Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[N:7]2[CH2:8][CH2:9][S:10](=O)[C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:6]2=[C:5]([C:17]([O:19][CH3:20])=[O:18])[CH:4]=[C:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S(Cl)([Cl:29])=O>>[Cl:29][CH:9]1[CH2:8][N:7]2[CH2:2][C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:4][C:5]([C:17]([O:19][CH3:20])=[O:18])=[C:6]2[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[S:10]1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1S(=O)CC2
Reactant: O=S(Cl)Cl
Product: COC(=O)C1=C2c3sccc3SC(Cl)CN2CC(c2ccccc2)=C1

Procedure:
(aa) 15.7 g of methyl 5,6-dihydro-8-oxo-9-phenyl-8H-pyrido[1,2-d]thieno[2,3-f][1,4]thiazepine-11-carboxylate 4-oxide were added portionwise to 70 ml of thionyl chloride with the exclusion of moisture in such a manner that the temperature of the reaction solution is at about 35°. After completion of the addition, the mixture was stirred until the reaction was completed. The excess thionyl chloride was removed in vacuo and the residue was treated with 100 ml of water. The crystals were removed by filtration and dried, whereupon they were chromatographed on silica gel. By recrystallization from toluene, there was obtained methyl 5-chloro-5,6-dihydro-9-phenyl-8H-pyrido[1,2-d]thieno-[2,3-f][1,4]thiazepin-11-carboxylate as yellow crystals of m.p. 192°-196°.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:16])=[CH:11][C:12]([O:14][CH3:15])=[O:13]>CO.O>[CH3:9][C:10]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: NCc1ccccc1
Reactant: COC(=O)C=C(C)C
Solvent: O
Solvent: CO
Product: COC(=O)CC(C)(C)NCc1ccccc1
Temperature: 55 °C
Yield: 27.6 %

Procedure:
To a solution of benzylamine (10.0 mL, 91.6 mmol) in 95% MeOH-water (180 mL) was added methyl 3-methyl-2-butenoate (12.3 mL, 100.8 mmol). The solution was heated at 55° C. and stirred for 2 weeks. The solution was then cooled to room temperature, concentrated in vacuo, and the residue purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) to provide methyl 3-methyl-3-[(phenylmethyl)amino]butanoate (5.5893 g, 28%) as a pale yellow oil. LCMS: (M+H)+: 222.1.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[C:23]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43]C)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([N:31]1[CH2:32][CH2:33][N:34]([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[CH2:35][CH2:36]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=C(c1ccccc1)N1CCN(c2ccc(O)cc2)CC1
Yield: 76.7 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-benzoyl-4-(4-methoxyphenyl)piperazine (193 mg), and the resulting crude product was purified on TLC (developer, chloroform: acetone=4:1) to provide 1-benzoyl-4-(4-hydroxyphenyl)piperazine (141 mg).
Reaction SMILES: [CH:1]([NH:4][C:5](=O)[CH2:6][O:7][CH3:8])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.N1C(C)=CC=CC=1C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:37]2[C:38]([C:44]([NH:46][NH2:47])=O)=[N:39][C:40]([Cl:43])=[CH:41][CH:42]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1.CC#N>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH:36][C:37]2[C:38]([C:44]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([CH2:6][O:7][CH3:8])=[N:47][N:46]=3)=[N:39][C:40]([Cl:43])=[CH:41][CH:42]=2)(=[O:34])=[O:35])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COCC(=O)NC(C)C
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)nc2C(=O)NN)cc1
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: COCc1nnc(-c2nc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C(C)C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A 25 mL scintillation vial was charged with N-isopropyl-2-methoxyacetamide (132 mg, 1.0 mmol), POCl3 (0.19 mL, 2.0 mmol), 2,6-lutidine (0.30 mL, 2.4 M), and CH3CN (10 mL). The vial was sealed, heated to 40° C., and stirred for four hours. The volatiles were then evacuated in vacuo and to the residue was added 4-tert-butyl-N-(6-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide (193 mg, 0.5 mmol), DIPEA (2.0 mL), and dioxane (2.0 mL). The vial was sealed, heated to 130° C., and stirred for two hours. The volatiles was then evacuated in vacuo, and the residue was purified via automated silica gel chromatography and then preparative HPLC to afford 4-tert-butyl-N-[6-chloro-2-(4-isopropyl-5-methoxymethyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide as a white powder: MS (ES) M+H expected 478.2. found 478.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(Cl)(=O)=O.C(N(CC)CC)C.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[CH3:26])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Reactant: CCCCNC
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(C)Cc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (4.1 g, 16.8 mmol) in anhydrous methylene chloride (35 mL) at −30° C. is added methanesulfonyl chloride (1.82 mL, 23.5 mmol) followed by triethylamine (4.7 mL, 33.6 mmol). The reaction mixture is stirred for 45 min at 0° C., and then filtered. The filtrate is added to N-methylbutylamine (6 mL, 50.4 mmol) and stirred at room temperature for 16 h. The solution is concentrated under reduced pressure, and the residue is purified by flash column chromatography (silica, 8% ethyl acetate/hexanes) to give the title compound. ESI MS m/z 314.1 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].[CH2:5]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH:6]1[O:8][CH2:7]1>[Ag]>[C:10]([O:9][CH2:5][CH2:6][CH2:7][O:8][CH2:3][CH:2]=[CH2:1])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: C=CCO
Agent: [Ag]
Product: C=CCOCCCOC(=O)C(=C)C
Temperature: 55 °C

