Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:29]=[C:24]1[NH:25][C:26](=[O:28])/[C:27](=[CH:1]\[C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][O:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:5][CH:4]=2)/[S:23]1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)c1ccc(OCCOc2ccc(C=O)cc2)cc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of 355 (1.59 g, 3.86 mmol) in toluene (10 mL) was added thiazolidine-2,4-dione (542 mg, 4.63 mmol), benzoic acid (61.3 mg, 0.50 mmol) and piperidine (57 μL, 0.58 mmol). The resultant mixture was refluxed with the Dean-Stark adapter for ½ h and cooled to the room temperature. A precipitate formed which was collected by filtration to afford the title compound (1.41 g, 92%). 1H NMR: (DMSO-d6) δ (ppm): 7.90 (d, J=8.8 Hz, 2H), 7.73 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.08 (d J=8.8 Hz, 2H), 4.42 (bs, 4H), 3.80 (s, 3H). LRMS (ESI): (calc.) 399.1; (found) 400.0 (MH)+.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19](=O)[CH:20]([CH3:22])[CH3:21].[CH3:24][O-:25].[Na+]>C(OCC)(=O)CC>[CH:20]([CH:22]1[C:24](=[O:25])[C:10]2[C:14]([C:13]([O:12][CH3:11])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=2[NH:8][CH:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:21])[CH3:19]
Reactant: CC(C)C=O
Reactant: O=C1OCc2c(N=Cc3ccccc3)cccc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: COC(=O)c1cccc2c1C(=O)C(C(C)C)C(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
4-(benzylideneamino)isobenzofuran-1(3H)-one (237 mg, 1 mmol), isobutyraldehyde (216 mg, 3 mmol), sodium methanolate (162 mg, 3 mmol) and ethyl propionate (20 mL) were added and the mixture was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 5:1). 35 mg of solid methyl-3-isopropyl-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate was obtained. (yield: 11%). LC-MS (ESI) m/z: 308 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH2:11].FC(F)(F)C(O)=O.COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](CC1C=CC(OCC2C=CC=CC=2)=CC=1)N.[C:76]([O:80][C:81]([NH:83][C@H:84]([C:94](O)=[O:95])[CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:82])([CH3:79])([CH3:78])[CH3:77].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH:11][C:94](=[O:95])[C@H:84]([CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:77])[CH3:78])=[O:82]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Nα -t-Butoxycarbonyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester trifluoroacetic acid salt by neutralizing to litmus with triethylamine in the cold and then adding 1.4 ml. (10 mmol) of additional triethylamine (pH 8.5). The cold solution is treated with 2.95 g. (10 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-serine, 1.35 g. of 1-hydroxybentriazole and 2.2 g. of dicyclohexylcarbodiimide. The mixture is stirred for two and one-half hours at -5° C. and overnight at room temperature. The mixture is filtered, the solid rinsed with dimethylformamide and the filtrate evaporated at 40° C. under reduced pressure. The residue is dissolved in 50 ml. of ethyl acetate and 200 ml. of ether and washed three times with 5% sodium bicarbonate solution and with saturated salt solution, dried over magnesium sulfate and evaporated. The residue is crystallized from a minimum of methanol by adding ether; 6.6 g. The product is recrystallized from methanol-ether; 6 g.; m.p. 67°-71° C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=C.[CH2:11](C1C=CC=CC=1CC)[CH3:12].[CH2:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=1)[CH3:22]>>[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][CH:24]=1)=[CH2:22].[CH2:11]([CH:10]=[CH:9][C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:12]
Reactant: CCc1ccc(CC)cc1
Reactant: C=Cc1ccccc1C=C
Reactant: CCc1ccccc1CC
Product: C=Cc1ccc(C=C)cc1
Product: CCC=Cc1ccccc1

Procedure:
