Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C:13]1[S:17][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:14]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C)[CH:25]=[O:26]>>[CH:25]([C:20]1[S:19][C:18]([C:16]2[S:17][C:13]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)=[CH:22][CH:21]=1)=[O:26]
Reactant: CN(C)C=O
Reactant: CCCCCCCc1ccc(-c2cccs2)s1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1ccc(-c2ccc(C=O)s2)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Dimethyl formamide (DMF) (8 ml) was stirred at 0° C. for 10 minutes, POCl3 (1 ml) was added and then stirred for 1 hours. 5-Heptyl-2,2'-bithiophene (0.5 g) dissolved in dimethyl formamide (5 ml) was added and stirred at room temperature for half an hour at room temperature, then the temperature was raised to 60° C. and was further stirred for 4 hours. The reaction solution was then extracted with dichloromethane, neutralized with sodium acetate, washed with water to neutrality, dried, concentrated and separated by silica gel chromatography eluted with ethyl acetate/n-hexane (1/15). Light yellowish oily product (0.86 g, 86%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Reactant: CCC(N)C(C)O
Solvent: CS(C)=O
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC)C(C)O
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (250 mg, 0.78 mmol) and 3-amino-pentan-2-ol (320 mg, 3.13 mmol) in DMSO was heated in 130° C. oil bath for 24 hr. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 280 mg of crude product as an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as a yellow solid, mp 116-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.C(O)CCCCCCC>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCCCCO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a mixture of 307 mg (purity: 98.0%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 833 mg (5.57 mmol) of 2-cyclopropyl-6-methylphenol were added 1-octanol (3.36 mL) and 324 mg (5.50 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 113 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 23%) and 1.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.3%) were obtained.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(O)C.N>[Ni]>[C:2]1([CH2:1][NH2:10])[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccc(CN)cc1
Temperature: 150 °C

Procedure:
5.1 g of terephthalonitrile, 1.0 g of catalyst (Ni 5136P from Harshaw/Filtrol--contains 65% nickel on a silica-alumina support), and about 85 g of ethanol/ammonia (contains about 10 wt % ammonia) were charged to a 300 cc stainless steel pressure reactor. After a nitrogen purge, the vessel was charged to a pressure of 500 to 1000 psi with hydrogen. The temperature was then increased until the reaction temperature of 150° C. had been obtained (typically 20-30 min). After the desired reaction interval, the contents were cooled and sampled. Product analysis and conversion were determined by gas chromatography. Yields of para-xylylenediamine varied between 63-81% depending on hydrogen pressure and reaction time which is preferrably from 2 to 8 hours. The remainder of the product was saturated para-xylylenediamine (1.4 bis (aminomethyl) cyclohexane. Table IV sets forth specific examples of reactions run to obtain the diamines from hydrogenation of terephthalonitrile.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([F:20])[C:15]([F:19])=[C:16]([F:18])[CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC=C(c2cc(F)c(F)c(F)c2)CC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: CCCCCc1ccc(-c2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C

Procedure:
1-(4-Pentylcyclohexen-1-yl)-3,4,5-trifluorobenzene as an intermediate obtained in Example 1 (5 g) was dissolved in xylene (50 ml), followed by adding chloranil (4.5 g), reacting the mixture under reflux for 10 hours, cooling the resulting material down to room temperature, filtering off the resulting deposited hydroquinone derivative, washing the filtrate with a dilute alkali aqueous solution, washing with water till the washing water became neutral, drying over anhydrous sodium sulfate, distilling off xylene from the organic layer, dissolving the residue in n-hexane, purifying the solution according to silica gel column chromatography, collecting fractions exhibiting a single spot according to thin layer chromatography, distilling off n-hexane and recrystallizing the residue from ethyl alcohol to obtain 4'-pentyl-3,4,5-trifluorobiphenyl (3.2 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[C:16]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:19]2=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]2[CH:17]=1.[CH3:36]I>CN(C)C=O.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:36])[CH:9]=[C:8]2[C:16]1[N:25]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[C:19]2=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]2[CH:17]=1
Reactant: CI
Reactant: COc1cc2[nH]cc(-c3cc4c(C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(-c3cc4c(C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 4 h

