Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[C:31]([O:32]C)=[CH:30][C:29]3[C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][C:25]([CH3:37])([CH3:36])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].ClCCl.B(Cl)(Cl)Cl>C1COCC1>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([C:22]2[C:31]([OH:32])=[CH:30][C:29]3[C:28]([CH3:35])([CH3:34])[CH2:27][CH2:26][C:25]([CH3:37])([CH3:36])[C:24]=3[CH:23]=2)=[O:21])[CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: COc1cc2c(cc1C(=O)COc1ccc(C(=O)OCc3ccccc3)c(O)c1)C(C)(C)CCC2(C)C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C(=O)COc3ccc(C(=O)OCc4ccccc4)c(O)c3)c(O)cc21
Temperature: 0 °C
Yield: 79.3 %

Procedure:
4 g (8 mmol) of benzyl 2-hydroxy-4-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylmethoxy)benzoate and 20 ml of dichloromethane are introduced into a flask. 24 ml (24 mmol) of a solution of boron trichloride in THF (1M) are added dropwise at -78° C. and under a stream of nitrogen and the temperature is allowed to rise to -20° C., then the reaction mixture is poured into ice-water. The mixture is extracted with ethyl ether, and the organic phase is separated, dried over magnesium sulphate and evaporated. The residue obtained in purified by chromatography on a silica column, eluted with a dichloromethane/hexane mixture (50:50). 3.1 g (80%) of the expected ester of melting point 127°-128° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[Na+].[F:18]F>C(#N)C>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[F:18][N+:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: FF
Reactant: Clc1cccc(Cl)n1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[n+]1c(Cl)cccc1Cl
Temperature: -40 °C

Procedure:
A 100 ml (milliliters) 3-necked round bottom flask was equipped with a magnetic stirring bar, a fluorine-helium inlet tube, and a gas outlet tube connected to a granular alumina trap and then to a 5 percent aqueous caustic trap. A 1.0 g (gram) (6.8 mmol (millimole)) sample of 2,6-dichloropyridine, 1.03 g (6.0 mmol) of sodium trifluoromethanesulfonate, and 40 ml of anhydrous acetonitrile were added and the mixture cooled to -40° C. A 1:9 mixture of fluorine and helium then was passed into the mixture with stirring at the rate of 30 ml per minute until 15 mmol of fluorine had been added. The fluorine gas mixture was replaced with nitrogen gas and the mixture was allowed to warm to ambient temperature. The mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure to obtain 0.75 g (40 percent of theory) of the title compound as a yellowish solid. The compound had 19FNMR absorptions (CD3CN, CFCl3 standard) at 31.6 ppm (s) N-F and -78 ppm (s) CF3 in a 1:3 ratio as required by the structure.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:16]1[CH2:21][CH2:20][C:19]([CH3:27])([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:28][CH2:29]I.C(O)(=O)C>C1COCC1>[Cl:28][CH2:29][C:22]([C:19]1([CH3:27])[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:21][CH2:20]1)=[O:24]
Reactant: ClCI
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CCl)CC1
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
Lithium diisopropylamide (30.9 mL, 46.4 mmol) was added dropwise to a solution containing ethyl N-Boc-4-methylpiperidine-4-carboxylate (2.52 g, 9.28 mmol), and chloroiodomethane (6.55 g, 37.1 mmol) in THF (100 mL) at −78° C. over 30 minutes. After addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (5 mL) in THF (45 mL) was added while keeping reaction mixture below −65° C. The reaction was stirred for an additional 10 minutes and partitioned between ethyl acetate and brine, washed with saturated bicarbonate, concentrated and purified by silica gel (10%-20% ethyl acetate in hexanes) to afford tert-butyl 4-(2-chloroacetyl)-4-methylpiperidine-1-carboxylate (1.15 g, 44.92% yield).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH:13]([NH:16][C:17]([NH2:19])=[O:18])([CH3:15])[CH3:14].Cl>C(O)C.O>[CH:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)NC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)N1C(=O)CC(=O)NC1=O
Yield: 95.8 %

