Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11]>>[CH3:1][C:2](=[C:4]([O:8][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]([CH3:7])[CH3:6])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C(=O)C(C)C
Product: CC(C)=C(O[Si](C)(C)C)C(C)C

Procedure:
Reaction between 2,4-dimethyl-3-pentanone (1.2.4.3), trimethylsilyl chloride, and base gave 2,4-dimethyl-3-trimethysilyloxy-2-pentene (1.2.4.4) which was reacted with 1-fluoropyridinium triflate (1.2.4.5) to form 2,4-dimethyl-2-fluoro-3-pentanone (1.2.4.6). This product was reacted with (CH3)3S(O)+I− to form the title compound (1.2.4.2). 1.2.4.7 2,2-Bis-isopropyl oxirane.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18](O)[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.O.[CH:23]([OH:25])=[O:24]>>[CH:23]([O:25][CH2:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH:13]=[C:14]4[C@:15]3([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19]4)[C@@H:7]1[CH2:8][CH2:9][C:10]2=[O:11])=[O:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=CO
Solvent: O
Product: C[C@]12CCCCC1=CC[C@H]1[C@@H]3CCC(=O)[C@@]3(COC=O)CC[C@@H]12
Temperature: 60 °C

Procedure:
Following the procedure described by Ringold (H. J. Ringold, et al., J. Am. Chem. Soc. 78, 816, 1956), dehydroepiandrosterone (2.88 g, 10 mmol) dissolved in 85% formic acid (100 mL) is heated at 60° C. for 1 h. After cooling, the mixture is poured into iced water and after 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)/[C:5]/1=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][C:30](=[O:32])[CH3:31])[CH:22]=1)(=[O:3])[CH3:2].C(O)C>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([O:14][CH3:15])[CH:10]=2)[C@H:5]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][C:30](=[O:32])[CH3:31])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2/c3cc(OC(C)=O)c(OC)cc3CCN2C(C)=O)cc1OC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(C[C@@H]2c3cc(OC(C)=O)c(OC)cc3CCN2C(C)=O)cc1OC(C)=O
Temperature: 23 °C
Reaction time: 62 h
Yield: 87.8 %

Procedure:
In a dried Schlenk-tube having its atmosphere displaced with argon, 118.6 mg (0.270 mmol) of (Z)-N-acetyl-7-acetoxy-1-(3-acetoxy-4-methoxyphenylmethylene)-6-methoxy-1,2,3,4-tetrahydroisoquinoline was charged and dissolved in 1.5 ml of methylene chloride. To the solution was further added 7.5 ml of ethanol, followed by degasification by freezing three times. Separately, in a dried Schlenk-tube having its atmosphere displaced with argon, 1.1 mg (6.5×10-4 mmol) of Ru2Cl4 ((R)-(+)-BINAP)2N(C2H5)3 was charged and dissolved in 1.5 ml of methylene chloride which had been previously degassed by freezing three times. To the solution was further added 7.5 ml of ethanol. Both the solutions were transferred to a pressure bottle and subjected to hydrogenation under a hydrogen pressure of 4 atms. at 23° C. for 62 hours while stirring. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel: 15 g, eluent: ethyl acetate/hexane=3:1 by volume) to give 104.7 mg (0.237 mmol) of (R)-N-acetyl-7-acetoxy-1-(3-acetoxy-4-methoxyphenylmethyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (hereinafter referred to as acetylated N-acetylnorreticurine) in a yield of 88%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:20][CH2:21][C:22]([O-])=[O:23].Cl>CCOCC.C(Cl)CCl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:22](=[O:23])[CH2:21][CH2:20][C:19]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=1
Reactant: Fc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCCl
Product: CCOC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Temperature: 60 °C
Yield: 76.9 %

