Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([Cl:17])[N:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH3:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[ClH:17].[CH2:1]([N:8]1[C:12]2=[C:13]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][C:21]([CH3:20])=[CH:22][CH:23]=3)[N:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH3:18])=[C:9]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(Cl)nccc12
Product: Cc1ccc(CNc2nccc3c(C)c(C)n(Cc4ccccc4)c23)cc1
Product: Cl
Yield: 50 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 1-benzyl-7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 50%)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.CN(C1C=CC=CN=1)C>ClCCl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][O:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CC[C@@H](CO)N1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
(S)-5-hydroxymethylpyrrolidin-2-one (1.15 g) was dissolved in dichloromethane (40 mL), triethylamine (1.67 mL), p-toluenesulfonyl chloride (2.00 g) and dimethylaminopyridine (0.12 g) were added under ice-cooling, and the mixture was stirred at room temperature 18 hr. The reaction mixture was concentrated under reduced pressure, 0.5N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and the solvent was evaporated to give the title compound (1.88 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:17]=O.[CH3:19][CH:20]1[C:24](=[O:25])[NH:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21]1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:19][C:20]4([CH3:17])[C:24](=[O:25])[NH:23][C:22]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:21]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC1N=C(c2ccccc2)NC1=O
Reactant: C=O
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Product: CC1(CN2CCN(c3cccc4c3OCCO4)CC2)N=C(c2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(1,4-benzodioxan-5-yl)piperazine (4.96 g; prepared in a similar manner to that described in Example 2), 37-40% aqueous formaldehyde solution (1 ml) and industrial methylated spirit (40 ml) was stirred at ambient temperature under nitrogen for 30 minutes, then a suspension of 4-methyl-2-phenyl-2-imidazolin-5-one (3.82 g; prepared in a similar manner to that described in Example 37) in industrial methylated spirit (100 ml) was added in one portion. The mixture was stirred and heated under reflux for 18 hours, then the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 1:1 mixture of ethyl acetate and ethanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave an oil. The oil was triturated with ethyl acetate, undissolved solid was removed by filtration, the filtrate was diluted with cyclohexane, and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-4-methyl-2-phenyl-2-imidazolin-5-one 1.1 hydrate as an off-white solid (0.6 g), m.p. 80-85° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13][CH2:14][C:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:38].[OH2:48]>ClCCl.[Cl-].[Na+].O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([CH2:14][C:15]([OH:32])([CH3:31])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:28])([F:29])[F:30])[CH:20]=2)=[O:17])(=[O:38])=[O:48])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O
Reactant: CC(O)(CSc1ccccc1-c1ccccc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)c1ccccc1-c1ccccc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-phenylphenylthio)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (41 mg, 0.093 mmol) in dichloromethane (0.13 mL) at −78° C. was added 30% hydrogen peroxide (15.5 μL, 0.54 mmol) followed by the slow addition of trifluoroacetic anhydride (63 μL, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 23 mg of desired product. Production of PLM4 was confirmed by 1-H NMR and 13-C NMR.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C=CC=CC=1.Cl[C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1>COCCOCCOC.[Cu].O>[O:7]([C:22]1[CH:21]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:19]=[CH:18][CH:23]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: c1ccc(Oc2cccc(Oc3cccc(-c4cccc(Oc5ccccc5)c4)c3)c2)cc1
Temperature: 100 °C

Procedure:
A 500 ml. reaction flask equipped with stirrer, condenser and Dean-Stark trap was charged with 250 g. (2.66 moles) of phenol. This was heated with stirring at 100°C. while 56 g. (1.0 mole) of potassium hydroxide was added in increments. Toluene (50 ml.) was then added to the fluld mass and water azeotroped from the system. After all toluene and water had been removed, 150 ml. of diglyme was added together with 5.0 g. (0.05 mole) of cuprous chloride and 1.0 g. of copper powder. To this mixture 20 g. (0.053 mole) of 3-chloro-3'-(m-phenoxyphenoxy)biphenyl in diglyme was added over a 30 minute period. Diglyme was distilled from the mixture which was then heated at 240° for 18 hrs. On cooling the mixture was slurried in 200 ml. of ether and salts were filtered off. The ethereal solution was washed with 25% potassium hydroxide solution, water until neutral and then dried over magnesium sulfate. The ether was removed under vacuum and the resulting oil distilled to give 13.1 g. of the desired product, bp 248°-253° /0.06 mm., nD25 1.6474.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=1)=[O:4].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>C(#N)C>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:26][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH:6]=2)=[O:4])=[O:25])=[CH:22][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)CBr)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone INT-4 (1.3 g, 4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN (30 mL) was added TEA (0.72 ml, 5.2 mmol). After stirring overnight, the mixture was poured onto aq. citric acid and EA then stirred for 10 min before the solid was collected by filtration. The cake was washed with water and iso-hexanes then dried to provide 905 mg (57%) of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate. LCMS-ESI (m/z) calculated for C22H25BrO4: 432.1; found 433.2 [M+H]+, tR=3.24 min (Method 8).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38](Cl)=[O:39]>>[Cl:34][C:35]1[CH:36]=[C:37]([C:38]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:39])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)c3cc(Cl)cc(Cl)c3)CC2)cc1

Procedure:
(3,5-Dichloro-phenyl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 3,5-dichlorobenzoyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 2.02-2.10 (m, 4H), 3.12-3.18 (m, 1H), 3.30 (methyl sulfonyl and water peak), 3.62-3.68 (m, 1H), 4.54-4.60 (m, 1H), 5.10-5.16 (m, 1H), 7.54-7.55 (m, 2H), 7.63-7.65 (m, 2H), 7.72-7.73 (m, 1H), 8.05-8.07 (m, 2H), 8.41 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=546, M+Na=478.
Reaction SMILES: F[C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([O:21][CH2:22][O:23][CH3:24])[CH:3]=1.[C-:25]#[N:26].[K+].CS(C)=O.C(OCC)(=O)C>O>[C:25]([C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([O:21][CH2:22][O:23][CH3:24])[CH:3]=1)#[N:26]
Reactant: COCOc1cc(F)c(F)cc1C(=O)c1ncccc1OCOC
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCOc1cc(C#N)c(F)cc1C(=O)c1ncccc1OCOC
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 2-(4,5-difluoro-2-methoxymethoxybenzoyl)-3-methoxymethoxy pyridine (7.18 g), potassium cyanide (4.47 g) and DMSO (100 ml) was stirred at 34°-40° C. overnight. To the reaction mixture were added ethyl acetate and water for extraction. The organic layer was washed with water and a saturated aqueous saline solution, successively, which was then dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give a mixture (7.05 g) of 2-(4-cyano-5-fluoro-2-methoxymethoxybenzoyl)-3-methoxymethoxypyridine and the starting compound (5:1). To this mixture (6.98 g) were added methanol (100 ml) and conc. hydrochloric acid (5 ml), which was stirred at 60° C. overnight. The reaction mixture was cooled by aeration, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic solvent was dried (anhydrous magnesium sulfate). The solvent was distilled under reduced pressure. The residue was washed with isopropylether to give 2-(4-cyano-5-fluoro-2-hydroxybenzoyl)-3-hydroxypyridine as crude crystals (4.59 g). This crude crystalline product was, without further purification subjected to reaction, in accordance with the method in Example 1, to lead to its oxime to give (Z)-2-(4-cyano-5-fluoro-2-hydroxybenzoyl)-3-hydroxyoyridine O-t-butyloxime (2.46 g) (Compound 176).