Procedure:
0.017 g of sodium hydride (60%) is added to a solution of 0.17 g of 2-[5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine in 7 cm3 of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. After stirring for one hour at the same temperature, 0.025 cm3 of methyl iodide is added. Stirring is continued at this temperature for 4 hours. The reaction mixture is taken up in 50 cm3 of water and then extracted with 100 cm3 of ethyl acetate, and the aqueous phase is re-extracted with 2×50 cm3 of ethyl acetate. The combined organic phases are washed successively with 50 cm3 of saturated aqueous sodium chloride solution and then with 50 cm3 of distilled water. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified on a Flash Chromabond RS 6 SiOH cartridge (3 g of silica). The elution was performed at a flow rate of 10 cm3/min with a dichloromethane/methanol mixture (95/05 by volume). The fractions containing the expected compound are combined and evaporated to give 2-[5,6-dimethoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine in the form of a beige-colored solid (0.130 g, 72%), the characteristics of which are as follows:
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C@@H:6]([C:11]([OH:13])=[O:12])[C:7]([SH:10])([CH3:9])[CH3:8].[CH3:14][N:15]([CH3:22])[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=O>C(O)C>[CH3:8][C:7]1([CH3:9])[S:10][C:18]([CH2:17][C:16]([N:15]([CH3:22])[CH3:14])=[O:21])([CH3:20])[NH:5][CH:6]1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(=O)CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C(=O)CC1(C)NC(C(=O)O)C(C)(C)S1
Yield: 76.1 %

Procedure:
In 40 ml of a mixture of chloroform and ethyl alcohol (1:1) were suspended 1.49 g (10 mmoles) of D-penicillamine and 1.89 g (15 mmoles) of N,N-dimethylacetoacetamide. The suspension was heated at 80°-90° C. with stirring under a stream of argon to concentrate to a half its volume. 20 ml of a mixture of chloroform and ethyl alcohol (1:1) was added. The concentration and addition of the solvent were repeated until the reaction mixture turned completely clear and a small amount of insolubles was removed by filtration. The solvent was distilled off, and the resulting residue was treated according to the same procedure as in Example 1 to give 1.98 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2)[CH2:2][CH2:3][CH3:4].CN([CH:23]=[O:24])C>>[CH2:1]([O:5][C:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:23]=[O:24])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOc1c2ccccc2cc2ccccc12
Product: CCCCOc1c2ccccc2c(C=O)c2ccccc12

Procedure:
10-Butoxyanthracene was formylated using DMF as both solvent and electrophile by the procedure of E. Campaigne and W. L. Archer, J. Amer. Chem. Soc. 75 989 (1953), affording 10-butoxy-9-anthracenecarbaldehyde mp 65°-67°, (pentane), (C,H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]2[CH2:22][CH:21](CS([O-])(=O)=O)[CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH:18]([N:19]1[CH2:22][CH:21]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:20]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)([O-])CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)c1ccccc1N
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccccc1NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
A mixture of 2-tert-butylaniline (0.50 g, 3.35 mmol) and 1-(diphenylmethyl)-3-azetidinylmethanesulfonate (1.60 g, 5.03 mmol) was heated at 100° C. for 15 min. After this toluene (5.0 ml) was added to the resulting yellow solid, the reaction mixture was cooled to room temperature, partitioned between THF and water and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 90:10 to 80:20 heptane/ethyl acetate) to provide 1-benzhydryl-N-(2-tert-butylphenyl)azetidin-3-amine (0.73 g, 59%) as a yellow gum-like substance.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[CH:11]=1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:12]4[CH:11]=[C:10]([CH3:9])[O:14][N:13]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: Cc1cc(CN)no1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C(=O)N(Cc4ccc(F)cc4)C[C@@H]3C)nc2C)no1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylisoxazol-3-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (70%): mp 174-175° C. (N,N-dimethylformamide/water); 1H NMR (300 MHz, DMSO-d6) δ 8.48 (t, J=5.8 Hz, 1H), 7.37-7.32 (m, 2H), 7.23-7.17 (m, 2H), 6.13 (d, J=0.7 Hz, 1H), 4.58-4.52 (m, 1H), 4.43 (d, J=4.3 Hz, 2H), 4.36 (d, J=5.8 Hz, 2H), 3.64-3.58 (m, 1H), 3.04 (dd, J=9.0, 3.4 Hz, 1H), 2.48 (s, 3H), 2.37 (d, J=0.7 Hz, 3H), 1.39 (d, J=6.0 Hz, 3H); MS (ES+) m/z 443.8 (M+1).
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25](COCC[Si](C)(C)C)[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC2CC2)C=1.C(=O)([O-])O.[Na+]>>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[NH:25][C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:2][CH2:3][CH2:4]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)cc2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(Cl)c2c(=O)[nH]ncc21
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CCC4)c3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
Reaction was carried out in the same manner as in Example 2-(b) except for using 0.46 g (0.96 mmol) of 2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 31-(a) in place of 3-chloro-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, to the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate to neutralize the mixture, and the mixture was extracted with a mixed solvent (chloroform/methanol=9/1 (V/V)). The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained solid were added methanol and 28% aqueous ammonia, and the mixture was stirred under room temperature for 3 hours. Then, the solution was concentrated under reduced pressure and the obtained solid was washed with chloroform and dried under reduced pressure to obtain 199 mg of the title compound as a white solid. (Yield: 60%)
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][SH:7].C[S-].Br[CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH2:11][S:7][CH3:6]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CS
Agent: CC[O-]
Agent: C[S-]
Agent: [Na+]
Product: CSCC(=O)C(C)(C)C

Procedure:
To a solution of sodium ethoxide prepared from 7.7 g (0.33 mol) of sodium metal and 200 ml of absolute alcohol was added 19 g (0.4 mol) of methanethiol over 10 min at ± 2° C. To this solution of thiomethoxide was added dropwise, over 25 min. 59 g (0.28 mol) of 1-bromo-3,3-dimethyl-2-butanone prepared according to the procedure of J. Am. Chem. Soc. 74, 4507 (1952). The temperature was maintained at 0° ± 3° C. during the addition and for a further 30 min. The reaction mixture was filtered and the solvent removed by distillation. Vacuum distillation of the residue gave the desired product as a colorless liquid, b. 73° C./9.3 mm Hg, nD24 1.4650 in 54% pure yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C@@H:12]1[C@@H:16]([C:17](OCC)=[O:18])[O:15][CH2:14][O:13]1)=O)C.O.[OH-].[Na+]>CCOCC>[OH:9][CH2:10][C@@H:12]1[C@@H:16]([CH2:17][OH:18])[O:15][CH2:14][O:13]1
Reactant: CCOC(=O)[C@H]1OCO[C@@H]1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC[C@H]1OCO[C@@H]1CO
Reaction time: 1 h