Procedure:
26.6 gm (0.2 mol) of powdered aluminum chloride were introduced over a period of 15 minutes into a mixture consisting of 17.2 gm (0.1 mol) of 2-fluoro-biphenyl, 16.4 gm (0.1 mol) of ethyl succinate chloride and 200 ml of ethylene chloride at 10° C, accompanied by stirring, and the resulting mixture was heated for 3 hours at 60° C. Thereafter, the reaction mixture was allowed to stand for several hours at room temperature, was then poured into a mixture of ice and hydrochloric acid, and 200 ml of ether were added to the mixture. The organic phase was separated, washed with water, with aqueous sodium bicarbonate and again with water, dried over sodium sulfate, and the solvent was distilled off. The oily residue was distilled in vacuo, yielding 23.1 gm (77% of theory) of ethyl 4-(2'-fluoro-4-biphenylyl)-4-oxo-butyrate, b.p. 190°-192° C at 0.4 mm Hg, which solidified into a crystalline substance after standing for some time and had a melting point of 56°-58° C after recrystallization from petroleum ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][C:14]#[N:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]#[N:15])[C:22]([O:23][CH2:24][CH3:25])=[O:26])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
The 4-benzyloxybenzyl cyanide from step (450a)(3.2 g, 14.33 mmol), sodium ethoxide (1.07 g, 15.7 mmol), and diethyl carbonate (2.23 g, 18.9 mmol) were combined in toluene (100 mL), heated to reflux for 3 h, cooled to rt, and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by chromatography on silica gel eluting hexane: ethyl acetate (80:20, v:v) to give ethyl 2-(4-benzyloxyphenyl)cyanoacetate (4.2 g, 99%) as an oil. MS (M+NH4)+ =313.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
4-Methoxyphenyl 4-iodophenyl ketone (722 mg) obtained in Example 176 was dissolved in dichloromethane (20 ml), a solution of 1.0 M boron tribromide in dichloromethane (9 ml) was added while cooled in ice, and the admixture was stirred at room temperature overnight. The reaction mixture was then poured into ice water and partitioned between water and chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and the solvent was removed by reduced-pressure distillation. The resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 380 mg of the title compound (yield: 55%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.ClCl>C(O)(=O)C>[Cl:1][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=2)[C:8]1=[O:12]
Reactant: Cl
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: ClCl
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2CC1Cl
Reaction time: 3 h

Procedure:
Hydrogen chloride gas is passed into a solution of 10.11 g (60 mmoles) of 5-chloro-1-indanone in 50 ml of glacial acetic acid at 10°-15° C. for 30 minutes. 4.25 g (60 mmoles) of condensed chlorine are then allowed to flow slowly into the solution at 10° C. and the mixture is allowed to come gradually to room temperature and is subsequently stirred for 3 hours. After standing overnight, the solution is poured onto ice, the oil which separates out is extracted with acetic acid ethyl ester and the solvent is distilled off under reduced pressure. The oil which remains crystallizes on standing. The product can be recrystallized from petroleum ether and then melts at 63°-66° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([CH2:15]O)([CH2:13][OH:14])[CH3:12]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:14][CH2:13][C:11]([CH3:15])([CH3:12])[CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2ccc(Br)cc2)OC1
Temperature: 25 °C
Yield: 64 %

Procedure:
The following describes an improved procedure at three times larger scale in much shorter time compared with the literature (Hewlins et al. (1986) J. Chem. Res. (M), 8: 2645–2696). 4-Bromobenzaldehyde (3.00 g, 16.2 mmol), neopentylglycol (1.86 g, 17.9 mmol) and p-toluenesulfonic acid (50 mg, 0.3 mmol) were dissolved in toluene (30 mL) and the solution was refluxed for 3 h. Then the solution was cooled to rt, washed twice with aq NaHCO3 (10%), twice with water and dried (Na2SO4). The solvent was evaporated and the oily residue was crystallized from hexanes, affording colorless needles (2.81 g, 64%). 13C NMR (APT) δ 21.7 (−), 22.9 (−), 30.1 (+), 77.5 (+), 100.8 (−), 122.7 (+), 127.8 (−), 131.3 (−), 137.5 ((+)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.Cl.[C:26](=N)(OCC)[CH3:27].C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH2:18][CH2:19][C:20]([F:21])([F:23])[F:22])[C:26]([CH3:27])=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NCCC(F)(F)F
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc(-c3nc4cc(Cl)ccc4o3)ccc2n1CCC(F)(F)F
Yield: 79.7 %

Procedure:
To a solution of 5-chloro-2-(2-(3,3,3-trifluoropropyl)aminoanilin-5-yl)benzoxazole (see Working Example 138-1) (200 mg, 0.562 mmol) in ethanol (5 mL) was added ethyl acetimidate hydrochloride (104 mg, 0.843 mmol), and this was heated to reflux for 5 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. The organic layer obtained was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude crystals that were washed with diethyl ether to yield the title compound (170 mg, 80% yield) as light green crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+].Cl>O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Yield: 81.4 %

Procedure:
A solution of Raltegravir potassium (˜2 g) in water was acidified with 2N HCl until pH 2 was obtained. The acidified solution was extracted with MTBE (600 ml). The organic extract was evaporated to dryness. Raltegravir free hydroxy (1.5 g) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:24]=[C:5]2[C:6]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:7][C:8]([CH3:10])=[CH:9][N:4]2[N:3]=1.[CH3:25][C:26]1[N:31]=[CH:30][N:29]=[C:28]([N:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)[CH:27]=1.C(Cl)Cl>C(Cl)Cl.CO>[CH3:10][C:8]1[CH:7]=[C:6]([C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH:12]=2)[C:5]2[N:4]([N:3]=[C:2]([NH:1][CH:35]3[CH2:36][CH2:37][N:32]([C:28]4[CH:27]=[C:26]([CH3:25])[N:31]=[CH:30][N:29]=4)[CH2:33][CH2:34]3)[N:24]=2)[CH:9]=1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2nc(N)nn2c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1

