Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:2]1
Reactant: O=C(c1ccsc1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1cc(CN2CCCC2)cs1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 1-(3-thienylcarbonyl) pyrrolidine (12 g) in dry diethylether (200 ml) was added to a slurry of lithium aluminium hydride (2.6 g) in dry diethylether (100 ml). The mixture was stirred for 1 hour, and aqueous 5 M sodium hydroxide (20 ml) was added. The mixture was filtered and the filtrate was distilled to give the title compound (9.8 g) as a colourless oil. b.p. 120/15 mm.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:9][CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C)c2cc(Oc3cc(F)cc(F)c3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2ccc(Oc3cc(F)cc(F)c3)cc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 7e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 7e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-7-(3,5-difluoro-phenoxy)-isoquinoline-3-carboxamido]acetic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][CH:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: CC1=NCCc2occc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC1NCCc2occc21

Procedure:
In close analogy to the procedure described above, 4-Methyl-6,7-dihydro-furo[3,2-c]pyridine is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:16]([C:19]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[N:23]=2)([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([S:16]([C:19]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C@@H:29]3[CH3:34])[N:25]=[C:24]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:40][CH:41]=3)[N:23]=2)([CH3:20])[CH3:21])(=[O:17])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Phenyl chloroformate (0.635 mL, 5.06 mmol) was added to 4-[4-(2-cyclopentylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.5 g, 3.37 mmol) and sodium hydrogen carbonate (0.425 g, 5.06 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (1.30 g).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2/[CH:11]=[CH:12]\[CH2:13][OH:14])=[N:3]1.[CH3:15]CCCCC.C([Zn]CC)C.ICI>C(Cl)Cl.[Cl-].[NH4+].O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:15][C@H:12]2[CH2:13][OH:14])=[N:3]1
Reactant: Cn1cc2c(/C=C\CO)cccc2n1
Reactant: CCCCCC
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: ICI
Solvent: O
Product: Cn1cc2c([C@H]3C[C@H]3CO)cccc2n1
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
Under argon gas atmosphere, to a suspension of (2Z)-3-(2-methyl-2H-indazol-4-yl)prop-2-en-1-ol (60.0 mg, 0.319 mmol) in methylene chloride (3 mL) was added 1 M diethylzinc hexane solution (1.60 mL, 1.60 mmol) under ice-cooling and the mixture was stirred for 10 min. Diiodomethane (128 μL, 1.59 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was diluted with saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (40.5 mg, yield 63%).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH:7]([C:11]1([CH2:15][CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12]1)[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[I:20]N1C(=O)CCC1=O>C(Cl)Cl.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[C:1]([Si:5]([O:6][CH:7]([C:11]1([CH2:15][CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12]1)[CH2:8][CH:9]=[CH:10][I:20])([CH3:19])[CH3:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: C#CCC(O[Si](C)(C)C(C)(C)C)C1(CCC)CCC1
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: CCCC1(C(CC=CI)O[Si](C)(C)C(C)(C)C)CCC1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Bis(cyclopentadienyl)zirconiumchloride hydride (3.1 g, 12.0 mmol) was added to a solution of alkyne 5 (1.7 g, 3.94 mmol) in CH2Cl2 (20 mL) at 23° C. After 0.5 h N-iodosuccinimide (2.6 g, 12.0 mmol) was added. The reaction was stirred for 0.5 h, concentrated in vacuo and the residue was diluted with pentane and washed with saturated aqueous sodium bisulfite. The organic portion was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by FCC (silica gel, 100% pentane) gave 1.2 g (71%) of the vinyl iodide 6 as a clear, light yellow oil.
Reaction SMILES: COC(=O)[C@@H](N(C(OCC1C=CC=CC=1)=O)CC=O)C.N[C@@H](CCO)CO.[CH2:28]([O:35][C:36]([N:38]1[C@@H:47]([CH3:48])[C:46](=[O:49])[N:45]2[CH:40]([O:41][CH2:42][CH2:43][C@H:44]2[CH2:50][OH:51])[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]([N:38]1[C@@H:47]([CH3:48])[C:46](=[O:49])[N:45]2[C@@H:43]([CH2:44][CH2:50][OH:51])[CH2:42][O:41][CH:40]2[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OCC[C@H]2CO
Agent: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: N[C@H](CO)CCO
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CCO

Procedure:
Condensation of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 1) with (S)-2-amino-butane-1,4-diol in analogy with examples 1/2F produced a nearly statistical mixture of the title compound [light yellow gum, MS: 335.5 (M+H)+] and (4S,7S)-4-hydroxymethyl-7-methyl-6-oxo-hexahydro-pyrazino[2,1-b][1,3]oxazine-8-carboxylic acid benzyl ester [light yellow gum, MS: 335.4 (M+H)|], which were separated by column chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]1([CH2:54][OH:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>>[Cl:17][C:18]1[C:19]([O:55][CH2:54][C:48]2([F:47])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC1(F)CCCCC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with (1-fluorocyclohexyl)methanol, the title compound was obtained as a colorless solid (0.08 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.30 (d, J=12.3 Hz, 1H), 4.24 (d, J=21.2 Hz, 2H), 2.88 (s, 6H), 1.96-1.87 (m, 2H), 1.72-1.50 (m, 7H), 1.37-1.24 (m, 1H); MS (ES−) m/z 409.1, 411.1 (M−1).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:18])=[N:10][N:11]2[CH2:14][C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:18])=[N:10][N:11]2[CH2:14][CH:15]([OH:17])[CH3:16])=[CH:7][CH:6]=1
Reactant: COc1ccc2c(C)nn(CC(C)=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(C)nn(CC(C)O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Sodium borohydride (0.21 g, 5.5 mmol) was added to a solution of the product from Step B (1.2 g, 5.5 mmol) in MeOH (10 ml) at room temperature. After stirring for 2 h at room temperature the solvent was evaporated and a saturated aqueous solution of ammonium chloride (10 mL) was added to the residue; this mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (10 ml), dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% to 30% ethyl acetate in hexane) to give an oil (0.68 g, 56%): MS (ES) m/z 221 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH2:23][CH2:22]2)[C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I.O>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([N:27]([CH3:38])[C:28]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH2:25][CH2:26]2)[C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(CO[C@H]2CC[C@H](NC(=O)C3CCCC3)CC2)nc2ccccc2c1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CO[C@H]2CC[C@H](N(C)C(=O)C3CCCC3)CC2)nc2ccccc2c1OCc1ccccc1

Procedure:
To a mixed solution (10 mL) of N-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)cyclopentanecarboxamide (260 mg) in THF-DMF (1:1) was added 60% sodium hydride (45 mg) under ice-cooling, followed by stirring at the same temperature. Methyl iodide (0.055 mL) was added thereto, followed by stirring at room temperature for 3.5 hours. The reaction mixture was ice-cooled, and 60% sodium hydride (45 mg) and methyl iodide (0.055 mL) were added thereto, followed by stirring at room temperature for another 17 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜50/50), and the solvent was evaporated under reduced pressure. The residue was dried under vacuum at room temperature to obtain 93 mg of N-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)-N-methylcyclopentanecarboxamide as a colorless viscous substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]1[CH:14]2[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]2)[CH2:10]1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[C:4]([CH2:5][NH:6][C:7](=[O:17])[O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:3]=1
Reactant: O=C(NCc1cccc(Br)c1)OC1CN2CCC1CC2
Reactant: OB(O)c1ccccc1
Product: O=C(NCc1cccc(-c2ccccc2)c1)OC1CN2CCC1CC2
Yield: 46.7 %