Procedure:
300 ml of diethyl ether was added to 25.75 g of lithium aluminum hydride, and the mixture was heated while refluxing. A solution of 130.46 g of (4S,5S)-4,5-bis (ethoxycarbonyl)-1,3-dioxolane (obtained in Example 2) in 100 ml of ether was slowly added dropwise to this mixture. After the addition, the refluxing was continued for further about one hour. After allowing the reaction mixture to cool, 30 ml of water was slowly added under ice-cooling to decompose an excessive amount of lithium aluminum hydride. Then, 30 ml of 4N aqueous solution of sodium hydroxide and 90 ml of water were added dropwise. The reaction mixture was filtered with suction and the precipitate was extracted with 1000 ml of an ethanol-dioxane mixture at about 60° C., followed by filtration of the extract with suction. This procedure was repeated three times. The filtrate was concentrated to obtain crude (4R,5R)-4,5-bis(hydroxymethyl)-1,3-dioxolane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](O)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH3:23]>FC(F)(F)C(O)=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:6]2[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=2)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH3:23]
Reactant: CCC(O)(CC)c1ccc(Br)c(C)c1
Reactant: Cc1cccc(C)c1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(Br)c(C)c1)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
2,6-Dimethylphenol (950 mg, 7.78 mmol) was added to a solution of 3-(4-bromo-3-methyl-phenyl)-pentan-3-ol (Example 38-(1); 2.0 g, 7.78 mmol) in trifluoroacetic acid (20 mL), and the mixture was stirred at room temperature for two hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (2.62 g, 93%).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH2:13][OH:14])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[CH2:32](Cl)Cl.CCCCCC>>[CH:1]([C:4]1[C:5]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:7]([CH:13]([OH:14])[CH3:32])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: Cc1ccc(COCc2c(C(C)C)cc(C(C)C)c(CO)c2-c2ccc(F)cc2)cc1
Solvent: CCCCCC
Product: Cc1ccc(COCc2c(C(C)C)cc(C(C)C)c(C(C)O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared by subjecting the intermediate obtained in Step A to the procedures described in Example 244, Steps I-K. mp 84-86° C.; Rf=0.1 (80% CH2Cl2/hexane); 1H NMR (300 MHz, CDCl3): δ 7.39 (s, 1H), 7.27 (m, 2H), 7.09 (m, 6H), 4.76 (dq, J=1.5, 7 Hz, 1H), 4.22 (s, 2H), 4.03 (s, 2H), 3.89 (septet, J=6.6 Hz, 1H), 3.26 (septet, J=6.6 Hz, 1H), 2.35 (s, 3H), 1.66 (s, 1H), 1.40 (d, J=6.6 Hz, 3H), 1.26 (m, 12H); FAB-MS calcd for (C29H35FO2) 434, found 417 (M—OH); Anal. Calcd for C29H35FO2: C, 80.15; H, 8.12; F, 4.37. Found: C, 80.10; H, 8.30; F, 4.24; [α]22=+30.7.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:26][CH3:27])=[C:7]([CH:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=2[Cl:11])[CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:16](=[O:25])[NH:15][CH:13]([C:7]1[CH:8]=[C:9]([Cl:12])[C:10]([Cl:11])=[C:5]([CH:3]2[CH2:4][N:1]([CH2:41][C:42]([F:45])([F:44])[F:43])[CH2:2]2)[C:6]=1[O:26][CH3:27])[CH3:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CNC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(CC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of benzyl [1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]carbamate (170 mg, 0.43 mmol) in THF (5.8 mL) was treated with triethylamine (110 μL, 0.82 mmol), cooled to 0° C., treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (150 mg, 0.64 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered and concentrated to give the desired product (190 mg, 92%) that was used without further purification. LCMS for C22H24Cl2F3N2O3 (M+H)+: m/z=491.1, 493.1. Found: 491.1, 493.1.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[F:14][C:15]([F:31])([F:30])[C:16]1[CH:17]=[C:18]([C:26](=O)[CH2:27]Br)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1>>[F:14][C:15]([F:30])([F:31])[C:16]1[CH:17]=[C:18]([C:26]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:27]=2)[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cs2)c(C)s1
Yield: 5 %

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 101 mg (0.3 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethane-1-one in a manner similar Example 8, step (a) to give methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (7 mg, 5%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.75 (s, 1H), 8.73 (m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3.87 (s, 3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H11NO2S3F6, 484.0 (M+H), found 484.0.