Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:22])[CH3:21].[I-].[K+]>C(OCC)(=O)C.[I-].[K+].CN(C)C=O>[CH:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(OC(C)C)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a mixture of methyl 3-hydroxy-4-methylbenzoate (5.28 g, 31.8 mmol), potassium carbonate (6.59 g, 47.7 mmol) and N,N-dimethylformamide (50 mL) were added 2-bromopropane (3.58 mL, 38.2 mmol) and potassium iodide (0.53 g, 3.18 mmol) under stirring at room temperature, and the mixture was stirred at 80° C. for 7 hr. To the reaction mixture were added 2-bromopropane (1.79 mL, 19.1 mmol) and potassium iodide (0.27 g, 1.59 mmol), and the mixture was further stirred at 80° C. for 15 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1-hexane/ethyl acetate=4/1) to give the title compound (6.3 g, yield 96%) as a colorless oil.
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]2[C:28]3[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][C:21]3[CH2:20][CH2:19][CH2:18][C:17](=[O:30])[C:16]2=3)[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].[H-].[Na+].Cl[CH2:34][O:35][CH2:36][CH3:37]>C(O)(=O)C>[CH2:36]([O:35][CH2:34][N:22]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17](=[O:30])[C:16]=2[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[C:28]2[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]1=2)[CH3:37]
Reactant: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C1=C(CCCC1=O)N2
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOCN1C2=C(C(=O)CCC2)C(c2cccc([N+](=O)[O-])c2)C2=C1CCCC2=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 10 ml. of dimethylformamide was suspended 0.5 g. of 9-(3-nitrophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridine and after adding to the suspension 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 1.5 hours at room temperature. After cooling the mixture to -10° C., 0.5 ml. of chloromethoxyethane was added thereto, the temperature of the mixture was elevated to room temperature over a period of about 20 minutes, stirred for 2 hours and the mixture was cooled again to -10° C. Then, after adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then ether was distilled away. The residue became crystallized by the addition of 5 ml. of ethanol. The crystals were filtered, dissolved in 2 ml. of chloroform and recrystallized by the addition of ethanol and 0.4 g. of pale brown prismatic crystals of 10-ethoxymethyl-9-(3-nitrophenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8,9,10-decahydroacridine melting at 222° C. were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[C:14](OC(=O)C)(=[O:16])C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(O)=O>[CH:14]([O:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1)=[O:16]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=CO
Product: C=C1CC(OC=O)CCC2=C(C)CCC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
2.67 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene were treated at 0° firstly with half of a mixture of 4.08 g of acetic anhydride, 1.84 g of formic acid and 37 mg of pyridine. The mixture was stirred for 24 hours at room temperature and with exclusion of light. Then the other half of the reagent was added and the mixture stirred for further 24 hours. The solution was poured on to a mixture of ice and sodium carbonate and worked up in a conventional manner. The crude product so obtained (3.18 g) was distilled under high vacuum and yielded 2.70 g (87%) of pure 6-formyloxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.005 50°; IR(film):νmax = 3120, 1728, 1645, 1460/45, 1190/82, 1015/1000, 905/900 cm-1. The compound smells woody, cedar-like, slightly ionone-like.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([CH3:34])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH:12]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([CH3:34])[N:33]=3)=[CH:26][CH:25]=2)[CH:8]=1)[CH3:5]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
(4R)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrol-2-yl]-4-methyl-4,5-dihydro-1,3-oxazole (1.18 g, 2.42 mmol) synthesized in Example (107b) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 3.00 mL, 3.00 mmol) was added at room temperature, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=1%-3%) to afford the desired compound (720 mg, yield 90%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=3)O)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=3)[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: CCc1ccc(C(O)(c2ccc(CC)cc2)C2CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C(c2ccc(CC)cc2)C2CCN(Cc3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
