at room temperature for 20 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (1:1, v/v) eluate fractions, methyl (2-(3-pyridyl)-6-benzoxazolyl)acetate (360 mg, 23%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:28]([OH:40])(=[O:39])[CH2:29][C:30]([CH2:35][C:36]([OH:38])=[O:37])([C:32]([OH:34])=[O:33])[OH:31]>>[C:28]([CH2:29][C:30]([CH2:35][C:36]([OH:38])=[O:37])([OH:31])[C:32]([O-:34])=[O:33])([OH:40])=[O:39].[C:1]12([C:11]3[CH:27]=[CH:26][C:14]([O:15][CH2:16][C:17]([N:19]4[CH2:24][CH2:23][NH+:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: C[NH+]1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Product: O=C(O)CC(O)(CC(=O)O)C(=O)[O-]
Yield: 94.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone (1.0 g, 2.7 mmol), prepared from the example 3, and citric acid (0.52 g, 2.7 mmol) according to the example 43, which was given 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)-1-methylpiperazin-1-ium 3-carboxy-2-(carboxymethyl)-2-hydroxypropanoate as a crystalline white solid (1.43 g, 94% yield).
Reaction SMILES: Br.[NH2:2][C@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][C@H:28]([NH:43]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[C:29](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:30])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:10]=[C:9]1[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@@H:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:3]1[NH:2][C:29](=[O:30])[C@H:28]([CH2:27][C:24]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=1)[NH2:43]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,3S)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (91 mg) in 10 mL of THF was added Fmoc-Phe-Opfp (185 mg) followed by DIEA (58 μL). The reaction mixture was stirred for 30 min and treated with DBU (0.1 mL) and stirred for 10 min. The material thus produced was used in the next step without purification or characterization.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Product: CN1CCN(c2ccc(Nc3nc4cccc(-c5cccc(S(C)(=O)=O)c5)n4n3)cc2)CC1

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75 mg, 0.26 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (73 mg, 0.28 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine