Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1.[BH3-][C:55]#N.[Na+]>C=O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([CH3:55])[CH2:50][CH2:49]1)[C:3](=[O:45])[C:4]1[CH:44]=[CH:43][CH:42]=[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]=2[C:22]2[CH:27]=[C:26]([C:28](=[O:41])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[CH:32]=3)[CH:25]=[CH:24][N:23]=2)=[O:8])[CH:5]=1
Reactant: CN(CCN1CCNCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N1-methyl-N1-(2-(piperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (150 mg, 0.21 mmol, 1.00 equiv) in HCHO (in water) (6 mL), NaBH3CN (15 mg, 1.10 equiv), and acetic acid (5 drops). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 5 mL of sodium bicarbonate, extracted with 2×5 mL of dichloromethane, and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 1×5 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 13.3 mg (9%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.96 (d, J=5.1 Hz, 1H), 8.76 (d, J=9.3 Hz, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 8.05 (s, 2H), 7.89˜7.87 (m, 1H), 7.71˜7.62 (m, 5H), 7.59˜7.56 (m, 2H), 4.72 (s, 2H), 3.79 (s, 2H), 3.66 (d, J=5.1 Hz, 4H), 3.50˜3.34 (m, 2H), 3.15˜3.04 (m, 6H), 2.89˜2.85 (m, 6H), 2.80˜2.60 (m, 2H), 2.04 (d, J=4.5 Hz, 4H), 1.83 (d, J=5.4 Hz, 2H). MS (ES, m/z): 742 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][OH:12])[NH:2]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>ClCCl>[OH:12][CH2:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CO

Procedure:
This compound is obtained using a protocol from the literature (R. B. Kawthekar et al South Africa Journal of Chemistry 63, 195, 2009) starting from 15 g of (3S)-1,2,3,4-tetrahydroisoquinolin-3-ylmethanol (91.9 mmol) in the presence of benzyl chloroformate and triethylamine in solution in dichloromethane. After purification by chromatography over silica gel using petroleum ether and ethyl acetate as eluants, the title product is obtained in the form of an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH2:16][CH2:17][S:18][CH2:19][CH:3]12.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.O.C(OCC)(=O)C>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH2:16][CH2:17][S:18][CH2:19][CH:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)C1CSCCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Nc2cc(CO)cnc2N2CCSCC12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 143.3 %

Procedure:
Methyl 6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine-3-carboxylate (386 mg, 1.38 mmol) was taken up in tetrahydrofuran (25 mL) in an inert environment. To the stirred suspension at room temperature was added NaH (60% dispersion in mineral oil, 121 mg, 3.03 mmol) and stirred 30 min. The reaction was cooled to −78° C. and lithium aluminum hydride (3 mL, 2M in THF) was added. The reaction was stirred at a temperature between −20 and −10° C. for 3 h. The reaction was cooled back to −78° C. and MeOH (1 mL) followed by water (1 mL) was added. The reaction was allowed to stir at ambient temperature for 2 h and then poured into ethyl acetate (200 mL) and water (100 mL). The biphasic mixture was stirred vigorously and then filtered through a medium frit. The layers were separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with brine (100 mL), dried with sodium sulfate and concentrated to afford the title compound (497 mg, 98%) as a white solid. [M+H] calc'd for C, 11; H, 13; N, 3; O, 2; S, 252; found, 252.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[NH:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[CH2:46]([O:48][C:49](=[O:70])[C@H:50]([OH:69])[CH2:51][N:52]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:62]=2[F:68])=[CH:57][CH:56]=1)[NH2:53])[CH3:47].CCN(C(C)C)C(C)C>CCOC(C)=O.CC(O)=O>[CH2:46]([O:48][C:49](=[O:70])[C@H:50]([OH:69])[CH2:51][N:52]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:62]=2[F:68])=[CH:59][CH:60]=1)[NH:53][C:13]([C:4]1[NH:3][C:2](=[O:1])[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)=[O:15])[CH3:47]
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)[nH]1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1nn(-c2ccccc2)c(=O)[nH]1
Reaction time: 0.17 h
Yield: 1.4 %