Procedure:
13.8 g (0.6 mole) of sodium are dissolved in 250 ml of anhydrous ethanol. 61.2 g (0.46 mole) of diethyl malonate and 47.3 g of isopropyl urea (0.46 mole) are added to the resulting solution. The mixture thus formed is heated for 7.5 hours to 120° C. (temperature of the bath). After cooling, a solution of concentrated HCl and water (1:4) is slowly added until the precipitate formed during the reaction has dissolved. The resulting solution is evaporated until a precipitate appears and is then left standing at 0° C. The precipitate is then filtered, washed with cold water and dried, giving 75 g of colourless crystals.
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:8]>>[C:2]([OH:8])(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: O
Reactant: c1ccccc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
A publication in J. Amer. Chem. Soc. 70 (1948), 1,629-1,632 discloses that the reaction can also be carried out with the free base in the absence of hydrochloric acid, at from 180° to 220° C.; as shown by the description and all the Examples, the reaction is intended to be carried out with a molar ratio of the reactants of 1:1, and in the presence of benzene in the reaction mixture. During the reaction, an azeotropic mixture of benzene and water is distilled off. In spite of this special procedure, substantial amounts of a high-boiling by-product are always found alongside the imidazoline. The publication describes, and shows with Examples, that the yield of this by-product increases with the number of carbon atoms in the alkanecarboxylic acid molecule; for example, reactions with acetic acid give a 32.7 percent yield, and those with myristic and a 92.5 percent yield, of high-boiling by-product. In the case of stearic acid, only the by-product is obtained, the yield being virtually quantitative. The yields of imidazoline are 26.6 percent in the case of acetic acid, 13.3 percent in the case of formic acid, 12.9 percent in the case of propionic acid and 15.4 percent in the case of caproic acid. The yields for longer-chain carboxylic acids are not stated. The recovery of a part of the imidazoline from the by-product is only possible by laborious methods, for example by treatment with aqueous sodium hydroxide solution, extraction with ether, drying the ether extract over solid potassium hydroxide, evaporation of the ether and fractional distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[O:4]C(C(OC)=O)C(OC)=O.Cl.[C:21]([NH2:24])(=[NH:23])[CH3:22]>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:3]=1[O:4][N:23]1[C:3](=[O:4])[CH:14]=[C:15]([OH:18])[N:24]=[C:21]1[CH3:22]
Reactant: CC(=N)N
Reactant: COC(=O)C(Oc1cc(OC)ccc1Cl)C(=O)OC
Agent: Cl
Product: COc1ccc(Cl)c(On2c(C)nc(O)cc2=O)c1

Procedure:
In analogy to Example 1, paragraph d), dimethyl (2-chloro-5-methoxy-phenoxy)malonate was condensed with acetamidine hydrochloride to give (2-chloro-5-methoxy-phenoxy)-2-methyl-6-hydroxy-4(3H)-pyrimidinone. Therefrom in analogy to Example 1, paragraph e), there was obtained 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-2-methyl-pyrimidine, m.p. 125°-130° C., and therefrom in analogy to Example 1, paragraph f), there was obtained 4-tert-butyl-N-[6-chloro-5-(2-chloro-5-methoxyphenoxy)-2-methyl-pyrimidin-4-yl]-benzenesulfonamide, m.p. 182° C. (from MeOH).
Reaction SMILES: N/C(/C#N)=C(\N[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[F:18])=[O:8])/C#N.FC1C=C(OC)C=CC=1N.C(Cl)(=O)OC(Cl)(Cl)Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[N:9]=[C:7]=[O:8]
Reactant: COc1ccc(NC(=O)N/C(C#N)=C(\N)C#N)c(F)c1
Agent: COc1ccc(N)c(F)c1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(N=C=O)c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
(Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-fluoro-4-methoxyphenyl)urea. In a 100 mL round-bottomed flask was added 2-fluoro-4-methoxyaniline (0.79 g, 5.60 mmol) and trichloromethyl carbonochloridate (0.68 mL, 5.60 mmol) in toluene (6 mL) to give a purple suspension. The mixture was then stirred at 110° C. for 3 h. Upon heating, the suspension becomes a homogeneous solution. After 3 h, no starting material remained (TLC, 3:1 hex/EtOAc). The reaction mixture was concentrated to afford 2-fluoro-1-isocyanato-4-methoxybenzene (0.936 g, 5.6 mmol, quant.) as a green oil. The intermediate 2-fluoro-1-isocyanato-4-methoxybenzene (0.936 g, 5.6 mmol) was then dissolved in acetonitrile (20 ml) and reacted with 2,3-diaminomaleonitrile (0.605 g, 5.60 mmol) according to General Procedure A. The product was filtered to give the title compound (1.36 g, 88%). MS (ESI) m/z 276.3[M+1]+.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[SH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccc(OC)cc1
Reactant: Oc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(OC)cc1
Yield: 82 %