Procedure:
Using general procedure E, quinuclidin-3-yl 3-bromobenzylcarbamate (237 mg, 0.700 mmol), phenylboronic acid (171 mg, 1.4 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a viscous semi-solid (110 mg, 47%). 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=7.5 Hz, 2H), 7.50 (m, 2H), 7.62-7.38 (m, 3H), 7.35 (t, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 5.32-5.17 (m, 1H), 7.78 (m, 1H), 4.42 (d, J=6.0 Hz, 2H), 3.26 (m, 1H), 2.95-2.65 (m, 5H), 2.05 (m, 1H), 1.84 (m, 1H), 1.70 (m, 1H), 1.58 (m, 1H), 1.42 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 155.2, 140.7, 139.8, 138.0, 128.1, 127.8, 126.4, 126.1, 125.5, 125.4, 125.3, 70.1, 54.4, 46.2, 45.3, 44.1, 24.3, 23.1, 18.2 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.44 min; (M+1) 337.
Reaction SMILES: CC1C=C(COC2C=C(CCC(O)=O)C=CC=2)C=CC=1C1C=CC=C(OC)C=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([Mg]Br)[CH:34]=[CH:35][CH:36]=1.[CH3:39][C:40]1([CH3:51])[O:45][C:44](=[O:46])[C:43](=[C:47]([CH3:49])[CH3:48])[C:42](=[O:50])[O:41]1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:47]([CH:43]2[C:42](=[O:50])[O:41][C:40]([CH3:39])([CH3:51])[O:45][C:44]2=[O:46])([CH3:49])[CH3:48])[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Reactant: COc1cccc([Mg]Br)c1
Agent: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2C)c1
Product: COc1cccc(C(C)(C)C2C(=O)OC(C)(C)OC2=O)c1

Procedure:
The 5-(2-(3-methoxyphenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (85.C) was prepared via the procedure described in Huang, X.; et. al.; Tetrahedron Letters; 1982, (1); pp. 75-76. from (3-methoxyphenyl)magnesium bromide (1.0 M in THF solution from Aldrich) and 85.B. 1H NMR (400 MHz, CDCl3) ppm 7.26 (1H, t, J=8.0 Hz), 6.94 (1H, d, J=7.8 Hz), 6.89 (1H, t, J=2.2 Hz), 6.79 (1H, dd, J=8.2, 2.3 Hz), 3.81 (3H, s), 3.62 (1H, s), 1.67 (6H, s), 1.66 (3H, s), 1.34 (3H, s).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc2cn[nH]c2c1
Yield: 76.8 %

Procedure:
6-Iodo-1H-indazole (1.00 g, 4.10 mmol) was reacted with trimethylsilyl acetylene (0.61 mL, 4.30 mmol) in analogy to GP8a to give 675 mg (77%) of pure 6-(trimethylsilyl)ethynyl-1H-indazole.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[N:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(Cl)ccc1N1CCOC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(Cl)ccc1N1CCOC1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
(Step 4) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.50 g), 3-[2-(aminomethyl)-4-chlorophenyl]-1,3-oxazolidin-2-one hydrochloride obtained in Step 3 (0.67 g) and potassium carbonate (0.88 g) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.29 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][OH:7])(=O)[CH3:2].[H-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15]C(F)=C[C:12]=1[C:18]([F:21])([F:20])[F:19]>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:1]([O:4][CH2:5][CH2:6][OH:7])=[CH:2][C:12]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(=O)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCOc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In an atmosphere of nitrogen, a mixture of 2-hydroxyethyl acetate, sodium hydride and DMF was stirred at room temperature for 15 minutes and then 1-bromo-4-fluoro-2-(trifluoromethyl)benzene was added, followed by stirring at room temperature for 1.5 hours to obtain 2-[4-bromo-3-(trifluoromethyl)phenoxy]ethanol.
Reaction SMILES: [NH2:1][C:2]1[N:15]([CH2:16][CH3:17])[C:6]2[N:7]=[C:8](S(C)(=O)=O)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>CS(C)=O>[NH2:1][C:2]1[N:15]([CH2:16][CH3:17])[C:6]2[N:7]=[C:8]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: CCn1c(N)c(C(N)=O)c(=O)c2cnc(S(C)(=O)=O)nc21
Solvent: CS(C)=O
Product: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(O)cc3)nc21
Temperature: 110 °C
Yield: 20.5 %