Procedure:
5-Oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid (89.5 mg, 436 μmol) was combined with HCTU (244 mg, 589 μmol) in DMF (1.0 mL, 13 mmol) and stirred for 10 minutes. (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (80.0 mg, 0.2 mmol) and DIPEA (0.1 mL, 0.7 mmol) were added, and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc (10.0 mL) and washed with water (3.0 mL), saturated aqueous NaHCO3 (2×3.0 mL), and saturated aqueous NaCl (3.0 mL), then dried over Na2SO4, filtered and concentrated to give a yellowish solid. A portion (20 mg) of the solid was dissolved in AcOH (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (1.6 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H23ClFN3O3, 554.15. found 554.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][CH2:14][CH2:15]O)[S:10][C:9]=2[C:17]=1[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:40]I.O>C1C=CC=CC=1.N1C=CC=CC=1>[I:40][CH2:15][CH2:14][CH2:13][CH:11]1[S:10][C:9]2[C:17]([CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]=2[O:12]1
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCO)O2
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCI)O2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1.0 g of 3-(5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 85) was dissolved in a mixture of 15 ml of benzene and 1.5 ml of pyridine, and then 1.7 g of triphenylphosphine, followed by 1.7 g of iodine, was added to the solution. The mixture was stirred for 40 minutes at room temperature. The product was poured into water and extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off to yield a crude product, which was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with benzene.
Reaction SMILES: [SH2:1].Br[C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2>C1C2C(CCCC2)CCC1>[CH:15]1[C:16]2[C:11](=[CH:10][C:9]3[C:4]([C:3]=2[S:1][C:3]2[C:16]4[C:11]([CH:10]=[C:9]5[C:4]=2[CH:5]=[CH:6][CH:7]=[CH:8]5)=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:12]=[CH:13][CH:14]=1
Reactant: S
Reactant: Brc1c2ccccc2cc2ccccc12
Solvent: C1CCC2CCCCC2C1
Product: c1ccc2c(Sc3c4ccccc4cc4ccccc34)c3ccccc3cc2c1

Procedure:
Hydrogen sulphide is passed into a solution of 20 g (0.08 mole) of 9-bromoanthracene in decahydronaphthalene at a temperature of 180° C for 14 hours, the solvent is separated by filtration, the residue is recrystallized from toluene to obtain 8.5 g (63.3 percent by weight) of di(9-anthryl) sulphide. This is a yellow crystalline substance melting at 257° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]#[N:12].[CH3:13][O:14]CCl>[N+](C)([O-])=O.ClCCl.ClCCl>[C:11]([C:7]1[N:6]([CH3:5])[CH:10]=[C:9]([CH:13]=[O:14])[CH:8]=1)#[N:12]
Reactant: COCCl
Reactant: Cn1cccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: Cn1cc(C=O)cc1C#N
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Aluminum trichloride (24.24 g, 180.86 mmol) was dissolved in nitromethane/dichloromethane (1/1, 320 ml), the solution was cooled to −20° C., and 1-methylpyrrole-2-carbonitrile (8 g, 75.36 mmol) was added. α,α-Dichlorodimethyl ether (10.4 g, 90.43 mmol), dissolved in dichloromethane (42 ml), was subsequently added dropwise. After stirring for 4 h at 0° C., the batch was poured onto ice (200 g). The aqueous phase was extracted with diethyl ether. The combined organic phases were washed until neutral with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. After drying over sodium sulfate, the solvent was removed in a rotary evaporator. The crude product was employed in the reactions below without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([OH:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>ClC1C=CC=CC=1>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:22]1[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:20]([F:19])[CH:21]=1)#[N:13]
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: Clc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc([N+](=O)[O-])c(F)c3)c2cc1C#N
Yield: 62.5 %

Procedure:
4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline (1.7 g) and 3-fluoro-4-nitrophenol (2.0 g) were suspended in chlorobenzene (20 ml), and the suspension was heated to reflux for 6 hours. After completion of the reaction, the solvent was distilled off, ethyl acetate was added, and a solid precipitated. The solid was filtered out and washed with ether, washed with 1N sodium hydroxide water and with water, and then dried to obtain 1.55 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12]Br.[F-].[K+].[F-].[Cs+]>CN(C)C=O>[CH:7]1[C:4]([CH:5]=[O:6])=[CH:3][C:2]2[O:1][CH2:12][O:10][C:9]=2[CH:8]=1
Reactant: BrCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cs+]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(c1)OCO2
Yield: 90 %