Procedure:
A mixture of 87 grams (1.5 mols) of allyl alcohol and 1 milliliter of boron trifluoride-diethyl etherate is heated to 55° C. in a reaction vessel provided with reflux condenser, thermometer and dropping funnel. To this mixture are constantly added 71 grams (0.5 mol) of methacrylic acid-glycidyl ester within 80 minutes. The reaction is exothermic. Subsequently the reaction mixture is rectified via a 40 centimeter silver-coated column, in which process 57 grams of unreacted allyl alcohol are at first distilled off at 25° C. and a pressure of 16 millibars. By a subsequent distillation at 0.3 millibar there are obtained 61.8 grams (61.8% of the theory) of (3-methacryloyloxy-propyl)-allyl ether having a boiling point of 99° C. and a refractive index nD20 =1.4120.
Reaction SMILES: C[C:2]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][CH2:11][C:12](Cl)=[O:13].O>C(O)(=O)C>[Cl:10][CH2:11][C:12]([NH:4][C:3]1[CH:2]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:13]
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCl)Nc1ccccc1
Yield: 80 %

Procedure:
In accordance with the present invention there is provided a method for the preparation of a scintillographic agent which comprises dissolving 2,4-dimethylaniline in acetic acid at room temperature, mixing the resulting solution with chloracetyl chloride under vigorous mixing. The solution then is kept several hours at a temperature of 4° C. The reaction mixture is poured into water with ice. The sediment is crystallized from alcohol and from post-crystallizatic bases, diluted in water, a further quantity of sediment is regained which gives a total yield 80 to 82 %. The ω-chloracetanilide produced in this way is dissolved, together with the sodium salt of iminodiacetic acid, in aqueous ethanol wherein the proportion by volume of water to ethanol is 1:1.2. The mixture is warmed during several hours under a water circulation cooler. After the evaporation of solvent, the dry sediment is dissolved in water, the non-reacted component is separated, and the residual water solution is adjusted to the pH value about 2.5. The precipitated sediment is dissolved in absolute ethanol, non-reacted component is separated and, after the evaporation of solvent, the derivative of iminodiacetic acid is crystallized from water at pH about 2.5. The yield is 25 to 35 %. Further, the derivative of iminodiacetic acid, produced in this way, is dissolved in water with a possible addition of stannous chloride in hydrochloric acid and the pH value is adjusted to 4 to 6 depending on the supplied chelating radiometal. The solution is then passed through a sterile filter, freeze-dried and stored in sterile ampoules fixed in nitrogen or filled at a reduced pressure. At least half an hour prior to an intravenous administration the sterile solution of pertechnetate 99 m Tc or another radiometal is added to the derivative of iminodiacetic acid. The scintillographic agent according to the invention is durable up to 24 hours.
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].C([O:23][C:24](=[O:26])[CH3:25])(=O)C>C(OCC)C>[C:2]([O:1][CH:2]([CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:25][C:24]([OH:23])=[O:26])[S:7]([CH3:10])(=[O:9])=[O:8])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)NCCCC(O)COc1ccc(F)cc1
Solvent: CCOCC
Product: CC(=O)OC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)COc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A mixture of 7-{N-[4-hydroxy-45-(4-fluorophenoxy)- pentyl]methanesulfonamido}heptanoic acid (12.3 g., 0.03 mole) (Example 1, Step E) and acetic anhydride (6.1 g., 0.06 mole) is kept at room temperature for 18 hours. This mixture is taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-{N-[4- acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}- heptanoic acid as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2cccc(Cl)c2nc1Cl
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of 2,8-dichloroquinoline-3-carboxaldehyde (43.0 g, 0.19 mol) in anhydrous THF (500 mL) was added titanium(IV) isopropoxide (114 mL, 0.38 mol) at r.t. After stirring for 15 minutes, (R)-2-methyl-2-propanesulfinamide (23.0 g, 0.19 mol) was added and stirring was continued for 17 h at r.t. Water (1 L) was added to the reaction mixture and the resulting precipitate was filtered and washed with DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound (61 g, 97%) as a pale yellow solid. δH (CDCl3) 9.11 (1H, s), 8.83 (1H, s), 7.93 (1H, dd, J 7.54, 1.31 Hz), 7.88 (1H, dd, J 8.22, 1.31 Hz), 7.55 (1H, t, J 7.88 Hz), 1.33 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)c1cnc(-c2ccc(Cl)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-[2-(4-chlorophenyl)thiazol-5-yl]ethanone (2.38 g, 10 mmol) in methanol (20 ml) at 0° C. is added sodium borohydride (379 mg, 10.5 mmol) in one portion. The resultant solution is allowed to warm to room temperature, and is then stirred at room temperature for 3 hours. The reaction is quenched with saturated aqueous ammonium chloride solution (200 ml) and extracted with chloroform (200 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuuo to give desired product as a brown solid (2.32 g)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH:8]([CH2:12][S:13]C(=O)C)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH:8]([CH2:12][SH:13])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(CC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CS)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.4 %