Procedure:
Ethyl bromo(4-methoxyphenyl)acetate (16.5 g, 60.4 mmol) was added to a stirring solution of triethyl amine (10 ml), and 4-mercaptophenol (7.63 g, 60.4 mmol) in Chloroform (200 ml). The mixture was heated at reflux overnight before it was concentrated and the residue was extracted in ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The compound was isolated using silica-gel column chromatography by eluting it with 20% ethyl acetate: hexane solution. Ethyl[(4-hydroxyphenyl)sulfanyl](4-methoxyphenyl)acetate was isolated as a yellow oil (15.82 g). Yield 82%; MS: 317.2 (M−H)−
Reaction SMILES: C([CH:3](C([O-])=O)[C:4]([O-:6])=[O:5])C.[K+].[K+].C(N([CH2:17][CH3:18])CC)C.[Cl-].[Mg+2].[Cl-].[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25](Cl)=[O:26]>C(#N)C>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25](=[O:26])[CH2:3][C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: COc1cccc(F)c1C(=O)Cl
Reactant: CCC(C(=O)[O-])C(=O)[O-]
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1c(F)cccc1OC
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Potassium ethylmalonate (2.1 g, 12 mmol, 2.1 equiv) was suspended in acetonitrile (20 mL), cooled to 5° C. and treated with successively with triethylamine (2.6 mL, 18 mmol, 3.2 equiv) and magnesium(II) chloride (1.4 g, 14 mmol, 2.5 equiv). The ice bath was removed and the mixture was warmed and stirred at ambient temperature for 2.5 hours. An acetonitrile solution (5 mL) of 2-fluoro-6-(methyloxy)benzoyl chloride (1.1 g, 5.8 mmol) was added and the mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo and the residue was suspended in toluene (50 mL), cooled to 0° C. and treated with hydrochloric acid (20 mL, 12 N aqueous) with vigorous stirring. The ice bath was removed after 10 minutes and the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 1:1; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:26])[C:21](=[O:25])[CH:22](Br)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:19][N:20]([CH3:26])[C:21](=[O:25])[CH:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: Oc1ccc(Oc2ccc3ccccc3n2)cc1
Reactant: CC(Br)C(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(Oc1ccc(Oc2ccc3ccccc3n2)cc1)C(=O)N(C)C
Yield: 88 %

Procedure:
In 100 ml of methyl ethyl ketone, 2.3 g of the intermediate of Preparation 1 of 2-(4-hydroxyphenoxy)quinoline, 1.8 g of N,N-dimethyl-α-bromopropionic acid amide and 1.4 g of potassium carbonate were added and the mixture was refluxed for 5 hours. After the reaction, the precipitated crystal was separated by a filtration and the solvent was distilled off and the product was dried under a reduced pressure. The resulting crude crystal was recrystallized from a solvent of methanol-water to obtain 3.6 g (yield 88%) of white crystal of the object compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:28][CH2:27][CH2:26][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[CH2:29]1COCC1.C[Mg]Cl.[Cl-].[NH4+]>O.C(Cl)Cl.C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:28][CH2:27][CH2:26][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([OH:25])([CH3:29])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A 100 mL round bottom flask was charged with 1-(6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanone (2.74 g, 7.20 mmol, Example #35, Step G). THF (36.0 mL) was added and the mixture was stirred at ambient temperature for about 15 min. The slurry was cooled to about −40° C. and methylmagnesium chloride (3.0 M in THF, 6.00 mL, 18.0 mmol) was added slowly while keeping the internal temperature between about −40-−30° C. After about 15 min, the mixture was cooled to about −55° C. followed by the slow addition of a saturated solution of ammonium chloride (about 10 mL). The mixture was then warmed to ambient temperature and diluted with water (50 mL) and DCM (75 mL). The layers were separated. The aqueous layer was extracted with DCM (2×50 mL) then the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give a foam. The material was dissolved in 95:5 DCM/MeOH (about 20 mL) with warming and sonication and then loaded onto a 120 g silica column and eluted with 94:6 DCM/MeOH (about 1 L) followed by 92:8 DCM/MeOH (about 500 mL). Concentration of the fractions containing product under reduced pressure gave the title compound as a foam (2.88 g, 91%) that contained about 9 wt % DCM by 1H NMR. This material was combined with a second batch of the title compound (3.4 g, also contained about 9 wt % DCM). The combined material (5.7 g) was dissolved into ACN (150 mL), followed by a rapid precipitation of the title compound as an off-white powder. The material was collected by filtration and dried in a vacuum oven at 70° C. to give the title compound (4.69 g, 82% recovery): LC/MS (Table 1, Method g) Rt=1.58 min; MS m/z: 397.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:5]2.C(N(CC)CC)C.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>C(Cl)(Cl)Cl>[CH2:12]([N:7]1[C:8]2[C:4](=[C:3]([CH3:18])[C:2]([NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:10]([CH3:11])[CH:9]=2)[CH2:5][CH2:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCN1CCc2c1cc(C)c(N)c2C
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCN1CCc2c1cc(C)c(NC(=O)C(C)(C)C)c2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
5-Amino-4,6-dimethyl-1-hexylindoline (880 mg) was dissolved in chloroform (20 ml), and triethylamine (370 mg) and pivaloyl chloride (430 mg) were added, which was followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol=1:0-50:1) and recrystallized from ethanol to give 650 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:9]([C:11]([CH2:16][CH3:17])([CH2:14]O)[CH2:12][OH:13])[CH3:10].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([C:11]1([CH2:16][CH3:17])[CH2:12][O:13][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:14]1)[CH3:10]
Reactant: O=C1CCC(=O)CC1
Reactant: CCC(CC)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)COC2(CCC(=O)CC2)OC1
Temperature: 25 °C
Yield: 16365.5 %