Procedure:
To a solution of 0.40 g (1.29 mmol) of the product obtained in step 1.5 in 4 mL of anhydrous DMSO is added 0.160 g (1.47 mmol) of 4-aminophenol. The reaction mixture is heated at 110°C. overnight and then evaporated to dryness. The solid residue is purified by chromatography on silica gel, eluting with a dichloromethane/methanol gradient (100/0 to 90/10). 0.090 g of the expected product is obtained in the form of an off-white solid. Yield=20%. m.p. >260°C. M+H+=341.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24]CC2C=CC=CC=2)=[C:6]([C:8](=[O:23])[CH:9]([O:15]CC2C=CC=CC=2)[C:10]([O:12]CC)=O)[CH:7]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:24][C:10](=[O:12])[C:9]([OH:15])=[C:8]([OH:23])[C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(OCc1ccccc1)C(=O)c1cc(Cl)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1oc2ccc(Cl)cc2c(O)c1O
Reaction time: 2 h
Yield: 68.9 %

Procedure:
Catalytic hydrogenation. A solution of ethyl 5-chloro-β-oxo-α,2-bis(phenylmethoxy)benzenepropanoate (0.88 g, 0.002 mol) in 20 ml of EtOAc was hydrogenated over 0.18 g of 10% Pd/C at room temperature and 35 psi for 2 h. After filtration, the solvent was removed under reduced pressure affording a light yellow oil. The oil was treated as previously described, affording 0.293 g (69%) of 6-chloro-3,4-dihydroxy-2H-1-benzopyran-2-one as white solid.
Reaction SMILES: [C:1]12([CH3:12])[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:4](=[O:5])[C:2]2=[O:3].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-].B(F)(F)F>CCOCC>[C:16]([CH:15]1[C:4](=[O:5])[CH:6]2[C:9]([CH3:10])([CH3:11])[C:1]([CH3:12])([CH2:8][CH2:7]2)[C:2]1=[O:3])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC12CCC(C(=O)C1=O)C2(C)C
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1C(=O)C2CCC(C)(C1=O)C2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (±) camphorquinone [(1,7,7)-trimethylbicyclo[3,2,1]-heptane-2,3-dione] (15.0 g, 90.24 mmol) and ethyl diazoacetate (11.8 g, 103.7 mmol) in 120 ml of ether is added, at 0°, BF3.ether (4 ml). The mixture is stirred at RT for 24 hr. The reaction mixture is extracted with 5% K2CO3 /H2O until no polar ethyl carboxyl dione remains. The combined aqueous extracts are acidified with conc. HCl and extracted with ether. The combined organic extracts are dried and evaporated to dryness to give crystalline 3-carboethoxy-1,8,8-trimethylbicyclo[3,2,1]octane-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([C:10]2[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[C:4]([F:22])[CH:3]=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:10]2[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A mixture of 2.04 g of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-144) and 35 ml of 48% hydrobromic acid was dissolved in 12 ml of acetic acid, and the solution was stirred at 140° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 1.55 g (yield, 79%) of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61; m.p., 188.1° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:24]=1
Reactant: COC(=O)CCN
Reactant: CCCCCC=C(c1ccc(C(=O)O)cc1)c1ccc(OC)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(3-bromo-4-methoxy-phenyl)-hept-1-enyl]-benzoic acid (380 mg, 0.94 mmol) in methylene chloride (9 mL) are added triethyl amine (0.39 mL, 2.81 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (197 mg, 1.41 mmol) and EDCI (541 mg, 2.81 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (321 mg).