Procedure:
Prepared in analogy to example 1h, starting from tert-butyl 4-(2-amino-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a light yellow solid (yield: 32%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24].[CH2:26]([N:28]1[C:33](=[O:34])[N:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:31](=[O:42])[C:30]([C:43](O)=[O:44])=[N:29]1)[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:43]([C:30]2[C:31](=[O:42])[N:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:33](=[O:34])[N:28]([CH2:26][CH3:27])[N:29]=2)=[O:44])=[CH:18][C:17]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(C)C)c2cc1OC
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C(C)C)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-isopropyl-phenylamine and 2-ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid using the procedure for example 1. mp=155-156° C.; LCMS m/z=600 (M+1); 1H NMR (CDCl3) δ: 10.78 (s, 1H), 8.47 (d, 1H, J=5.5 Hz). 7.72 (s, 1H), 7.66 (d, 1H, J=8 Hz), 7.59 (s, 1H), 7.43 (s, 1H), 7.31-7.24 (m, 3H), 7.07 (d, 1H, J=9 Hz), 6.35 (d, 1H, J=6 Hz), 4.34 (q, 2H, J=7.3 Hz), 4.05 (s, 6H), 3.11 (m, 1H), 1.58 (t, 3H, J=6 Hz), 1.19 (d, 6H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6]C)=O.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]2[C:3]=1[C:4]([OH:6])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:1]2
Reactant: COC(=O)c1c(N)cccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(Cl)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of methyl 2-amino-6-chlorobenzoate (3.00 g, 16.2 mM) and dimethyl acetylenedicarboxylate (2.64 g, 18.6 mM) in t-butanol (25 mL) was refluxed under a nitrogen atmosphere for 18 hr. The reaction mixture was cooled to room temperature and potassium t-butoxide (2.09 g, 18.6 mM) was added in one portion whereupon a precipitate formed. After refluxing this mixture for 1.5 hr, it was cooled to room temperature and filtered to separate the solids. The solids were dissolved in water and the resulting solution acidified with 1N H2SO4 to form a precipitate. The mixture was filtered and the collected solids were washed with water and air dried to give dimethyl 5-chloro-4-hydroxyquinoline-2,3-dicarboxylate (3.84 g, 80.2%) as a tan solid. An 0.25 g portion of this material was recrystallized from ethyl acetate to provide an analytical sample (0.152 g) of the title compound as an off-white solid, mp 174°-176° C.; MS(CI): 296 (M+H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC1C=CC(S([N:31]=[N+:32]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([C:13](=[N+:31]=[N-:32])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of ethyl 3,5-bis(trifluoromethyl)phenylacetate (Step M, 26.0 g, 87 mmol) and 4-methylbenzenesulfonyl azide (Step L, 18.0 g, 91 mmol) in dry acetonitrile (150 mL) was added DBU (14.3 mL, 95 mmol) dropwise at −10° C. over 15 min with stirring. The mixture was stirred at −10° C. for a further 0.5 hr. The solvent was removed and the residue was partitioned between ether and water. The organic layer was washed with aqueous NaHCO3, brine, dried over Mg2SO4, and the solvent was removed. The residue was chromatographed (eluted with 9:1 hexane:ethyl acetate) to afforded a yellow solid. 1H-NMR (CDCl3): δ: 8.0 (2H, s), 7.68 (1H, s), 4.41 (2H, d, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si](C)(C)[C:14]([F:17])([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:15][C:14]([F:17])([F:16])[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)[OH:9]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-nitro-benzaldehyde (2.5 g, 17 mmol) in tetrahydrofuran (35 ml) was treated with trimethyl-trifluoromethyl-silane (2N in tetrahydrofuran, 10 ml, 20 mmol, 1.2 equiv.) and cooled to 0° C. A solution of tetrabutylammonium fluoride (1N in tetrahydrofuran, 1.70 ml, 2 mmol) was added, upon which the solution turned bright orange and then black. The mixture was stirred at 0° C. for 10 min, then at room temperature for 1 hour. The mixture was quenched with HCl 3N (6 ml), and stirred at room temperature overnight. The reaction was then diluted with ethyl acetate and brine and the two phases separated. The organic phase was washed with water, dried with Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethanol as a yellow solid, 2.1 g (57%). MS (ISP): m/e=220.1 (M−H), δH (300 MHz; CDCl3) 8.28 (2H, d), 7.70 (2H, d), 5.19 (1H, m), 2.84 (1H, d).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][N:5]=[CH:6][C:7](=[N:10][OH:11])[C:8]#[N:9]>C(O)CCC>[NH2:9][C:8]1[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[CH:6][C:7]=1[N:10]=[O:11]
Reactant: N#CC(C=NNCCO)=NO
Solvent: CCCCO
Product: Nc1c(N=O)cnn1CCO
Reaction time: 1 h
Yield: 65.1 %