To a stirred solution of 1.0 gram (0.002 mole) of N-(4-methoxyphenylmethyl)-4-[bis(4-ethylphenyl)hydroxymethyl]piperidine (prepared in the manner of Example 1) in 10 mL of methylene chloride was slowly added 1.1 mL (0.007 mole) of triethylsilane, followed by 1.0 mL (0.013 mole) of trifluoroacetic acid. The reaction mixture was then stirred at ambient temperature during a five hour period. After this time the reaction mixture was neutralized with solid sodium carbonate. The mixture was then partitioned between 100 mL of methylene chloride and 50 mL of water. The organic layer was separated and washed with two 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was then dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was purified by subjecting it to preparative thin layer chromatography, with 25% acetone in methylene chloride as the eluant, yielding about 0.5 gram of N-(4-methoxyphenylmethyl)-4-[bis(4-ethylphenyl)methyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][C:12]=1[I:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: II
Reactant: FC(F)(F)Oc1ccc(OCc2ccccc2)cc1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
Iodine (71.96 g, 0.28 mol) in chloroform was added dropwise to a mixture of 2-benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.06 g, 0.27 mol) and silver trifluoroacetate (71.57 g, 0.32 mol) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate (5%, 2×2 l), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate, to give the title compound as a colorless oil (108.03 g), containing 11% unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. 1H NMR (360 MHz, CDCl3) δ 7.67 (1H, d, J=2.8 Hz), 7.40 (5H, m), 7.16 (1H, dd, J=8.9, 2.8 Hz), 6.82 (1H, d, J=8.9 Hz), and 5.14 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[NH2:14])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].C(=O)([O-])O.[Na+].C(=O)(O)[O-].[CH:24]([CH:26]=O)=O.[Na+].[OH-].[Na+]>O.C(OCC)(=O)C>[N:14]1[C:13]2[C:2](=[CH:3][C:4]([CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[CH:11][CH:12]=2)[N:1]=[CH:26][CH:24]=1
Reactant: O=CC=O
Reactant: Nc1ccc(CCOCCO)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: OCCOCCc1ccc2nccnc2c1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
In 20 mL of water is dissolved 1.50 g of 2-[(3,4-diaminophenethyl)oxy]-1-ethanol. After adjusting pH of the solution to 6.5 with sodium hydrogen carbonate, 2.22 g of sodium glyoxal bicarbonate is added at 60° C., and the mixture thus formed is stirred at the same temperature as above for 30 minutes. Ethyl acetate is added to the reaction mixture, pH is adjusted to 10 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 0.73 g of 2-[2-(6-quinoxalinyl)-ethoxy]-1-ethanol as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:40])[N:22]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:16]([O:20][C:21](=[O:40])[N:22]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:15])[CH2:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cnc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To 20 mL of a chloroform solution containing 355 mg of (7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 553 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 98 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 549 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1] to give 655 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].N[CH2:17][CH2:18][CH2:19][OH:20]>O>[OH:20][CH2:19][CH2:18][CH2:17][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([OH:13])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Reactant: NCCCO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(NCCCO)cc1O

Procedure:
A mixture consisting of 0.2 mol (42.8 g) of 4,5-dinitro-2-methoxyphenol, prepared in Example 2, 0.6 mol (45.7 g) of 3-amino-1-propanol and 30 ml of water is heated at the refluxing temperature of water for 3 h 30 min.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[N:20]=[C:19]([CH:21]2[CH2:26][CH2:25][NH2+:24][CH2:23][CH2:22]2)[O:18][N:17]=1>N1C=CC=CC=1>[C:1]1([NH:7][C:8]([N:24]2[CH2:25][CH2:26][CH:21]([C:19]3[O:18][N:17]=[C:16]([C:12]4[S:11][CH:15]=[CH:14][CH:13]=4)[N:20]=3)[CH2:22][CH2:23]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
40 μl (1 eq.) of phenyl isocyanate were added to a solution of 100 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride in 0.6 ml of pyridine. The reaction medium was stirred at room temperature overnight and then evaporated under reduced pressure. The residue obtained was chromatograph on a thick layer of silica (eluent: CH2Cl2/MeOH (95/5; v/v)). After evaporating off the solvent, 48 mg (37%) of the expected compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][CH2:11][CH2:10][SH+:9]2)=[CH:4][CH:3]=1.[ClH:13]>CCl>[Cl-:13].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:9][CH2:10][CH2:11][SH+:12]2)=[CH:6][CH:7]=1
Reactant: Cl
Agent: CCl
Agent: Cc1ccc(C2SCC[SH+]2)cc1
Product: [Cl-]

Procedure:
The U.V. spectrum of a solution of 1 mg 2,2'-[1,2-ethanediylbis (thio)]-2,2'-di(4-methylphenyl)bis(1,3-dithiolane) in 100 ml of 0.8% hydrogen chloride in methyl chloride is measured: max 243,275,376 nm, the latter indicating the presence of 2-(4-methylphenyl)-1,3-dithiolanium cation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35]Br)[CH:32]=[CH:31][N:30]=1)=[O:28])[CH3:25]>CN(C=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)[CH:32]=[CH:31][N:30]=1)=[O:28])[CH3:25]
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: CCOC(=O)c1cc(CBr)ccn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)ccn1
