Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[N:30]5[N:31]=[C:32]([CH3:34])[N:33]=[C:29]5[C:28](CC5C=CC(C6C=CC=CC=6C6N(C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)N=NN=6)=CC=5)=[C:27]4[CH2:72][CH3:73])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:86]([C:88]1[CH:95]=[C:94]2[N:90]([N:91]=[C:92]([CH3:133])[N:93]2CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[N:89]=1)[CH3:87].C(C1C(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)=C2N(N=C(C)N2)N=1)C.C(C1N(CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)N2C(C=1)=NC(C)=N2)C>>[CH2:72]([C:27]1[N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[N:8]([C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:80]4[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=4)[C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[N:9]=[N:10][N:11]=3)=[CH:24][CH:23]=2)[N:30]2[C:29]([CH:28]=1)=[N:33][C:32]([CH3:34])=[N:31]2)[CH3:73].[CH2:86]([C:88]1[CH:95]=[C:94]2[N:90]([N:91]=[C:92]([CH3:133])[NH:93]2)[N:89]=1)[CH3:87]
Reactant: CCc1c(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c2nc(C)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1cc2n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c(C)nn2n1
Agent: CCc1cc2nc(C)nn2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCc1nn2nc(C)[nH]c2c1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCc1cc2[nH]c(C)nn2n1

Procedure:
In the same manner as described in Example 38, 0.40 g of 5,7-bis[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-6-ethyl-2-methyl-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 49a), 2.96 g of 6-ethyl-2-methyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 49b), 0.29 g of 6-ethyl-2-methyl-7-[[2' -(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 49c) and 1.75 g of 6-ethyl-2-methyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 49d) were obtained from 1.84 g of 6-ethyl-2-methyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7](CC2C=CC(OC)=CC=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]1=[O:29].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[NH2:1][CH:2]1[C:3](=[O:29])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=2[NH:7][C:8]1=[O:9]
Reactant: COc1ccc(CN2C(=O)C(N)C(=O)N(c3ccccc3)c3ccccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a stirred solution of 3-amino-1-(4-methoxybenzyl)-5-phenyl-1,5-dihydrobenzo [b] [1, 4] diazepine-2,4-dione (0.50 g) in acetonitrile/H2O (9:1, 12 ml) at ambient temperature was added cerric ammonium nitrate (1.84 g) portionwise over a ten minute period. The solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resultant solid partitioned between saturated aqueous potassium carbonate (40 ml) and ethanol (60 ml). The phases were separated and the aqueous phase extracted with ethanol (4×50 ml). The ethanol portions were combined, dried over sodium sulfate and concentrated in vacuo to a tan solid. This solid was extracted exhaustively with boiling CH2Cl2 (10×60 ml), the organics combined, dried over sodium sulfate, filtered and concentrated to give the title compound (0.30 g) as a tan solid. 1H (300 MHz, DMSO-d6): d 1.98 (br s, 2H), 4.08 (s, 1H), 6.86 (d, J=8.4 Hz, 1H), 7.11-7.46 (m, 8H), 10.78 (br s, 1H); 13C (75.429 MHz, DMSO-d6): d 56.98, 123.41, 126.22, 126.51, 127.34, 128.30, 128.89, 130.15, 132.29, 134.42, 142.36, 168.13, 169.39. MS (FAB): m/z=268.10 (MH+); TLC (CH2Cl2 /CH3OH,15:1): Rf =0.21.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.O[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:18][C:2]([F:17])([F:1])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:10]([CH3:16])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Reactant: OCCCCc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCCc1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To a suspension of 0.44 g (1.8 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.25 g (1.66 mmol) of 3-(4-hydroxybutyl)-pyridine, and 0.52 g (1.99 mmol) of triphenylphosphine in 30 ml of methylene chloride under nitrogen at 0° C. was added dropwise a solution of 0.35 g (1.97 mmol of DEAD in methylene chloride, and the resulting mixture was allowed to warm to room temperature. After adding 70 mg of triphenylphosphine, the mixture was stirred at room temperature for 2 days. The solution was concentrated in vacuo and the residue was purifed by MPLC (26 id Kieselgel 60 column; hexane/ethyl acetate 3:1) to yield 0.56 g (86.1%) of 3-[4-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-butyl]-pyridine, as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11](Cl)(=[O:13])C.[C:15]([Cl:19])(Cl)([Cl:17])[Cl:16]>>[Cl:16][C:15]([Cl:19])([Cl:17])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)=[O:13]
Reactant: CC(C)(C)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)Cl
Product: CC(C)(C)c1ccc(C(=O)C(Cl)(Cl)Cl)cc1

Procedure:
Illustrative examples of compounds according to the general formula hereinbefore defined are: 2-chloro-4'-tert.butylacetophenone; 2,2-di-chloro-4'-tert.butylacetophenone; 2-chloro-4'-octylacetophenone; 2,2-di-chloro-4'-octylacetophenone; 2-chloro-4'-n-C8-13 -alkylacetophenone; 2,2-dichloro-4'-n-C8- alkylacetophenone; 2,2,2-trichloro-4'-n-C8-13 alkylacetophenone in which the alkyl groups range from 8-13 carbon atoms (derived from C8-13 alkylbenzene with the trade name Dobane 83 X); 2,2-dichloro-4'-octyloxyacetophenone; 2,2,2-trichloro-4'-octyloxyacetophenone; 2,2-dichloro2',4'-diisopropylacetophenone; 2,2,2-trichloro-2',4'-diisopropylacetophenone or mixtures of these compounds. Preferably, however, the new compund 2,2,2-trichloro-4'-tert.butylacetophenone is used. This compound may be prepared in an analogous way to that described in J.A.C.S. 72 (1950) pages 3952-3 for the preparation of trichloroacetophenone, namely by treating 4-tert.butylacetophenone with chlorine. The starting 4-tert.butylacetophenone may be obtained in the manner described in J.A.C.S. 68 (1946) page 1107 by a Friedel-Crafts acetylation of tert.butylbenzene with acetyl chloride in a solvent, such as carbon tetrachloride. The compound 2,2,2-trichloro-4'-tert.butylacetophenone may also be obtained in an analogous way to that described in Houben-Weyl 5/3 page 790 for the preparation of trichloro-2',4',6'-trimethylacetophenone. The compound may also be prepared directly by a Friedel-Crafts reaction of tert.butylbenzene with trichloroacetyl chloride in carbon disulphide as described in J. Indian Chem. Soc. 26 (1947) pages 287-9. It is also possible to use trichloro-acetonitrile instead of trichloro-acetyl chloride as described in J. Prakt. Chem. (2) 123 (1929) 313.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2.C(O)(=O)C.O>C1(C)C=CC=CC=1.CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Temperature: 100 °C

Procedure:
and 2.3 g of (2R,4R/S)-4-(,4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 140 mg (0.88 mmol) of 5-aminoquinolin-2(1H)-one are dissolved in 19 ml of toluene and the solution is admixed with 0.55 ml (1.75 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 539 mg of (5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one as a crude product. The imine is dissolved in 44 ml of CH2Cl2 and the solution is cooled to −30° C. 8.9 ml (8.9 mmol) of a 1M BBr3 solution in dichloromethane are added slowly dropwise over 15 minutes and the mixture is allowed to warm to room temperature over 22 hours. The reaction solution is poured onto a mixture of saturated NaHCO3 solution and ice. It is extracted repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 134 mg of the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22]Br)[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:12]([O:13][C:14](=[O:16])[CH3:15])[CH:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2([CH2:22][N:25]=[N+:26]=[N-:27])[CH2:21][CH:6]1[NH:7][C:8](=[O:24])[O:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C2CC(CBr)(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC1C2CC(CN=[N+]=[N-])(OC(=O)N2)C(OC(C)=O)C1OC(C)=O
Reaction time: 8 h

Procedure:
6,7,8-Triacetoxy-1-bromomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (as described in Example 1 of the Japanese Patent Application No. 144309/1981, pp. 37) (4.1 g) is dissolved in dimethylformamide (15 ml), and sodium azide (1.0 g) is added to the solution, followed by stirring under heating on a bath of the temperature of 130° to 140° C. for 7 hours. The reaction mixture is concentrated under reduced pressure and further freed of the dimethylformamide azeotropically with toluene, under reduced pressure. 20% Aqueous methanol (100 ml) is added to the residue, which is then allowed to stand overnight in a refrigerator. The resultant crystals are recovered by filtration, washed with 20% aqueous methanol cooled with ice, and dried to produce 6,7,8-triacetoxy-1-azidomethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (2.7 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13](=O)[CH2:14][C:15](=O)[CH3:16]>C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:12])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C)cc2C)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (118.7 g, 0.68 mol) in 300 mL of glacial acetic acid was added 2,4-pentanedione (68.0 g, 0.68 mol). The resulting solution was stirred at 100° C. for 18 h and then was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, filtered through a pad of silica gel and concentrated to afford 131 g (95%) of the title compound, which was used without purification. LRMS (NH4−CI): 203.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:16](=[O:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].CO.[BH4-].[Na+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH:16]([OH:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9]2)=[CH:4][C:3]=1[C:23]([F:26])([F:24])[F:25]
Reactant: COC(=O)C1C(=O)c2ccccc2OC1c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1C(O)c2ccccc2OC1c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2.25 h
Yield: 96.8 %

Procedure:
A solution of methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxochroman-3-carboxylate (300 mg, 780 μmol) in tetrahydrofuran (2.0 mL) was diluted with methanol (4.0 mL, 780 μmol) and treated at rt with sodium borohydride (30 mg, 780 μmol). After 2.25 h, the solution was poured into water (about 25 mL), treated with 1.0 M aqueous HCl (about 1 mL) and then extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to provide crude racemic methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxychroman-3-carboxylate as a white solid (292 mg). Without further purification, this material was dissolved in dichloromethane (9.5 mL) and treated with trifluoroacetic acid (0.5 mL). After standing at rt for 1.5 h, the solution was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography (silica gel, 2-10% ethyl acetate/hexane) to provide crude racemic methyl 2-(4-chloro-3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxylate as a colorless gum (65 mg). Without further purification, a solution of a portion of this gum (60 mg) in methanol (2.0 mL) was treated with 1.0 M aqueous sodium hydroxide (2.0 mL) and heated at reflux for 4.5 h. After this time, the solution was cooled to rt. Once at the prescribed temperature, a white solid formed, which was removed by filtration and washed with water. The combined filtrate and wash were acidified with 1.0 M aqueous HCl, giving a gummy material. A small amount of methanol was added to the gummy material and the resulting mixture was heated briefly, then stirred while cooling to rt, thereby forming a white solid, which was collected by filtration, washed with water and dried under vacuum to provide Example 2-1 (29 mg). 1H NMR (400 MHz, CDCl3) δ ppm 6.26 (s, 1 H) 6.83 (d, J=8.1 Hz, 1 H) 6.96 (t, J=7.1 Hz, 1 H) 7.23 (dd, J=7.6, 1.0 Hz, 1 H) 7.29 (m, 1 H) 7.41 (d, J=8.1 Hz, 1 H) 7.46 (dd, J=8.6, 2.0 Hz, 1 H) 7.72 (d, J=1.5 Hz, 1 H) 7.83 (s, 1 H. Mass spectrum m/z 355.24 (M+H)+, 377.16 (M+Na)+.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]([C:32](=[O:34])[CH3:33])[CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:11]2[CH:35]=[C:36](Br)[CH:37]=[CH:38][C:10]1=2)=[O:8])([CH3:5])[CH3:4].Cl.[CH3:41][OH:42]>>[C:32]([N:16]([CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH:12]1[CH2:13][CH2:14][CH2:15][N:9]([C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[O:8])[C:10]2[CH:38]=[CH:37][C:36]([C:41]([OH:42])=[O:1])=[CH:35][C:11]1=2)(=[O:34])[CH3:33]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(Br)cc21
Reactant: CO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(C(=O)O)cc21
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Add 2 N sodium hydroxide solution (2 mL) to a solution of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.100 g, 0.174 mmol) in methanol (5 mL) at 0° C. and allow to stir for 30 min. Acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by triturating with water, to provide the title compound as a white solid (0.091 g, 96%): APCI MS 561 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F-:10].[K+]>CN1CCCC1=O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[F:10][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: [F-]
Reactant: N#Cc1ccnc(Cl)c1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccnc(F)c1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
Treat a solution of 2-chloro-4-cyanopyridine (6.0 g, 43.5 mmol) and potassium fluoride (7.56 g, 130.3 mmol) in 1-methyl-2-pyrrolidinone (20 mL) with tetrabutylphosphonium bromide (14.8 g, 43.7 mmol) and heat to 100° C. for 18 hours. Dilute with water and extract with EtOAc. Wash EtOAc with water, brine, dry with Na2SO4, and concentrate to give the title compound (2.3 g, 43%). MS (ES) 123.1 (M+1)+. 1H NMR (400 MHz, CHCl3) δ 8.43 (d, 1H, J=5.2 Hz), 7.45 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[C:22]([O:26][C:27](=[O:30])[CH2:28][NH2:29])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:29][CH2:28][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Temperature: 120 °C
Reaction time: 17 h
Yield: 49.2 %

