Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=2)[CH:8]=[N:7]1)[CH3:3].Cl.Br[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:3][N:2]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:13]=2)[CH:8]=[N:7]1)[CH3:1]
Reactant: Brc1ccncc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2cnn(CCN(C)C)c2c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)CCn1ncc2ccc(-c3ccncc3)cc21
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A solution of 1-(2-(N,N-dimethylamino)ethyl)-6-tributylstannyl-1H-indazole (49.1 mg, 0.10 mmol), 4-bromopyridine hydrochloride (21.6 mg, 0.11 mmol), tetrakistriphenylphosphine palladium(0) (10-20 mg, catalytic) in toluene (0.5 mL) was heated at reflux under an inert atmosphere for 18 h. After cooling to room temperature the reaction was quenched by the addition of aqueous sodium hydroxide (1 M, 2 mL) and water (10 mL), and the product extracted into ethyl acetate (50 mL). The organic layer was washed sequentially with water and brine, dried over sodium sulfate and the solvent removed in vacuo. Filtration through an SPE cartridge (Supelco, 6 mL, silica gel, 1000 mg, gradient from 0-10% 2M methanolic ammonia in dichloromethane) gave a crude product which was further purified by flash chromatography (silica gel, 4-10% 2M methanolic ammonia in dichloromethane) to give the title product (6.1 mg, 11%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[N:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[C:8]([C:7]1[C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])=[N:3][C:4]([C:10]([F:19])([F:18])[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[N:5][CH:6]=1)#[N:9]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cnc(C(F)(F)C(F)(F)C(F)(F)F)nc1N
Product: CN(C)C=Nc1nc(C(F)(F)C(F)(F)C(F)(F)F)ncc1C#N

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-heptafluoropropyl-pyrimidine-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28])#[N:17]>O1CCOCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]=2[C:16]#[N:17])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1c(S)ccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(SSc2ccc([N+](=O)[O-])cc2C(Cl)(Cl)Cl)ccc2ccccc12
Yield: 81.3 %

Procedure:
30.7 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 500 ml of dioxane is reacted with 18.5 g of 1-cyano-2-mercaptonaphthalene. There is obtained 37 g (81% of theory) of 2-(4-nitro-2-trichloromethylphenyldithio)-1-cyanonaphthalene; m.p.: 170° C. (recrystallized from toluene).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].O=[CH:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:15]/[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24](=[O:26])(=[O:25])[NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:19]=1
Reactant: O=CC#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of trimethyl phosphonoacetate (0.81 g, 4.5 mmol) in dry tetrahydrofuran (20 ml) under an argon atmosphere at 15-20° C. sodium hydride (0.12 g, 5.0 mmol) was added. The mixture was stirred at ambient temperature for 1 hour, and a solution of 3-(3-oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54a) (0.44 g, 1.5 mmol) in dry tetrahydrofuran (20 ml) was added dropwise at 15-20° C. The reaction mixture was stirred at ambient temperature for 1 hour and quenched by 3% HCl (20 ml). The product was extracted with ethyl acetate (50 ml), the extract was washed with 5% NaHCO3, water and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate-hexane (1:2, v/v) as eluent to give the title compound (0.39 g, 74%) as a white solid. M.p. 134-136° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.73 (3H, s, CH3); 6.49 (1H, d, J=15.5 Hz, CH); 7.03 (1H, d, J=15.5 Hz, CH); 7.01-7.38 (5H, m, C6H5); 7.41-7.89 (4H, m, C6H4); 10.34 (1H, s, NH).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:4][C:3](=[O:6])[NH:2]1.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]2[NH:25][C:26]([C@@H:28]([NH2:30])[CH3:29])=[N:27][C:23]=2[CH:22]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]2[NH:25][C:26]([C@@H:28]([NH:30][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:1]4[CH2:5][CH2:4][C:3](=[O:6])[NH:2]4)=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=3)[CH3:29])=[N:27][C:23]=2[CH:22]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2C(F)(F)F)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CCC(=O)N2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from the 4-(pyrazolidin-3-on-1-yl)-3-trifluoromethyl-benzoic acid and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine with TBTU and TEA in DMF.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[C:6]([N+:12]([O-])=O)[C:5]=1Cl.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)c(C)c([N+](=O)[O-])c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(N)c(C)c(F)c1
Temperature: 75 °C
Reaction time: 10 h
Yield: 88.5 %