Procedure:
30 g (0.27 mmol) of cyclohexane-1,4-dione, 35.4 g (0.27 mol) of 2,2-diethylpropane-1,3-diol and 360 mg of para-toluenesulfonic acid were heated in 200 ml of toluene on a water separator. After the mixture had been cooled to room temperature and the water of reaction separated off, the organic phase was washed with a semisaturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After the solvent had been evaporated, 65 g of crude product were obtained which was purified by flash chromatography (ethyl acetate/petroleum ether=1:4). The first fraction contained the 1,4-diketal which was formed as secondary product (10 g). The main fraction contained 28.5 g (47%) of a yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:15](N(CC)CC)[CH3:16].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[C:4]([Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH2:15][CH3:16])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCN(CC)CC
Reactant: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropan-1-ol (Registry No. 117932-70-4) (2.18 g, 10 mmol) in THF (30 ml) were added triethylamine (1.67 ml, 12 mmol) and methanesulfonyl chloride (0.85 ml, 11 mmol) under ice cooling. The reaction liquid was stirred at room temperature for 30 minutes, and to the reaction liquid was added an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (2.98 g, quant.) as colorless oily substance.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[CH3:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[N:16][CH:15]=[CH:14][N:13]=1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:14]1[CH:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[N:13]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: COc1nccnc1OC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)nc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 14.6 gm of N-bromosuccinamide, 32 ml of dry DMF was added to a stirred solution of 11 gm (0.078 mol) of 2,3 dimethoxypyrazine in 14 ml of DMF at 0° C. whereupon the reaction was warmed to 25° C. and stirred for 16 hours. The reaction mixture was then cooled in an ice bath and to it was added aqueous Na2SO3 to remove the bromine and this was poured into ice water. The resulting crystalline solid was filtered, triturated with water and dried to give the title compound. NMR (CDCl3) δ 4.0, 4.02(2s, 6H, --OCH3), 7.70(s,lH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#N)=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.C[Mg+].[Br-].[CH3:28][C:29]([CH3:33])=[CH:30][Mg]Br.C1C[O:37]CC1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[CH:11]=[C:12]3[C:16](=[O:37])[CH2:28][C:29]([CH3:33])([CH3:30])[O:15][C:13]3=[N:14][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:23][CH:22]=1
Reactant: C1CCOC1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: CC(C)=C[Mg]Br
Agent: C[Mg+]
Agent: [Br-]
Product: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
To the product of Step B (13.15 g, 35 mmol) in THF (160 mL) was added MeMgBr (1.4 M in toluene/THF, 26.25 mL, 36.75 mmol). After stirring 3 min, 2-methylprop-1-enylmagnesium bromide (0.5 M in THF, 100 mL, 50 mmol) was added and the temperature was increased to 50° C. After 20 min the reaction was cooled, quenched with 2 M HCl and diluted with EtOAc. The reaction was stirred for 3 days before work up. The solution was washed twice with brine, followed by twice with saturated aq NaHCO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-25% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 432.2 (M+1), 434.2 (M+3); Rt=4.15 mm.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[C:1]([O:8][C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: c1ccc2c(c1)CCCC2
Reactant: CCCCCC(=O)O
Product: CCCCCC(=O)Oc1cccc2ccccc12

Procedure:
The procedure of Example 2 was followed except that hexanoic acid (33 g.; 284 m mols) was used in place of octanoic acid and the reaction time was 31/2 hours. Analysis showed that about 55% of the tetralin was converted producing naphthyl hexanoate in 62% selectivity.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][C@@H]4CCCN4CC3)=[CH:8][C:6]=2[N:7]=1.Cl.[C:28]([O:32][C:33]([N:35]1[CH2:43][CH2:42][C:38]2(CN[CH2:39]2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:43][CH2:42][C:38]2([CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:39]2)[CH2:37][CH2:36]1)=[O:34])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@H]4C3)cc2n1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-[(S)-1-(hexahydro-pyrrolo[1,2-d]pyrazin-2-yl)methyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester hydrochloride in place of (S)-octahydro-pyrrolo[1,2-a]pyrazine. The title compound was obtained as a tan solid (209 mg, 84%).