Temperature: 80 °C
Yield: 63 %

Procedure:
3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (100 mg, obtained in Example 93, step 6) and ethyl-4-(bromomethyl)-pyridine-2-carboxylate (85 mg, [CAS Reg. No. 153994-03-7]) were dissolved in DMF (5 mL) followed by addition of silver carbonate (80 mg). The mixture was heated to 80° C. for 3 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow foam (98 mg, 63%). MS (m/e)=509.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:22])=[O:21]
Reactant: OCCc1c(F)cccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-(2-chloro-6-fluorophenyl)ethanol (500 mg, 2.87 mmol), was dissolved in dichloromethane (20 mL), and triethylamine (870 mg, 8.61 mmol) was added to the reaction mixture. The solution was cooled to 0° C. and methanesulfonyl chloride (492 mg, 4.31 mmol) was added slowly. After the addition was complete, the reaction was stirred at 0° C. for 15 min and at room temperature for 4 hours. Water was slowly added and the solution was extracted with dichloromethane. The organic layer was washed with brine, and dried over sodium sulfate and concentrated in vacuo to give the residue 2-chloro-6-fluorophenethyl methanesulfonate (52) as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]([NH2:26])=[S:25])[CH:17]=3)=[O:14])=[CH:11][C:10]=2[C:29]([F:32])([F:31])[F:30])[CH2:4][CH2:3]1.Cl.Br.Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=O.C(=O)([O-])O.[Na+]>O.C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([NH:23][C:24]4[S:25][CH:36]=[C:37]([C:39]5[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=5)[N:26]=4)[CH:17]=3)=[O:14])=[CH:11][C:10]=2[C:29]([F:32])([F:31])[F:30])[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1NC(N)=S
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nc(-c2ccncc2)cs1
Temperature: 65 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To 697 mg of 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethyl-N-[4-methyl-3-(thioureido)phenyl]benzamide (Reference Example 33) were added in turn 3 ml of ethanol, 1.5 ml of water and 1.5 ml of 1 N hydrochloric acid, and the mixture was heated in an oil bath at 65° C. 6 ml of an aqueous solution of 421 mg of 4-(bromoacetyl)pyridine hydrobromide (J. Heterocycl. Chem., 1970, 7, 1137-1141) was added thereto, and the mixture was stirred for 2 hours. After air-cooling the reaction solution, the reaction solution was diluted with water, alkalified by adding an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 701 mg of the objective compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21](O)[C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:19]([CH:34]([CH3:36])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:37])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:44])CC)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([F:44])[C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[C:19]([CH:34]([CH3:36])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:37])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Under argon, 159 mg (0.31 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethoxy)phenyl]-methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 58A) are dissolved in 3.1 ml of toluene, 49 μl (0.37 mmol) of diethylaminosulfur trifluoride are slowly added at −78° C. and the mixture is stirred at −78° C. for 2 h. Water is then added, and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, and dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase:cyclohexane/ethyl acetate 15:1). This gives 118 mg (74% of theory) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].O.[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])#[N:18]
Reactant: [C-]#N
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CC#N
Yield: 84.4 %

Procedure:
A mixture of the product of example 28 (˜90% pure, 729 mg, 2.46 mmol) in a mixture of DMF:H2O (3 mL:2 mL) and sodium cyanide (362 mg, 7.4 mmol) was stirred at room temperature overnight. The resulting mixture was quenched with saturated NaHCO3 (12 mL) and extracted with ethylacetate (3×30 mL). The extracts were combined and washed with saturated NaCl (2×30 mL) and water (2×30 mL). The organic layer was separated, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the titled product as colourless oil (503 mg, 85% yield).
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+].Cl>O>[F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCCCCCCCC=C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of 1.0 gram (0.004 mole) of methyl 12,12-difluoro-11-dodecenoate and 0.16 gram (0.004 mole) of powdered sodium hydroxide was stirred at ambient temperature for 16 hours. A few drops of water were added to the reaction mixture, and it was warmed to 75° C. where it stirred for 3-4 hours. The reaction mixture was cooled to ambient temperature, diluted with water and acidified to pH with aqueous 6N hydrochloric acid. The mixture was extracted with three portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 0.9 gram of 12,12-difluoro-11-dodecenoic acid. The nmr spectrum was consistent with the proposed structure.