Procedure:
One process for preparing piperonal from 3,4-dihydroxybenzaldehyde comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride and alkali in a non-protic polar solvent such as dimethyl sulfoxide, and gives a 61% yield of piperonal (British Pat. No. 1,097,270). Another process comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride in aqueous alkali under the influence of an interphasic moving catalyst such as quaternary ammonium compound, and gives a 70-73% yield of piperonal. However, the catalyst used in this process is expensive and, by nature, easily soluble in both aqueous and organic phases. Accordingly, the recovery of the catalyst is too low to make this process practicable (Japanese Patent Application Disclosure Nos. 23,265/'76 and 113,967/'77). In any event, neither of these process can provide satisfactory yields based on the amount of the starting material. In addition, James H. Clark et al. have described still another process in which 3,4-dihydroxybenzaldehyde is reacted with dibromomethane in N,N-dimethylformamide under the influence of an excess of potassium fluoride or cesium fluoride to give a 90% yield of piperonal [Tetrahedron Letters, No. 38, pp. 3361-3364 (1976)]. This process is of advantage in that no strong base is used, the reaction time is relatively short, and a high yield can be obtained. However, an expensive fluoride must be used in large excess as a halogen trapping agent and cannot be recycled because its fluorine component is stoichiometrically replaced by the halogen atoms in the dihalomethane used. Accordingly, this process is not satisfactory for industrial applications. Moreover, when based on the amount of pyrocatechol used, the yield attainable with this process does not reach 70%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][CH:4]=[C:3]3[C:14](=[O:16])[N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=[C:2]3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Reactant: NNc1ccccc1
Product: COc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1

Procedure:
The title compound was prepared following the procedure described in Step 3 using 3d and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 3.90 (3H, s), 7.17 (1H, m), 7.27 (1H, dd, J=9.06, 2.64 Hz), 7.40 (2H, m), 7.57 (1H, d, J=3.02 Hz), 7.67 (1H, d, J=9.06 Hz), 8.20 (2H, m), 8.63 (1H, s). m/z 292.3 (MH+).
Reaction SMILES: NC1C(O)=CC(Br)=CN=1.N.Br[C:12]1[N:17]=[C:16]2[O:18][CH:19]=[N:20][C:15]2=[CH:14][CH:13]=1.BrC1C=C2OC=NC2=NC=1.[CH3:31][N:32](C(OC(C)(C)C)=O)[CH:33]([CH2:35][CH:36]=[CH2:37])[CH3:34]>>[CH3:31][NH:32][CH:33]([CH2:35]/[CH:36]=[CH:37]/[C:12]1[N:17]=[C:16]2[O:18][CH:19]=[N:20][C:15]2=[CH:14][CH:13]=1)[CH3:34]
Reactant: Brc1ccc2ncoc2n1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: Brc1cnc2ncoc2c1
Agent: N
Agent: Nc1ncc(Br)cc1O
Product: CNC(C)C/C=C/c1ccc2ncoc2n1

Procedure:
In another example, 6-bromooxazolo[4,5-b]pyridine, when submitted sequentially to palladium catalyzed coupling to N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine and deprotection with trifluoroacetic acid, gives (4E)-N-methyl-5-(6-oxazolo[4,5-b]pyridinyl)-4-penten-2-amine. The requisite 6-bromooxazolo[4,5-b]pyridine can be produced from 2-amino-5-bromo-3-pyridinol by condensation with formic acid or a trialkyl orthoformate, using methodology similar to that of M-C. Viaud et al., Heterocycles 41: 2799-2809 (1995). The use of other carboxylic acids produces 2-substituted-6-bromooxazolo[4,5-b]pyridines, which are also substrates for the Heck reaction. The synthesis of 2-amino-5-bromo-3-pyridinol proceeds from furfurylamine (Aldrich Chemical Company). Thus, 5-bromo-3-pyridinol (produced from furfurylamine according to U.S. Pat. No. 4,192,946) can be chlorinated, using methods described by V. Koch et al., Synthesis, 499 (1990), to give 2-chloro-5-bromo-3-pyridinol, which in turn can be converted to 2-amino-5-bromo-3-pyridinol by treatment with ammonia. 5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine. The 5-bromooxazolo[5,4-b]pyridine can be synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by condensation with formic acid (or a derivative thereof) as described above. 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41: 729-741 (1967)) and subsequent tin(II) chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997)) of commercially available 3-nitro-2-pyridinol (Aldrich Chemical Company).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[C:15]([F:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(F)c(Cl)cc21
Temperature: 75 °C
Reaction time: 60 h
Yield: 60.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 1.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)#[N:2]>C(O)C.[Pd]>[C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1)#[N:2]
Reactant: N#CCCC1CN(C(=O)OCc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Product: N#CCCC1CNCCO1
Yield: 98.8 %

