Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:15])([F:14])[CH:8]([OH:13])[C:9]([F:12])(F)[F:10].[CH:16]12[CH2:22][CH:19]([CH:20]=[CH:21]1)[CH2:18][CH:17]2[CH:23]=[O:24].Cl.[O:26]1CCCC1>CCCCCC>[CH:16]12[CH2:22][CH:19]([CH:20]=[CH:21]1)[CH2:18][CH:17]2[CH:23]([OH:24])[C:9]([F:12])([F:10])[C:8]([OH:26])([OH:13])[C:7]([F:15])([F:14])[F:6]
Reactant: O=CC1CC2C=CC1C2
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: OC(C1CC2C=CC1C2)C(F)(F)C(O)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In a nitrogen atmosphere at −70° C., 1290 ml of 1.6M n-butyllithium in hexane was added to a mixture of 168 g of 1,1,1,3,3,3-hexafluoro-2-propanol and 1200 g of tetrahydrofuran. The mixture was allowed to warm up slowly to 0° C. and stirred at the temperature for 30 minutes. Then 134 g of 5-norbornene-2-carboxaldehyde was added at 0° C. The mixture was stirred for 1 hour, after which dilute hydrochloric acid was added to quench the reaction and neutralize the reaction mixture. This was followed by conventional aqueous work-up and purification by silica gel column chromatography, collecting 230 g of 1-(5-norbornen-2-yl)-2,2,4,4,4-pentafluorobutane-1,3,3-triol (yield 80% based on the 1,1,1,3,3,3-hexafluoro-2-propanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:13]3=[N:14][CH2:15][CH2:16][CH2:17][N:12]3[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:30][C:31]1[CH:32]=[N:33][CH:34]=C([Sn](CCCC)(CCCC)CCCC)[CH:36]=1.C[N:51](C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:13]3=[N:14][CH2:15][CH2:16][CH2:17][N:12]3[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[N:33]1[CH:32]=[C:31]([F:30])[CH:36]=[N:51][CH2:34]1
Reactant: CN(C)C=O
Reactant: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(Br)c2)C2=NCCCN12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(N3C=C(F)C=NC3)c2)C2=NCCCN12
Temperature: 150 °C
Yield: 56 %

Procedure:
A mixture of 8-(3-bromo-4-fluorophenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-ylamine (0.075 g, 0.159 mmol), 3-fluoro-5-(tributylstannyl)pyridine (0.092 g, 0.239 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.006 g, 0.008 mmol) in DMF is degassed, heated at 150° C. in a sealed tube for 1.5 h, cooled to room temperature and diluted with ethyl acetate (50 mL) and 5% aqueous LiCl. The reaction mixture is separated. The organic phase is washed with 5% aqueous LiCl, dried over sodium sulfate and concentrated. The resultant residue is purified by flash chromatography (silica, 95:5:0.25 methylene chloride/methanol/concentrated ammonium hydroxide as eluent) to afford the title product as a white solid, 0.043 g (56% yield), mp 94-105° C.; identified by NMR and mass spectral analyses. 1H NMR (300 MHz, CD3OD) 8.56 (d, J=1.3 Hz, 1H), 8.47 (d, J=2.6 Hz, 1H), 7.83 (d, J=9.7 Hz, 1H), 7.54-7.44 (m, 4H), 7.41-7.21 (m, 3H), 3.69 (m, 2H), 3.50 (m, 2H), 1.87 (m, 2H); ESI MS m/z 488 [C24H18F5N5O+H]+;
Reaction SMILES: [CH:1]([N:3]1C(=O)C2=CC=CC=C2C1=O)=[CH2:2].[CH:14]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH2:15].O1CCCC1.O.NN>C(O)C>[CH:1]([NH2:3])=[CH2:2].[CH:14]([N:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH2:15]
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: C=Cn1c2ccccc2c2ccccc21
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C=CN
Temperature: 25 °C