Procedure:
In a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.94 g (6 mmol) of 3-(2-hydroxyethyl)hydrazono-2-hydroxyiminopropionitrile synthesized by the same method as in Example 5 and 6 ml of n-butyl alcohol, and the mixture was reacted at 110° C. for 3 hours, and further at 5 to 10° C. for 1 hour. After completion of the reaction, the reaction mixture was filtered, and the filtrate was dried under reduced pressure to give 0.61 g (isolation yield: 64%) of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole as reddish orange crystal.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]1[N:16]([CH3:17])[N:15]=[N:14][N:13]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[C:3]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][N:13]=2)=[CH:4]1)[CH3:19]
Reactant: Cn1nnnc1-c1cnc2ccccc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2nnnn2C)c(=O)c2ccccc21

Procedure:
A mixture of 4-hydroxy-3-(1-methyl-1H-tetrazol-5-yl)quinoline (2 g), ethyl iodide (1.1 ml), anhydrous potassium carbonate (1.83 g) and dimethylformamide (100 ml) was stirred and heated on a steam bath for 18 hours. The mixture was evaporated under reduced pressure and the residue dissolved in industrial methylated spirit (100 ml). Dilution with diethyl ether (100 ml) gave a white precipitate which was collected and extracted with hot dichloromethane (100 ml). The extract was evaporated to give the novel compound 1-ethyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 170°-176°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:13]2[CH2:14][CH:10]([CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH:8]=1)(=O)=O.C(N(CC)CC)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:31][Si:32]([C:35]#[C:36][C:7]1[CH:13]2[CH2:14][CH:10]([CH2:11][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH:8]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC=C(C#C[Si](C)(C)C)C1C2
Yield: 58.9 %

Procedure:
To a solution of t-butyl 4-trifluoromethanesulfonyloxy-6-azabicyclo [3.2.1]oct-3-ene-6-carboxylate (1.8 g, 5.0 mmol) in 10 mL of toluene was added 20 mL of triethylamine, followed by trimethylsilylacetylene (0.49 g, 5.0 mmol). The mixture was degassed, placed under a nitrogen atmosphere, and copper iodide (50 mg) and bis (triphenylphosphine)palladium dichloride (100 mg) were added. The reaction mixture was heated under reflux for 16 h, then cooled and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, using 0-50% ethyl acetate in hexane as eluent, to give tert-butyl 4-trimethylsilylethynyl-6-azabicyclo [3.2.1]oct-3-ene-6-carboxylate (900 mg, 58.9%). This was dissolved in 25 mL of methanol and treated with solid potassium carbonate (−1 g) with vigorous stirring. After 4 h, the mixture was concentrated to dryness in vacuo, and the residue was column chromatographed on silica gel, eluting with 2:1 hexane/ethyl acetate, to give a yellow oil (300 mg, 25.8% for two steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([S:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[F:22])(=[O:20])=[O:19])[CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Fc1ccccc1I
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1F
Yield: 29.9 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (2.2 g, 7.13 mmol) and 1-fluoro-2-iodobenzene (820 μL, 7.03 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with 60% dichloromethane/isohexane gave 2-(4-fluorophenyl)-6-[(2-fluorophenyl)sulfonyl]naphthalene (0.80 g, 30%). 1H NMR (500 MHz, CDCl3) δ 8.66 (1H, s), 8.20-8.18 (1H, m), 8.07 (1H, d, J=8.5 Hz), 8.03 (1H, s), 7.98 (1H, d, J=8.7 Hz), 7.94 (1H, d, J=8.7 Hz), 7.83 (1H, dd, J=1.7, 8.5 Hz), 7.71-7.62 (2H, m), 7.60-7.56 (1H, m), 7.38-7.30 (1H, m), 7.21-7.17 (2H, m), 7.14-7.05 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([CH3:11])=[N:9][CH:10]=1)=[O:4].[CH3:13][CH:14]([SH:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:16][CH:14]([CH3:15])[CH3:13])=[N:7][C:8]([CH3:11])=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)S
Reactant: COC(=O)c1cnc(C)nc1Cl
Product: COC(=O)c1cnc(C)nc1SC(C)C
Yield: 90 %

Procedure:
4-Chloro-2-methyl-pyrimidine-5-carboxylic acid methyl ester (0.105 g, 0.56 mmol) and 2-propanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.114 g, 90%).