Procedure:
A solution of 2-(2-cyanoethyl)-4-benzyloxycarbonylmorpholine (10.7 g) in ethanol (60 ml) is hydrogenated over 5% palladium on carbon (1 g) at 25° C. After the calculated amount of hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound (5.4 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.C(OC(CC1C2SC=CC=2C(O[CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=CC=1)C(O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=[CH:8][CH:7]=1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Reactant: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c3sccc23)c(C)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)OC)c3ccsc23)c(C)o1

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (example 95) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]1([CH2:18][C:19]2[S:20][C:21]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC(Cl)(Cl)C(Br)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C(#N)C>[CH2:1]([NH:8][C:9]1[O:10][C:24]([C:21]2[S:20][C:19]([CH2:18][N:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:23][CH:22]=2)=[N:26][N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc(CNc2nnc(-c3ccc(CN4CCCCCC4)s3)o2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 33.1 %

Procedure:
0.13 ml (1.05 mmol) of benzyl isocyanate was added to 25 ml of acetonitrile solution containing 253 mg (1.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and the mixture was stirred at room temperature for 40 hours, 718 mg (2.2 mmol) of 1,2-dibromo-1,1,2,2-tetrachloroethane, 1.22 ml of triethylamine and 1.16 g of triphenylphosphine were added, and then the mixture was stirred at room temperature for 9 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 122 mg of the title compound in its free form. By subjecting 117 mg of this compound to salt formation using 27 mg of oxalic acid, 122 mg of the title compound was obtained.
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([S:6]([C:9]1[CH:37]=[CH:36][C:12]([O:13][C:14]2[C:28]([CH2:29][C:30](N(OC)C)=[O:31])=[CH:27][C:17]3[NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:5].[Cl-].[NH4+]>O1CCCC1>[CH2:4]([S:6]([C:9]1[CH:37]=[CH:36][C:12]([O:13][C:14]2[C:28]([CH2:29][C:30]([CH3:1])=[O:31])=[CH:27][C:17]3[NH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:20][C:16]=3[CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:5]
Reactant: C[Mg]Br
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CC(=O)N(C)OC)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
With cooling with ice, 14 μl of a tetrahydrofuran solution of 3.0 M methylmagnesium bromide was added to a tetrahydrofuran (500 μl) solution of 8.7 mg of the compound obtained from Example 138, and stirred at room temperature for 30 minutes. then, 14 μl of a tetrahydrofuran solution of 3.0 M methylmagnesium bromide was added to it, and stirred at room temperature for 5 minutes. With cooling with ice, aqueous saturated ammonium chloride solution was added to it, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain 4.0 mg of the entitled compound.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:17]([NH:20][C:21]1[CH:29]=[C:28]([NH2:30])[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=1[OH:31])(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:20][C:21]1[C:22]([OH:31])=[C:23]([C:24]([OH:26])=[O:25])[CH:27]=[C:28]([N:30]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:29]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(N)cc(C(=O)O)c1O
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-n2c(-c3ccccc3)cc3c2CCCC3)cc(C(=O)O)c1O

Procedure:
A mixture of 10.3 g. (0.048 mole) of 2-phenacylcyclohexanone, 10 g. (0.048 mole) of 3-acetamido-5-aminosalicylic acid, and 70 ml. of glacial acetic acid was heated under reflux under nitrogen for 1 hour, cooled and filtered. Recrystallization of the collected solid from acetic acid gave 10.5 g. (57%) of crystals, m.p. 232°-234°.