Procedure:
A solution of crude ethyl 6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-carboxylate (4100 mg, 12088 μmol) and glycine tert-butyl ester hydrochloride (2229 mg, 13297 μmol) in 1,4-dioxane (100 mL) was treated with DIPEA (4211 μL, 24176 μmol). The reaction was heated at 120° C. in a sealed vessel. After 17 hours, the reaction was cooled to 23° C., diluted with EtOAc (200 mL) and washed with 10% HCl solution (2×150 mL) and brine (100 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (eluant: 5-10% EtOAc/hexane) affording 2523 mg of 1,1-dimethylethyl N-((6-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate. MS m/e=422.0 (M−H)−.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18]Br.O>C(O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCC#CCOC1CCCCO1
Solvent: O
Solvent: CCO
Product: C(#CCSc1ccccc1)COC1CCCCO1

Procedure:
A stirred solution of sodium ethoxide in ethanol, obtained from 1.3 g of sodium and 50 ml of absolute ethanol was treated dropwise with 5.5 g (0.05mol) of thiophenol in 15 ml of absolute ethanol. The reaction mixture was refluxed for 1 hour and then treated with 5.84 g (0.025 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether, refluxing the mixture for 2 additional hours. It was then cooled, poured into water and extracted withmethylene chloride. The organic extract was washed with water, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, to produce 4-phenylthiobut-2-yn-1-ol tetrahydropyranyl ether, as an oil. Upon hydrolysis of the ether group with pyridinium p-toluenesulfonate in ethanol, in accordance with the method of Example 16, part E, there was obtained 4-phenylthiobut-2-yn-1-ol.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:6]=[CH:7][C:8](F)=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.O>CN(C=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([S:2][CH3:1])=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: Fc1ccc(Br)cc1C(F)(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cc1C(F)(F)F
Temperature: 50 °C
Yield: 68.3 %

Procedure:
A mixture of sodium thiomethoxide (317 mg) and 5-bromo-2-fluorobenzotrifluoride (1.0 g) in DMF (4 ml) was heated at 50° C. for 1 h then poured into water and extracted with isohexane. The organics were washed with brine, dried and concentrated in vacuo to give the sub-title compound (762 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](C(O)=O)=[CH:5]2.[Cl:15][C:16]1[C:17]([F:28])=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][C:22](C(O)=O)=[CH:21]2>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[C:17]([F:28])=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2
Reactant: O=C(O)c1cc2ccc(F)c(Cl)c2[nH]1
Reactant: O=C(O)c1cc2cc(Cl)c(F)cc2[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Fc1cc2[nH]ccc2cc1Cl
Product: Fc1ccc2cc[nH]c2c1Cl
Reaction time: 4 h
Yield: 39 %
Yield: 14 %

Procedure:
A suspension of 1.92 g of an almost 1:1 mixture of 5-chloro-6-fluoro-indole-2-carboxylic acid and 7-chloro-6-fluoro-indole-2-carboxylic acid in 45 ml of diphenyl ether was stirred at 260° for 4 hours. The reaction mixture was chromatographed over 100 g of silica gel with hexane and hexane-toluene (3:1). There were obtained 0.6 g (39%) of 5-chloro-6-fluoroindole as light brown crystals with m.p. 88°-90° and 0.22 g (14%) of 7-chloro-6-fluoroindole as a dark brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=O)[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:22])=[CH:15][C:14]=3[OH:13])=[N:24][NH:25][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c[nH]nc2-c2ccc(O)cc2O)cc1OC
Yield: 55.3 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(3,4-Dimethoxy-phenyl)-7-hydroxy-chromen-4-one (0.5 g, 1.68 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude product was columned to give 4-[4-(3,4-Dimethoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale yellow solid (0.29 g, 55.3%); Rf 0.2 Cf SM 0.7 ethyl acetate/hexane (75/25).