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:15]2)[N:3]=1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[N:15]2)[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COC(=O)Nc1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 142 mg (0.33 mmol) of the compound from example 1 were initially charged in THF (9.5 ml), the mixture was cooled to 0° C. and 13 mg (0.33 mmol) of sodium hydride (60% suspension in mineral oil) were then added. The mixture was stirred at 0° C. for 30 min, and 96 μl (0.67 mmol) of 2,2,2,-trifluoroethyl trichloromethanesulfonate were then added dropwise. The reaction mixture was stirred at RT overnight. The mixture was then diluted with ethyl acetate and the organic phase was washed twice with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase dichloromethane:methanol 60:1) and the product fractions were concentrated. The crude product obtained in this manner was re-purified by means of preparative RP-HPLC (acetonitrile:water (+0.1% formic acid)−gradient), then suspended in acetonitrile/water and finally dried by lyophilization. This gave 68 mg (40% of theory) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.C(N(CC)CC)C.[CH3:18][CH:19]([CH2:23][CH2:24][Cl:25])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:25][CH2:24][CH2:23][CH:19]([CH3:18])[C:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:21]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(CCCl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a stirred solution of 7 g of 3-amino-5-(1,1-dimethylethyl)isoxazole and 5.05 g triethylamine dissolved in 100 ml ethyl acetate was added 7.75 g of 2-methyl-4-chlorobutyric acid chloride dropwise. The mixture was stirred for about 16 hours at room temperature and the precipitated salt was collected by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene:diethyl ether. Fractions containing the major component as indicated by thin layer chromatography were combined and concentrated under vacuum to provide 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide. Yield 54%. This material was used in the following reaction without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Bromo-1H-pyrazolo[3,4-b]pyridine (1.39 g) in DMF (6 ml) was cooled in an ice-bath under nitrogen and treated portionwise with sodium hydride (0.308 g) (60% dispersion in oil) over a period of about 15 min. The reaction was left to stir in the ice-bath for 40 min, then treated with tosyl chloride (1.469 g) in DMF (2 ml). The reaction was left to stir in the ice-bath under nitrogen and the ice left to melt overnight. The reaction was stirred for a total of 20 h. The reaction was treated cautiously with water (6 ml) and stirred for 5 min. The reaction was poured onto water (60 ml), filtered and the residue treated with DCM (20 ml). The mixture was stirred, and then pushed through a frit into a cartridge with a hydrophobic frit. The solution was allowed to drip through, and then this procedure was repeated with further DCM (2×15 ml). The combined filtrates were evaporated to dryness to give the title compound as a brown solid, 1.802 g.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH2:17][CH3:18])=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[N:30]1([CH2:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:41]/[C:19](=[C:6]3\[C:5](=[O:29])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:16][CH2:17][CH3:18])=[C:10]([O:13][CH2:14][CH3:15])[CH:11]=4)/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OCC)c(OCC)cc21)c1ccccc1
Product: CCOc1cc2c(cc1OCC)/C(=C(/Nc1ccc(CN3CCCCC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-diethoxy-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([O-])(=[O:14])=[O:13])=[C:8]([CH3:16])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[K+].O=P(Cl)(Cl)[Cl:20]>>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([Cl:20])(=[O:14])=[O:13])=[C:8]([CH3:16])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(C)c(S(=O)(=O)[O-])sc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Product: COc1cccc2c(C)c(S(=O)(=O)Cl)sc12
Temperature: 60 °C
Yield: 46 %

Procedure:
A mixture of potassium 7-methoxy-3-methylbenzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the crude product was purified on a small amount of silica eluting with CH2Cl2 to give the title compound in 46% yield (43 mg).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[C:12]([C:15]([F:18])([F:17])[F:16])[NH:11][C:10]=2[C:9](=[O:19])[NH:8]/[C:7]/1=[N:20]\[NH2:21])[CH2:2][CH2:3][CH2:4][CH3:5].[C:22](OCC)(OCC)(OCC)[CH3:23]>>[CH3:22][C:23]1[N:8]2[C:9](=[O:19])[C:10]3[NH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[N:13][C:14]=3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[N:20][N:21]=1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Reactant: CCOC(C)(OCC)OCC