Procedure:
3.6 grams of a random copolymer of N-vinylphthalimide/N-vinylcarbazole (9.2/90.8 mole percent) are dissolved in a solution containing 100 milliliters of tetrahydrofuran and 10 milliliters of ethanol. After the copolymer has been dissolved, 0.13 grams hydrazine hydrate (85%) were added and the solution thereafter heated to boiling under refluxing conditions overnight. At the end of this interval, the solution apparently remains unchanged, it retaining its characteristic yellow color. An additional 2.6 grams of hydrazine hydrate are then added and the solution refluxed for an additional two days. At the end of this time, the characteristic yellow color of the solution has disappeared and a white precipitate formed. The solution is now allowed to cool to room temperature and the precipitate removed by filtration. This precipitate is believed to be phthalhydrazide. The polymer is separated from the solution by precipitation with hexane in a Waring blender. The number average molecular weight of the polymeric product is about 78,000.
Reaction SMILES: O[CH:2]([OH:18])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)=[O:4].[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.[C:29]1(C)C=CC=C[CH:30]=1>>[CH2:29]([O:18][CH:2]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=1)=[O:4])[CH3:30]
Reactant: Cc1ccccc1
Reactant: O=C(c1cccc(Oc2ccccc2)c1)C(O)O
Reactant: Nc1ccc(C(=O)O)cc1
Product: CCOC(Nc1ccc(C(=O)O)cc1)C(=O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C

Procedure:
A 5.1 g. portion of 2,2-dihydroxy-1-[(3-phenoxy)phenyl]ethanone and 2.75 g. of p-aminobenzoic acid in 40 ml. of toluene was refluxed under argon for one hour, then cooled and evaporated to dryness. The residue was added to 40 ml. of ethanol and refluxed for 30 minutes, then cooled to 0° C., giving the desired product, m.p. 117°-127° C. (dec.).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:13]1[C:26]2[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.[C:35]([NH-:52])([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36]>C(O)(=O)C>[CH:41]1[C:40]2[CH:39]([CH2:38][O:37][C:35]([NH:52][CH:13]3[C:26]4[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=4[O:20][C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:36])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CCCCOc1ccc2c(c1)C(O)c1ccccc1O2
Reactant: [NH-]C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)CCCCOc1ccc2c(c1)C(NC(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1O2

Procedure:
A solution of p-toluenesulfonic acid (0.15 g, 0.8 mmol) in glacial acetic acid (3 mL) was added dropwise at 25° C. over 15 minutes to a well-stirred suspsension of 5-(9-hydroxy-xanthen-2-oxy)valeric acid (2.0 g, 6.4 mmol) prepared as described above and Fmoc-amide (1.84 g, 8.2 mmol) in glacial acetic acid (50 mL). This mixture was stirred continuously and then filtered after 3 hours to collect a white solid which was washed with water (3×20 mL) and ehtyl ether (3×20 mL). The solid was dried in vacuo over P2O5 at 25° C. Yield: 2.35 g(61%, m.p. 210-211° C., Rf : 0.53 EtOAc/MeOh 5:1. NMR data and elemental analysis in accordance with structure. ##STR12##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](O)=[O:28])[CH2:22]2)=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([C:27](=[O:28])[NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:22]2)[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)C1CN(CC2=C(C(=O)OCC)C(c3ccc(F)cc3Br)N=C(c3nccs3)N2)CCO1
Yield: 82.1 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-2-carboxylic acid (0.8 g, 1.45 mmol) was reacted with ethyl 2-aminoacetate hydrochloride (0.31 g, 2.17 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.76 g, 82%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2F)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[NH:25]1[CH2:30]CC[CH2:27][CH2:26]1.O1CCOC[CH2:32]1>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:25]([CH:26]([CH3:32])[CH3:27])[CH3:30])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2F)Cc2ccccc2C1
Product: CCOC(=O)C1(NC(=O)c2ccncc2N(C)C(C)C)Cc2ccccc2C1
Reaction time: 0.01 h

Procedure:
A 10 mL microwave reaction vessel is charged with 2-[(3-fluoro-pyridine-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (354, 500 mg, 1.52 mmol), 1,4-dioxane (2 mL) and piperidine 2 mL, 29.5 mmol). A stirring bar is added. The reaction vial is crimped sealed. The reaction vial is placed in a Smith Microwave reaction apparatus. The temperature is set for 150° C. with a fixed hold time of 10 min. Pre-stir time is set for 20 sec. After this sequence is completed, the reaction vial is removed from the apparatus. The stirring bar is extracted. The contents of the flask are transferred to a round bottom flask and the solvent removed under reduced pressure. Pumping to a constant weight gives 0.71 g of brown syrup. This is dissolved in DCM (10 mL) and applied to an ISCO Companion that is fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 65% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 14 mL fractions of UV active eluent are collected. Fractions 5-11 are combined and evaporated by pumping to constant weight to give 0.29 g of an amorphous white solid (0.29 g, 51%).
Reaction SMILES: [Br:1][C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(OCC)C>[Br-:1].[CH3:13][NH+:14]1[CH:18]=[CH:17][N:16]([C:2]([CH3:12])([CH3:11])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH2:15]1
Reactant: Cn1ccnc1
Reactant: CC(C)(Br)C(=O)c1ccccc1
Solvent: CCOCC
Product: C[NH+]1C=CN(C(C)(C)C(=O)c2ccccc2)C1
Product: [Br-]
Yield: 62.3 %