Divinylbenzene can be prepared by the dehydrogenation of diethylbenzene. For example, there is a description in EP 0217492 A1 that the dehydrogenation of para-diethylbenzene with a purity of 93% in the presence of an alkaline dehydrogenation catalyst at a temperature of 620° to 630° C. and at a steam to diethylbenzene ratio (hereinafter referred to as S/D ratio) of 2 to 4 (by weight) occurred at a conversion of approximately 80% to yield approximately 38% by weight of para-divinylbenzene and approximately 30% by weight of para-ethylvinylbenzene. Another description is found in Japan Kokai Tokkyo Koho No. Sho 62-45,542 (1987) that diethylbenzene was dehydrogenated to divinylbenzene at a conversion of approximately 78% with a selectivity (mol) to divinylbenzene of approximately 55% under the conditions where the inlet temperature of the catalyst layer was 620° C., the LHSV based on diethylbenzene was 1 hr-1 and the S/D ratio was 3.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]I>CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH3:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To an ice cold solution of 1-benzhydrylazetidin-3-ol 9a (1.0 g, 4.2 mmole) in DMF (10 ml) was added 60% dispersion NaH in mineral oil (0.25 g, 6.3 mmole). After 30 min at 0° C., 5 ml more DMF was added along with methyl iodide (0.39 ml, 6.3 mmole). The ice bath was removed, and the reaction was stirred at room temperature (rt). After 1.5 hr, the reaction was poured into brine and extracted with Et2O (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed on silica gel eluting Hexanes/EtOAc (1:1) to give 919 mg (92%) of a colorless oil which crystallized on standing. 1H NMR (DMSO-d6) δ 7.42 (4H, d, J=7.3 Hz), 7.27 (4H, t, J=7.3 Hz), 7.13 (2H, t, J=7.3 Hz), 4.39 (1H, s), 3.95 (1H, p, J=5.8 Hz), 3.35 (2H, t, J=6.3 Hz), 3.11 (3H, s), 2.75 (2H, t, J=5.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[C:5]([CH3:18])[C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[Cl:28][CH2:29][C:30]([NH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][C:5]=1[CH3:18])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCCOc1cc(C)c(N)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCOc1cc(C)c(NC(=O)CCl)c(C)c1

Procedure:
Under a nitrogen atmosphere, 2,6-dimethyl-4-(octyloxy)-aniline (7.2 mmols) was dissolved in 50 mL dichloromethane. To this was added DIPEA (9.4 mmols). The reaction mixture was cooled in an ice bath, and chloroacetyl chloride (7.95 mmoles) dissolved in 50 mL dichloromethane was added by dropping funnel. After the addition was complete, the reaction was stirred at room until reaction was complete by TLC (approximately 0.5 hours). The reaction mixture was concentrated, and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3(×2), brine, dried over MgSO4, and filtered (rinsing with ethyl acetate). The filtrate was concentrated to yield 2-chloro-N-(2,6-dimethyl-4-octyloxyphenyl)-acetamide as a white solid (1.21 grams; 51%). The product was characterized by NMR (DMSO).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[NH2:16].[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:17]1[CH2:18][CH3:19]
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCl
Yield: 71.2 %

Procedure:
Using the general method of Example 1 Part D, N4-(3-chloropropyl)quinoline-3,4-diamine (˜37.6 mmol) was cyclized using triethyl orthopropionate (7.96 g, 45.2 mmol) in the presence of pyridine hydrochloride (0.43 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.33 g of 1-(3-chloropropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:17])[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([CH3:10])[C:8]=1[CH3:9])([CH3:3])[CH3:2].[Br:18]Br>O1CCOCC1.O.CCOC(C)=O>[Br:18][CH2:9][C:8]1[N:7]([CH3:10])[N:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5](=[O:17])[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: Cc1c(C(C)C)c(=O)n(-c2ccccc2)n1C
Reactant: BrBr
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 4-isopropyl-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (0.8 g) in a round bottom flask under argon in dioxane (15 mL) was added bromine (0.55 g). The reaction was stirred at ambient temperature for 5 hours. The reaction was diluted with water and EtOAc and the phases were separated. The aqueous phase was extracted with more EtOAc and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified via ISCO combiflash chromatography (EtOAc/heptane) to afford the desired 5-bromomethyl-4-isopropyl-1-methyl-2-phenyl-1,2-dihydro-pyrazol-3-one as a light brown solid. MS (ESI+): 309.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.I[C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1.[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1>>[CH3:33][C:31]1[N:32]=[C:28]([NH:27][C:2]2[N:3]=[CH:4][C:5]([C:17]3[CH:22]=[N:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[S:29][CH:30]=1