Procedure:
2-Chloro-5-fluoro-4-methyl-3-nitro-benzoic acid methyl ester (Example 252d, 53 g), 5% Pd/C (9 g) and ammonium formate (80 g) were stirred together in ethanol (500 mL) at 75° C. for 32 h. The reaction was filtered through celite and filtrate evaporated to a solid. This solid residue was dissolved in dichloromethane, washed with water. The separated aqueous layer was further extracted with dichloromethane (3×100 mL) and the combined organics dried (MgSO4) and evaporated. Analysis showed significant unreacted starting material. The reaction was repeated by new 5% P/C (9 g) and ammonium formate (80 g) together in ethanol (500 mL) and heating at 75° C. for 20 h. Further 5% Pd/C (9 g) and ammonium formate (80 g) were added and heating continued for 10 h. The mixture was filtered through celite and the filter cake was washed with further ethanol. The combined filtrates were evaporated, the residue dissolved in dichloromethane, washed with water. The separated aqueous layer was further extracted with dichloromethane (3×100 mL) and the combined organics dried (MgSO4) and evaporated to afford the subtitle compound (34.7 g).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>N1C=CC=CC=1>[CH2:1]([O:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 70 %

Procedure:
1-hexadecyl glycerol (105g, 0.33mol) and 93 g (0.33mol) tritylchloride were dissolved in 300 ml of pyridine. The mixture was heated at 100° C. for 16 hours. After cooling to room temperature 1500 ml of ethyl ether was added and the slurry washed 3 times with cold 0.5N H2SO4, 5% sodium bicarbonate and 2 times with water. The organic phase was dried over MgSO4, the ether removed on a rotary evaporator and the residue recrystallized from ethanol, yielding the intermediate 1-hexadecyl-3-trityl glycerol (129 g, 70%). The 2 position of this intermediate was alkylated with tetradecyl bromide in the same manner (powdered KOH in toluene) as described earlier for the dialkylation of benzyl glycerol in the preparation of 1,2-dihexadecyl glycerol. The resulting 1-hexadecyl-2-tetradecyl-3-trityl glycerol (128 g) was dissolved in 300 ml of petroleum ether. At room temperature 30 g of anhydrous hydrogen chloride was added. A precipitate formed within a short time. The slurry was stirred at room temperature for 4 hours and then filtered. The solids were recrystallized from acetone (10° C.) to give 45.6g of product, m.p. 42°-3° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(N)(C)C.[Cl:18][C:19]1[CH:56]=[CH:55][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5N(CC)[C:42]6C=CC(C(O)=O)=[CH:49][C:41]=6[N:40]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:56]=[CH:55][C:22]([C:23]2[C:28]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:39]5[N:40]([CH:41]([CH3:49])[CH3:42])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:35]=4)[N:30]=3)=[CH:27][C:26]([O:53][CH3:54])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)N
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C(C)C)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and isopropylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2s1
Yield: 23 %