Procedure:
A solution of 4.6 g (0.02 mol) of α-bromoisobutyrophenone and 1.8 g (0.022 mol) of 1-methylimidazole in 30 ml of diethyl ether was stirred at room temperature for approximately 48 hours. The solvent was decanted and the resulting oil was slurried in ethyl acetate. The solvent was again decanted and the residue was dissolved in acetonitrile prior to adding a small portion of ethyl acetate. A white precipitate was collected by filtration and recrystallized from methanol/ethyl acetate to afford 3.88 g of 1-methyl-3-(1,1-dimethyl-2-phenyl-2-oxoethyl)-1H-imidazolium bromide as glittering white flakes. (63% yield) mp=137°-140° C.
Reaction SMILES: [CH2:1]1OCCOCCOCCOCCO[CH2:2]1.[OH-].[Na+].C([C:20]([CH2:33][CH3:34])(P(O)(O)=O)/[C:21](/[CH3:28])=[C:22](\CC)/[C:23]([O-:25])=[O:24])C.[CH3:35][C:36](=[CH:38][CH2:39][CH2:40]/[C:41](=C/C=O)/[CH3:42])[CH3:37]>C1(C)C=CC=CC=1>[CH3:28]/[C:21](/[CH:20]=[CH:33]/[CH:34]=[C:41](\[CH3:42])/[CH2:40][CH2:39][CH:38]=[C:36]([CH3:37])[CH3:35])=[CH:22]\[C:23]([O:25][CH2:1][CH3:2])=[O:24]
Reactant: CC/C(C(=O)[O-])=C(/C)C(CC)(CC)P(=O)(O)O
Reactant: C1COCCOCCOCCOCCO1
Reactant: CC(C)=CCC/C(C)=C/C=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(C)/C=C/C=C(\C)CCC=C(C)C
Temperature: 0 °C
Yield: 876.6 %

Procedure:
15-crown-5 (0.9 g, 0.1 equivalents, 4.0 mmol) was dissolved in 50 ml of toluene at room temperature, and added with 32 ml of 50% aqueous sodium hydroxide solution. To the solution, triethyl-3-methyl-4-phosphonocrotonate (11.1 g, 1.05 equivalents, 42 mmol) and then 7 ml toluene solution of geranial (6.1 g, 40 mmol) were added under stirring at 0° C. The mixture was stirred at room temperature for 1.5 hours. The organic and aqueous layers were separated, and the organic layer was washed with saturated ammonium chloride solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 9.2 g of the title compound (yield 87%, 2E:2Z=93:7) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].C(NC(C)C)(C)C.I[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[CH:22]\[CH2:23][O:24][C:25]2[CH:36]=[CH:35][C:28]([O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:27]([CH3:37])[CH:26]=2)=[CH:17][CH:16]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:37][C:27]1[CH:26]=[C:25]([O:24][CH2:23]/[CH:22]=[C:21](\[C:18]2[CH:17]=[CH:16][C:15]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:20][CH:19]=2)/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:36]=[CH:35][C:28]=1[O:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N,N-Dimethylpropargylamine (0.11 mL, 1.03 mmol) and diisopropylamine (0.34 mL, 2.42 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethyl-phenyl)allyloxy]-2-methylphenoxy]acetate (300 mg, 0.515 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate as brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(O)C.O.[OH-].[Na+]>[C:13]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:12])[CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccccc2)cc1F
Temperature: 67.5 °C