Procedure:
To a stirring solution of the crude compound of example 24 (6.87 g; 26.19 mmoles) in degassed methanol (270 mL) at room temperature was added drop wise a 10% aqueous solution of potassium carbonate (7.24 g; 52.38 mmoles). The mixture was stirred for three hours at room temperature. After complete consumption of the starting material (as confirmed by TLC: 30% ethyl acetate-70% hexanes), the reaction mixture was poured into degassed water (500 mL) and was extracted with degassed dichloromethane (2×200 mL) and then was acidified with a 10% aqueous hydrochloric acid solution. The aqueous layer was finally extracted with ethyl acetate (4×500 mL). The organic extracts were combined, dried (anhydrous MgSO4), filtered and evaporated to yield 8.10 g of the crude desired compound. This residue was used directly in the next step without any further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][OH:20])=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:20][CH2:19][C@@H:16]1[CH2:17][CH2:18][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@H]1CCN1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (5 ml) in dichloromethane (5 ml) was added to a stirred solution of (S)-N-tert-butoxycarbonyl-azetidin-2-ylmethanol (1.17 g, 6.25 mmol) in dichloromethane (8 ml) cooled to [5° C. under nitrogen. The reaction was stirred for 18 h with the temperature being allowed to rise slowly to RT. Solvent and excess acid were removed in vacuo to give the product (S)-2-hydroxymethylazetidine, trifluoroacetate salt as a viscous oil (1.26 g). Triethylamine (0.61 ml, 4.38 mmol) was added slowly to a solution of 0.19 g of (S)-2-hydroxymethylazetidine trifluoroacetate salt (0.94 mmol) and 2-fluorobenzoyl chloride (0.16 ml, 1.30 mmol) in dichloromethane (8 ml) cooled to ˜5° C. and under nitrogen. The reaction was stirred for 18 h with the temperature being allowed to rise slowly to room temperature. Water (15 ml) and dichloromethane (20 ml) were added and the layers were separated. The aqueous layer was washed with more dichloromethane (20 ml) and the combined organic layers were dried (MgSO4), filtered and solvent removed in vacuo. The crude residue was purified by chromatography on silica gel using ethyl acetate:petroleum ether (40/60) 1:1, as eluant giving (S)-N-(2-fluorobenzoyl)-2-hydroxymethylazetidine (0.15 g; 0.72 mmol) as a viscous oil, EIMS: m/z=192 f(M+H)-H2O]+
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]=1.[I:17]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.O.C1COCC1.C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([I:17])[C:13]([F:16])=[CH:12][N:11]=1
Reactant: II
Reactant: Fc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cnc(Cl)cc1I
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Lithium N,N-diisopropyl amide (2M THF/ethylbenzene/heptane solution) (2.9 ml) was mixed with THF (20 ml), and a THF (5 ml) solution containing 2-chloro-5-fluoropyridine (500 mg) was added to the mixture in a nitrogen atmosphere at −75° C., followed by stirring for 3 hours. Subsequently, a THF (5 ml) solution containing iodine (1.16 g) was added to the mixture, followed by stirring at −75° C. for 1 hour. Next, water/THF (2 ml/8 ml), water (10 ml), and a 3M sodium thiosulfate aqueous solution were added to the reaction solution at −75° C., −50° C., and −35° C., respectively. The reaction solution was adjusted to room temperature, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=20:1 to 10:1). A white solid of 2-chloro-5-fluoro-4-iodopyridine (457 mg) was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=CC3C4C(=C5C=CC(C6NC(C7CCCN7C(=O)C(NC(OC)=O)C(C)C)=NC=6)=CC5=CC=4)[O:27][CH2:26][C:25]=3[CH:59]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].FC(F)(F)S([O:66][C:67]1C=CC2[C:71]([CH:92]=1)=[CH:72][CH:73]=[C:74]1C=2OCC2C=C(OS(C(F)(F)F)(=O)=O)[CH:82]=[CH:83][C:75]1=2)(=O)=O>>[CH3:1][O:2][C:3](=[O:60])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:59]=[C:25]3[CH2:26][O:27][C:74]4[C:75]5=[C:92]([CH:71]=[C:72]([C:19]6[NH:20][C:16]([CH:12]7[CH2:13][CH2:14][CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:60])[CH:6]([CH3:7])[CH3:8])=[N:17][CH:18]=6)[CH:73]=4)[CH2:67][O:66][C:82]([CH:22]=2)=[C:83]35)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=S(=O)(Oc1ccc2c(c1)COc1c-2ccc2cc(OS(=O)(=O)C(F)(F)F)ccc12)C(F)(F)F
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare (1-{2-[5-(2-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6-H-dibenzo[c,h]chromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, substituting trifluoro-methanesulfonic acid 7-trifluoromethane sulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-yl ester for trifluoro-methanesulfonic acid 2-trifluoromethanesulfonyloxy-6-H-dibenzo[c,h]chromen-8-yl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH:13]3[CH2:19][CH2:18][C:17]4[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:14]3=[O:30])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:20]1[C:17]2[CH2:18][CH2:19][CH:13]([N:11]3[CH:12]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:37][C:34]5[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=5)[CH:3]=4)[N:9]=[N:10]3)[C:14](=[O:30])[N:15]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:16]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccncc1
Reactant: O=C1C(n2cc(-c3cccc(Cl)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C1C(n2cc(-c3cccc(Nc4ccncc4)c3)nn2)CCc2c(F)cccc2N1CC(F)(F)F