Reactant: FC(F)(F)c1cncc(I)n1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cc1csc(N)n1
Product: Cc1csc(Nc2ncc(-c3cncc(C(F)(F)F)n3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=403.3 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 2-iodo-6-trifluoromethyl-pyrazine (Example O) and 2-amino-4-methylthiazole.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].C[OH:8].[CH2:9]([S:17][C:18]1[N:23]=[N:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:40])[F:39])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[C:11]1([CH2:10][CH2:9][S:17]([C:18]2[N:23]=[N:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)=[O:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(SCCc3ccccc3)nn2)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(S(=O)CCc3ccccc3)nn2)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To an ice-cold solution of sodium periodate (0.025 g, 0.12 mmol) in 1:1 mixture of water and methanol was added [4-(6-phenethylsulfanylpyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone. The reaction mixture was stirred at room temperature over night, diluted with water and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous MgSO4 and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (41 mg, 69.2%). 1H NMR (400 MHz, CDCl3) δ 7.86, 7.75, 7.63-7.66, 7.56-7.59, 7.37, 7.25-7.28, 7.21-7.17, 7.07-7.09, 4.04-4.10, 3.83-3.91, 3.70-3.80, 3.45-3.35, 3.26-3.30, 3.2-3.15.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][CH:4]=1)[CH3:2].C(O[CH2:14][C:15]1[NH:19][C:18]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[C:17]([CH3:30])[C:16]=1[CH2:31][CH3:32])(=O)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1>C(O)C>[CH2:43]([O:22][C:20]([C:18]1[NH:19][C:15]([CH2:14][C:4]2[NH:5][C:6]([CH2:14][C:15]3[NH:19][C:18]([C:20]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:21])=[C:17]([CH3:30])[C:16]=3[CH2:31][CH3:32])=[C:7]([CH2:8][CH3:9])[C:3]=2[CH2:1][CH3:2])=[C:16]([CH2:31][CH3:32])[C:17]=1[CH3:30])=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCc1c[nH]cc1CC
Reactant: CCc1c(COC(C)=O)[nH]c(C(=O)OCc2ccccc2)c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1c(Cc2[nH]c(Cc3[nH]c(C(=O)OCc4ccccc4)c(C)c3CC)c(CC)c2CC)[nH]c(C(=O)OCc2ccccc2)c1C
Temperature: 60 °C
Yield: 82 %

Procedure:
3,4-Diethylpyrrole (2A, FIG. 2A)28 (0.6 g, 4.9 mmol), benzyl 5-(acetoxymethyl)-3-methyl-4-ethyl-pyrrole-2-carboxylate (2B, FIG. 2A)29 (2.5 g, 7.9 mmol), and p-toluenesulfonic acid (0.15 g) were dissolved in 60 mL of absolute ethanol and heated at 60° C. for 8 h under nitrogen. The resulting suspension was reduced in volume to 30 mL and placed in the freezer for several hours. The product was then collected by filtration, washed with a small amount of cold ethanol, and recrystallized from dichloromethane-ethanol to afford a white powder (2.07 g, 82%): mp 211° C. NMR spectra and high resolution mass spectral data were obtained as described and are reported 13a.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]3[C:18]([C:21](=[O:47])[NH:22][C:23]4[CH:28]=[C:27]([C:29](=[O:45])[NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[N:38]5[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]5)[CH:26]=[CH:25][C:24]=4[F:46])=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[F:48][CH2:49][CH2:50][NH2:51]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]3[C:18]([C:21]([NH:22][C:23]4[CH:28]=[C:27]([C:29](=[O:45])[NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[N:38]5[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]5)[CH:26]=[CH:25][C:24]=4[F:46])=[O:47])=[CH:19][N:20]=[C:14]3[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4](=[O:5])[NH:51][CH2:50][CH2:49][F:48]
Reactant: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccccc5N5CCN(C)CC5)ccc4F)cnc3c2)cc1F
Reactant: NCCF
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(F)c(NC(=O)c3cnc4cc(-c5ccc(C(=O)NCCF)c(F)c5)ccn34)c2)CC1

Procedure:
The title compound was prepared from methyl 2-fluoro-4-(3-(2-fluoro-5-(2-(4-methylpiperazin-1-yl)benzylcarbamoyl)phenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)benzoate (step) and 2-fluoroethanamine analogously Example 8.1 steps 1 and 2; LC-MS: Rt 0.74 mins; MS m/z 670/671 {M+H}+; Method 2minLC_v003