Procedure:
4-Bromo-2-fluoro-phenylacetic acid (0.25 gm, 1.1 mmole), phenylboronic acid (0.15 gm, 1.2 mmole) and 50% water wet 10% Palladium carbon (0.07 gm, 0.033 mmole Pd) were added to 10 ml of 5:1 water isopropanol mixture, then Na2CO3 (0.14 gm, 1.3 mmole) dissolved in 3 ml of water was added to the above mixture, the reaction was heated at 65-70° C. overnight, the reaction was cooled to room temperature, diluted with 20 ml of 70:15:1 i-PrOH/H2O/10% NaOH, filtered, the catalyst was washed with 20 ml×3 using the above mixture, the filtrate was acidified using 20% H2SO4, filtered and dried (0.2 gm, 83%) H1-NMR INOVA-500 (DMSO d6) δ 3.675(s, 2H), 7.382-7.518(m, 6H), 7.707(d, J=7.5 Hz, 2H), 12.498(s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58](OC(=O)C)(=[O:60])[CH3:59]>ClCCl>[C:58]([O:50][CH:45]1[CH2:44][CH2:43][CH:42]([CH:41]=[C:40]([CH:24]2[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28](=[O:29])[CH:30]([CH2:35][CH:36]=[CH2:37])[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]3[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]3[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]3[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]3)[C:21](=[O:22])[O:23]2)[CH3:51])[CH2:47][CH:46]1[O:48][CH3:49])(=[O:60])[CH3:59]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 5 h

Procedure:
To a solution of the FR-900506 substance (10.4 mg) in dichloromethane (0.2 ml) were added Dvridine (0.1 ml) and acetic anhydride (0.05 ml) at room temperature, and the mixture was stirred for 5 hours. The solvent was removed from the reaction mixture under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent: diethyl ether and dichloromethane, 1:2 v/v) to give 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:13]=1>N1C2C(=CC=CC=2)C=CC=1.C(OCC)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2s1
Agent: [Cu]
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: Clc1ccc2ccsc2c1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of the above 6-chlorobenzo[b]thiophen-2-ylcarboxylic acid (3.0 g) and copper powder (1.2 g) in quinoline (20 ml) was stirred at 210° C. for 40 minutes. The mixture was cooled to room temperature and diluted with diethyl ether, and insoluble materials were filtered off. The filtrate was washed successively with 10% aqueous hydrochloric acid solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 6-chlorobenzo[b]thiophene (1.79 g) as colorless crystals. (3) The above 6-chlorobenzo[b]thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give 5-bromo-2-chloro-1-(6-chlorobenzo[b]thiophen-2-ylmethyl)benzene as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1[S:37]([NH:40][CH2:41][CH2:42][OH:43])(=[O:39])=[O:38]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:28]([S:37]([NH:40][CH2:41][CH2:42][OH:43])(=[O:38])=[O:39])=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccc(C(F)(F)F)cc2S(=O)(=O)NCCO)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C20H15F4N5O3S, 481.08; m/z found, 482.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.35-8.31 (m, 1H), 8.26 (s, 1H), 8.10-8.05 (m, 1H), 7.91-7.86 (m, 1H), 7.71 (d, J=7.9, 1H), 7.68-7.63 (m, 1H), 7.46 (dd, J=10.9, 1.7, 1H), 7.43-7.36 (m, 3H), 4.75 (t, J=5.4, 1H), 3.40-3.33 (m, 2H), 2.88-2.78 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1N
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Br)cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and 4-bromophenyl acetohydroximoyl chloride (168 mg, 0.677 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 15 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (33 mg, 24%).
Reaction SMILES: [F:1][CH:2]([F:36])[O:3][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:18]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:35])[CH:27]=4)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.FC(F)O[C:40]1C=C(S(Cl)(=O)=O)C=C[CH:45]=1>>[CH2:40]([O:31][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]3[O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:36])[CH:5]=4)(=[O:12])=[O:11])[C:18]=3[CH:19]=2)=[O:24])=[CH:27][C:28]=1[F:35])[CH3:45]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(OC(F)F)c1)CCO2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)F)c2)CCO3)cc1F

Procedure:
4-{[4-(3-Difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=521.2 (M−H), was prepared as described for example 21, steps 1 to 8. Step 7 was performed using 3-difluoromethoxy-benzenesulfonyl chloride and yielded 4-{[4-(3-difluoromethoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]ox-azine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][C:31]([C:34](O)=[O:35])=[CH:30]2>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:31]3[NH:32][C:33]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[F:24])=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc2cccc(F)c2[nH]1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cc4cccc(F)c4[nH]3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 7-fluoro-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=493.1.