Product: CCCCCn1c2nc(C(F)(F)F)[nH]c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione-2-hydrazone (0.020 g, 0.14 mmol) and triethyl orthoacetate (2 mL, 10 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and the residue was purified by preparative LCMS. The product fractions were collected and lyophilized to yield pure product as white powder. LCMS calculated for C13H15F3N6O: (M+H) 329.1. found: 329.1.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][C:8]([CH3:30])=[CH:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:33][C:34](=O)[C:35]([F:38])([F:37])[F:36])[CH3:32].O>CCCCCC.O1CCCC1>[F:36][C:35]([F:38])([F:37])[C:34]([O:33][CH2:31][CH3:32])=[CH:10][CH:9]=[C:8]([CH3:30])[CH3:7]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=CC=C(C)C)C(F)(F)F
Yield: 41.7 %

Procedure:
96 ml of a 20% strength solution of n-butyl-lithium in hexane were added dropwise to a suspension of 82.2 g (0.2 mol) of dry 3,3-dimethylallyl-triphenylphosphonium bromide in 300 ml of anhydrous tetrahydrofuran at 0° C. under nitrogen, while stirring. The deep red solution thus obtained was stirred at 0° C. for a further 15 minutes and 28.4 g (0.2 mol) of trifluoroacetic acid ethyl ester were then added dropwise at 0°-10° C. The mixture was then stirred at room temperature until it was almost decolorized (about 12 hours). 600 ml of water were then added to the reaction mixture and the mixture was extracted 5 times with 200 ml of petroleum ether each time. The petroleum ether phases were dried over magnesium sulphate and the solvent was then stripped off in a rotary evaporator under a waterpump vacuum. 150 ml of n-hexane were added to the residue and the mixture was then filtered. The solvent was subsequently distilled off from the filtrate under normal pressure and the oily residue was then distilled in vacuo. 16.2 g (41.8% of theory) of 1,1,1-trifluoro-2-ethoxy-5-methyl-2,4-hexadiene were obtained as a slightly yellowish liquid with a boiling point of 72° C./36 mbar.
Reaction SMILES: [Br-].O[C@@H]1CCC[N+](CC(=O)NC2C=CON=2)(C)C1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1.[Br:27]CC(NC1C=CON=1)=O.[C:37]1([CH2:43][CH2:44][CH2:45]Br)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Br-:27].[OH:26][CH:23]1[CH2:24][CH2:25][N+:20]([CH3:19])([CH2:45][CH2:44][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:21][CH2:22]1
Reactant: CN1CCC(O)CC1
Reactant: O=C(CBr)Nc1ccon1
Reactant: BrCCCc1ccccc1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CCCc2ccccc2)CCC(O)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate C) by replacing (R)-1-methyl-piperidin-3-ol (step C3) with 1-methyl-piperidin-4-ol and by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) with 3-phenyl propylbromide.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].C1COCC1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.O>[CH3:9][C:2]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:1])[CH2:3][CH2:4][OH:5]
Reactant: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(CCO)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: -10 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (213 mg, 0.000481 mol) in THF (5 mL, 0.0616 mol) at −78° C. was added diisobutylaluminum hydride in DCM (1.00 M, 1.1 mL) dropwise. The reaction mixture was stirred for 3 hours during which time the reaction slowly warmed to −10° C. To the mixture at −10° C. was carefully added K/Na tartrate tetrahydrate in water. The mixture was stirred for 2 hours, then was extracted with three portions of ethyl acetate. The combined organic extracts were washed with two portions of water and one portion of brine, then dried over sodium sulfate, filtered and concentrated to afford 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (185 mg, 96%), which was used without further purification. A portion of the alcohol so obtained (15 mg, 0.000037 mol) was stirred in TFA (1 mL) for 2 hours. The TFA was removed in vacuo and the residue was stirred with 2 mL MeOH containing 0.5 mL NH4OH for 16 hours. Volatiles were removed and the product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 3-methyl-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butan-1-ol as the trifluoroacetate salt (8.0 mg, 57%). 1H NMR (300 MHz, d6-DMSO): δ 12.17 (s, 1H), 8.58 (br s, 1H), 8.32-8.22 (br m, 2H), 7.62 (br s, 1H), 7.53 (br d, 1H), 7.03 (br s, 1H), 3.25 (t, 2H), 2.07 (t, 2H), 1.62 (s, 6H); MS(ES): 271 (M+1).