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:32])=[O:30])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3)sc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (48 mg, 0.115 mmol) was dissolved in DMF (3.00 mL). The vial was charged with HATU (65.6 mg, 0.173 mmol), DIEA (0.060 mL, 0.345 mmol), and NH4Cl (6.16 mg, 0.115 mmol). The reaction mixture was stirred for 10 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol, 85% yield) as a pale orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.77 (s, 3H) 6.40 (d, J=15.66 Hz, 1H) 6.78-6.90 (m, 3H) 6.95-7.06 (m, 2H) 7.16 (d, J=8.59 Hz, 1H) 7.29-7.49 (m, 4H) 7.55-7.69 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH3:17])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4].[I:18]N1C(=O)CCC1=O>CC(N(C)C)=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([I:18])=[C:9](/[C:11](=[N:15]/[O:16][CH3:17])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CO/N=C(\C(=O)O)c1csc(NC(=O)CCl)n1
Solvent: CC(=O)N(C)C
Product: CO/N=C(\C(=O)O)c1nc(NC(=O)CCl)sc1I
Temperature: 60 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 13.9 g of 2-(2-chloroacetamidothiazol-4-yl)-2(Z)-methoxyiminoacetic acid in 30 ml of dimethylacetamide, 17.0 g of N-iodosuccinimide is added and the mixture is stirred at 60° C. for 1 hour. Then, the reaction mixture is processed as in Reference Example 37 to give 19.6 g (97% yield) of the above-identified compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].Cl[C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[N:39](C=O)C>C1COCC1.O>[NH2:39][C:25]1[N:30]=[C:29]([O:18][C:14]2[CH:13]=[C:12]([CH2:11][CH2:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]([F:21])([F:22])[F:23])[CH:4]=3)=[O:19])[CH:17]=[CH:16][CH:15]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN(C)C=O
Reactant: O=C(CCc1cccc(O)c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nccc(Oc2cccc(CCC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)n1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of N-[4-chloro-3-(trifluoromethyl)phenyl]-3-(3-hydroxyphenyl)propanamide (1.63 g, 4.70 mmol), 2,4-dichloropyrimidine (0.883 g, 5.90 mmol) and cesium carbonate (2.32 g, 7.10 mmol) in THF (60 mL) containing a drop of DMF was heated at reflux overnight. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic solutions were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound (1.60 g, 77%). LCMS, FA: Rt=1.28 min, [MH+ 520.2].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[N:45]=[C:44]1[CH3:52]>C(#N)C>[CH3:42][N:43]1[CH:47]=[C:46]([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])[N:45]=[C:44]1[CH3:52]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cn1C
Yield: 51.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0316 g, 0.0685 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.411 mmol) and 1,2-dimethylimidazole-4-sulfonyl chloride (0.0400 mL, 0.205 mmol) to obtain 4-(1,2-dimethylimidazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0217 g, yield 51%).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][C:11]=2[OH:13])[CH:6]=[C:5]([S:18]([OH:21])(=[O:20])=[O:19])[C:4]=1N=[N:23][C:24]1[CH:29]=[C:28]([S:30]([OH:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1[S:34]([OH:37])(=[O:36])=[O:35]>O>[NH2:23][C:24]1[C:25]([S:34]([OH:37])(=[O:36])=[O:35])=[CH:26][CH:27]=[C:28]([S:30]([OH:33])(=[O:32])=[O:31])[CH:29]=1.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][C:11]=2[OH:13])[CH:6]=[C:5]([S:18]([OH:21])(=[O:20])=[O:19])[CH:4]=1
Reactant: Nc1c(N=Nc2cc(S(=O)(=O)O)ccc2S(=O)(=O)O)c(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: [Na]
Solvent: O
Product: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Product: Nc1cc(S(=O)(=O)O)ccc1S(=O)(=O)O

Procedure:
The suspension of the diazonium betaine was run into a precooled solution of the sodium salt of 28 g of 1-amino-8-hydroxy-2-(2',5'-dihydroxysulfonylphenylazo)naphthalene-3,6-disulfonic acid (obtained by strongly acid coupling of diazotized aniline-2,5-disulfonic acid to 1-amino-8-hydroxynaphthalene-3,6-disulfonic acid) in 300 ml of water, and the pH was brought to 5 with 25% strength by weight aqueous sodium acetate solution. After stirring had been carried out for two hours at from 10° to 15° C., the resulting dye of the formula ##STR15## was precipitated by saturation with potassium chloride, filtered off under suction and reacted further as a water-moist filter residue.