Procedure:
Benzothiophene-2-carboxylic acid was treated with 1.5 equivalents of oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF to form benzothiophene-2-carbonyl chloride. Following procedures described for Example 1 and substituting this acyl chloride for 3-trifluoromethylbenzoyl chloride, compound 77 was prepared in 23% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(C)c1Cc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: Cc1nn(C)c(C)c1Cc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (88%, oil). HPLC-MS: m/z=350.0 (M+1); Rt: 3.52 min. (66% purity).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:13][C:12]=1[Cl:22].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[Cl:22]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 4-[N′-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 3.37 mmol) in THF (30 ml) was added 0.25 N NaOH (30 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 4-[N′-(2bromophenyl)ureido]-3-chlorophenylacetic acid (1.03 g, 80%) as colorless powder. 1H-NMR (DMSO ) δ3.56 (s, 2H), 7.00 (m, 1H), 7.17 (dd, J=9.0, 1.7 Hz, 1H), 7.32-7.40 (m, 2H), 7.62 (dd, J=8.0, 1.2 Hz, 1H), 7.95 (m, 2H), 8.83 (s, 1), 9.01 (s, H), 12.41 (br, 1H); MS(FAB) m/z 385 (M++2), 386 (M++4), 388 (M++6).
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:17]([CH3:16])[NH2:18])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(N)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Di-t-butyl-dicarbonate (10.91 g, 50 mmole) was added to a solution of methyl hydrazine (2.3 g, 50 mmole) in 100 ml of tetrahydrofuran and 100 ml of water. The pH of the mixture was maintained at 8-9 with 2N sodium hydroxide, and the solution stirred overnight at this pH. The organic solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and distilled in vacuo to give the title compound as an oil, 3.68g.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[CH2:10][CH:11]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:7]([F:25])([F:6])[C:8]1[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=1[CH2:10][CH:11]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]1[C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccccc2C(F)(F)F)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.5 %

Procedure:
Methyl chloroformate (1.399 mL, 18.07 mmol) in DCM (40 mL) was added to a solution of methyl 2-(2-(trifluoromethyl)benzyl)piperidine-4-carboxylate (4.19 g, 13.9 mmol) and DIPEA (7.28 mL, 41.69 mmol) in DCM (60 mL). The reaction mixture was stirred for 1.5 h at room temperature, then washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to give crude dimethyl 2-(2-(trifluoromethyl)-benzyl)piperidine-1,4-dicarboxylate (5.42 g, 109%). MS m/z 360 (M+H)+
Reaction SMILES: C([S:4][CH:5]1[CH2:22][CH2:21][C:8]2([CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=O)C.[H][H].N>CO.O1CCCC1>[SH:4][CH:5]1[CH2:6][CH2:7][C:8]2([CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)[CH2:12][CH2:13]2)[CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: CC(=O)SC1CCC2(CCC(CCc3ccoc3)CC2)CC1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: SC1CCC2(CC1)CCC(CCc1ccoc1)CC2
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A solution of 0.100 g of 9-acetylthio-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane in 5 ml of methanol/tetrahydrofuran 3/1, was saturated with hydrogen and successively with gaseous ammonia and kept on standing for 3 hrs at room temperature. The mixture was evaporated to dryness and purified by flash chromatography (SiO2 ; n-hexane/diethylether 80/20) to give 0.080 g of 9-mercapto-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane as a white sticky oil. TLC: Rf=0.38 (SiO2 plates, n-hexane/diethylether 80/20). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.36 (1H, m), 7.20 (1H, m), 6.27 (1H, m), 2.90 (1H, m), 2.48 (2H, t), 1.90-0.85 (19H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[CH3:19][C:20]1([CH3:37])[O:24][C@@H:23]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:25][C@H:23]4[CH2:22][O:21][C:20]([CH3:37])([CH3:19])[O:24]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2cccc3c2CCc2cc(Cl)ccc2C3=O)O1
Yield: 53 %

Procedure:
For the preparation of the title compound, 0.50 g (1.9 mmol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.75 g (2.6 mmol) of (R)-toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester and 0.80 g (5.8 mmol) of K2CO3 in 10 ml of dry DMF are reacted by method M. Yield: 53%; C21H21ClO4 (Mr=372.85); GC 22.8 min
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: N#Cc1cccc(S(=O)(=O)N=C=O)c1
Product: N#Cc1cccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)c1
Yield: 20.1 %