Procedure:
3-[4-(3-Chlorophenyl)-1H-1,2,3-triazol-1-yl]-6-fluoro-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (20 mg, 0.046 mmol), pyridin-4-amine 6.39 mg, 0.068 mmol), palladium(II) acetate (2.047 mg, 9.12 μmol), Xantphos (7.91 mg, 0.014 mmol), and cesium carbonate (44.6 mg, 0.137 mmol) were combined and dissolved in dioxane (912 μl). The reaction was irradiated in the microwave at 180° C. for 15 minutes. The completed reaction was filtered and concentrated in vacuo. Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% formic acid. Lyophilisation afforded 6-fluoro-3-{4-[3-(pyridin-4-ylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][CH2:9][CH2:10][N:11]=2)=[CH:3][CH:2]=1.[Ba]>C(Cl)Cl>[NH:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: c1cc(C2=NCCN2)ccn1
Agent: [Ba]
Solvent: ClCCl
Product: c1cc(-c2ncc[nH]2)ccn1
Reaction time: 24 h
Yield: 68.1 %

Procedure:
2-(4-pyridyl)-imidazoline (7.0 g, 0.047M) and barium mangnate (52.5 g) in CH2Cl2 (500 ml) were refluxed with stirring for 24 hrs. The reaction mixture was then filtered through diatomaceous earth, washed with methylene chloride and then ethylacetate. The combined filtrates were concentrated and crystallized from ethylacetate-petroleum ether to give 4-(1H-imidazol-2-yl)pyridine (4.7 g, 67% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O=[C:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:26][CH:28]2[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C1CC(C(=O)O)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1CC(Nc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (183 mg, 0.506 mmol) and 3-oxocyclobutanecarboxylic acid (63.5 mg, 0.557 mmol) in DCM (2.5 mL) and triethylamine (212 μl, 1.519 mmol) was added titanium(IV) chloride in DCM (0.759 ml, 0.759 mmol) at ambient temperature. The reaction mixture was concentrated, suspended in water, filtered, washed with water, and dried in a vacuum oven to give 3-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)phenyl)amino)cyclobutanecarboxylic acid as yellow solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.4 (M++H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[Br:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:27](=[O:28])[CH2:26][Br:25])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C(Cl)CBr
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)CBr)C1O
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of 180 mg (0.765 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 117 μl (0.842 m mol) of triethylamine and 20 ml of methylene chloride were added 73 μl (0.842 m mol) of bromoacetyl chloride with stirring at the room temperature, followed by further stirring for 1 hour. After the completion of the reaction, the precipitated crystal was filtered to obtain 199 mg of the intended compound. (yield: 73%).