Procedure:
1.14 g (5.49 mmol) of 3-cyanobenzenesulfonylisocyanate and 943 mg (5.50 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 399 mg of the above-identified compound (yield 20.0%). Properties: colorless crystal, Melting point: 225°-226° C., PMR (δppm, DMSO-d6); 7.13 (1H,s), 7.24 (1H,d), 7.89 (2H,m), 8.24 (1H,d), 8.43 (1H,d), 8.55 (1H,s), 11.76 (1H,br).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[S:8]1[CH2:13][CH2:12][CH2:11][S:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1.CN(C=O)C>[CH:7]1([CH2:6][C:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:8][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1SCCCS1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC2CC2)SCCCS1
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a suspension of NaH (95%, 2.8 g, 111 mmol) in dry toluene (120 mL) stirring at 0° C. was dropwise added, over 10 minutes, a solution of bromomethylcyclopropane (15 g, 111 mmol), and ethyl 1,3-dithiane-2-carboxylate (17.77 g, 92.58 mmol) in dry DMF (40 mL). The ice bath was removed and the solution was stirred overnight at rt. Water was added to the solution and the phases were separated. The organic phase was dried over MgSO4, then evaporated to give 19.6 g (50%) of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate, which was used in the next step without purification. 1H NMR (CDCl3): δ 4.26 (2H, q, J=7.2 Hz), 3.30-3.23 (2H, m), 2.69-2.64 (2H, m), 2.16-2.11 (1H, m), 1.96 (2H, d, J=6.8 Hz), 1.91-1.81 (1H, m), 1.34 (3H, t, J=7.2 Hz), 0.93-0.86 (1H, m), 0.52-0.47 (2H, m), 0.20-0.16 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[CH:15][N+:12]([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(F)c(C=O)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)c(C=C[N+](=O)[O-])c1
Yield: 58.6 %

Procedure:
2-Fluoro-5-methoxy-benzaldehyde (4 g, 25.95 mmol) was reacted with nitro methane (1.58 g, 25.95 mmol), 10N NaOH (2.2 mL, 27.24 mmol) to afford 3 g of the product (58.7% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=1.[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>O1CCCC1>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([N:13]([CH2:23][O:22][CH2:20][CH3:21])[C:14](=[O:17])[O:15][CH3:16])[CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=1
Reactant: C=CCC(Cc1ccc(Cl)cc1)NC(=O)OC
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(Cl)cc1)N(COCC)C(=O)OC
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A suspension of 10.0 g of sodium hydride (80% in mineral oil, 333 mmol) in dry THF (tetrahydrofuran) is heated to reflux under argon. A solution of 60.5 g (238 mmol) of methyl [1-(4-chlorobenzyl)but-3-enyl]carbamate in 50 ml of dry THF is added dropwise in the course of 1 hour. The mixture is then boiled under reflux for a further 2 hours until the evolution of gas subsides. The mixture is cooled to 0° C. and chloromethyl ethyl ether is added dropwise so that the reaction temperature does not rise above 5° C. After this, the mixture is slowly heated to 25° C. and stirred for 12 hours. Excess sodium hydride is cautiously destroyed with 1 ml of water before more water is added. The phases are separated and the aqueous phase is extracted again with tert-butyl methyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is distilled at 0.1 mbar and has a boiling range of 120-125° C. TLC: ethyl acetate/hexane (1:6) Rf =0.34, FD-MS: M+ =311(313).
Reaction SMILES: [CH3:1][C:2]1([CH:8]=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30]>O1CCCC1>[F:28][C:29]([F:31])([F:30])[CH:8]([C:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[OH:9]
Reactant: CC1(C=O)CCOCC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(O)C(F)(F)F)CCOCC1
Yield: 46.5 %

Procedure:
According to Reference Example 8-12, by use of 4-methyltetrahydro-2H-pyran-4-carbaldehyde (165 mg, 1.29 mmol) dissolved in tetrahydrofuran (5 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.258 mL, 0.258 mmol) and (trifluoromethyl)trimethylsilane (0.229 mL, 1.55 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(4-methyltetrahydro-2H-pyran-4-yl)ethanol (Compound EC) (119 mg, yield: 47%).
Reaction SMILES: [C:1]([C:5]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:22]=[C:21]([CH2:23][Br:24])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccc(C)cc1C(C)(C)C)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(C)(C)C)c1ccccc1
Yield: 21.7 %

Procedure:
To a solution of 0.494 g (1.58 mmol) of the product of Step A dissolved in 10 mL of CCl4 was added 0.310 g (1.74 mmol) of N-bromosuccinimide and 15 mg (catalytic amount) of AIBN and the mixture was heated at reflux for 3.5 hours. The reaction was cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 3% ethyl acetate/hexane to afford 0.134 g (22%) of the title compound.