Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]([S:11][C:12]2[N:20]=[C:19]3[C:15]([N:16]=[CH:17][NH:18]3)=[C:14](N)[N:13]=2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:22]([NH:26][S:27]([CH2:30][CH2:31]Cl)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].C[N:40](C=O)C>>[NH2:40][C:15]1[N:16]=[CH:17][N:18]=[C:19]2[C:14]=1[N:13]=[C:12]([S:11][C:3]1[C:2]([I:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=1)[N:20]2[CH2:31][CH2:30][S:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:29])=[O:28]
Reactant: Nc1nc(Sc2cc3c(cc2I)OCO3)nc2[nH]cnc12
Reactant: CN(C)C=O
Reactant: CC(C)(C)NS(=O)(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)NS(=O)(=O)CCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of 8-((6-iodobenzo[d][1,3]dioxol-5-yl)thio-9H-purin-6-amine (56 mg, 0.13 mmol) in DMF (2 mL) was added N-t-butyl-2-chloroethanesulfonamide (50 mg, 0.25 mmol) and Cs2CO3 (88 mg, 0.27 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS47 as a white solid (10 mg, 13%). 1H NMR (500 MHz, CDCl3/MeOH-d4): δ 8.22 (s, 1H), 7.39 (s, 1H), 7.08 (s, 1H), 6.06 (s, 2H), 4.69 (t, J=7.0 Hz, 2H), 3.57 (t, J=7.1 Hz, 2H), 1.35 (s, 9H); 13C NMR (125 MHz, CDCl3/MeOH-d4): δ 158.3, 156.4, 155.1, 153.9, 153.4, 151.5, 129.2, 123.5, 123.3, 117.8, 106.6, 98.1, 58.5, 57.3, 42.7, 33.8; HRMS (ESI) m/z [M+H]+ calcd. for C18H22IN6O4S2, 577.0189. found 577.0217.
Reaction SMILES: C(N1CC[CH2:6][CH:5](CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)[CH2:4]1)C.[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:51][CH3:52])[N:41]2[CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[C:37]([NH2:53])[N:36]=1)[CH2:31][CH2:32][CH3:33].IC(C)C>>[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:51][CH3:52])[N:41]2[CH2:44][CH:45]2[CH2:46][CH2:47][N:48]([CH:5]([CH3:6])[CH3:4])[CH2:49][CH2:50]2)=[C:37]([NH2:53])[N:36]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CC(C)I
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][Si](C)(C)C)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:18]1([S:24]([NH:27][C:28]2[C:33](I)=[CH:32][C:31]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[K+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[C:18]1([S:24]([N:27]2[C:28]3[C:29](=[CH:30][C:31]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:32][CH:33]=3)[CH:13]=[C:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A mixture of 5-ethoxycarbonyl-2-trimethylsilylethynylpyridine (3.80 g), 2-benzenesulfonylamino-3-iodo-5-methanesulfonylbenzene (3.50 g), potassium acetate (6.00 g), cuprous iodide (75 mg), dichlorobis(triphenylphosphine)palladium (0.27 g) and N,N-dimethylformamide (10 ml) was stirred under nitrogen atmosphere at 100° C. for 8 hours. To the reaction solution was then added water and ethyl acetate. The insolubles were filtered off. The filtrate was extracted with ethyl acetate and washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (methanol:dichloromethane=1:100) to obtain 1.22 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH:24]=O)[C:21]([O:26][CH2:27][O:28][CH3:29])=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH3:34][NH2:35].B.[Na]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:35][CH3:34])[C:21]([O:26][CH2:27][O:28][CH3:29])=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cc(C=O)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Reactant: CN
Agent: B
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CNC)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In 30 ml of methanol was dissolved 500 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole. Thereto was added 3 ml of a 30% methylamine solution. The mixture was stirred at room temperature for 14 hours and at 70° C. for 1 hour. Thereto was added 530 ml of sodium boron hydride with stirring under ice-cooling. The mixture was stirred at room temperature for 3 hours. The solvent was removed from the reaction mixture by distillation. The residue was mixed with 40 ml of ethyl acetate and 20 ml of water, and phase separation was conducted. The organic layer was washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was subjected to silica gel chromatography (eluent: dichloromethane/methanol=49/1 by v/v). From the eluate was obtained 150 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylaminomethylphenyl)thiazole.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])SC)#[N:2].[NH2:18][CH2:19][CH2:20][NH2:21]>>[C:1]([NH:3][C:4]([NH:18][CH2:19][CH2:20][NH2:21])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[N:13]=[CH:14][NH:15][C:16]=1[CH3:17])#[N:2]
Reactant: NCCN
Reactant: CSC(=NCCSCc1nc[nH]c1C)NC#N
Product: Cc1[nH]cnc1CSCCN=C(NC#N)NCCN

Procedure:
Reaction of N-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea with excess 1,2-diaminoethane at room temperature gave N-cyano-N'-(2-aminoethyl)-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine, m.p. 164°-167°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18]O>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:18])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: CO
Product: COc1ccc(C(=O)Cc2ccccc2)c(O)c1
Yield: 87.9 %

Procedure:
Using the previous procedure and starting from 1-(2,4-dihydroxyphenyl)-2-phenylethanone (7.08 g, 31.0 mmol) and methanol (1.32 mL, 32.55 mmol), 6.60 g (88%) of the title compound was obtained as a white solid: mp 87-88° C. (lit. 92° C.); IR (KBr) 1635, 1620, 1589, 1437, 1350, 1291, 1230, 1206, 1127, 1021, 958, 802, 739, 729, 551 cm−1; 1H NMR (400 MHz, CDCl3) δ 12.71 (br s, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.31-7.34 (m, 2H), 7.23-7.26 (m, 3H), 6.40-6.44 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.38, 166.61, 166.30, 134.82, 132.47, 129.76, 129.16, 127.50, 113.58, 108, 27, 101.44, 56.00, 45.27.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.ClCl.[Cl:9][CH2:10][C:11](=[O:16])CC(Cl)=O.[CH3:17][S:18](C(O)C)(=[O:20])=[O:19]>C(Cl)Cl.O.N1C=CC=CC=1>[Cl:9][CH2:10][C:11](=[O:16])[CH2:3][C:4]([O:6][CH2:2][CH2:1][S:18]([CH3:17])(=[O:20])=[O:19])=[O:5]
Reactant: CC(O)S(C)(=O)=O
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cl)CC(=O)CCl
Agent: ClCl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)CCOC(=O)CC(=O)CCl
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 260 ml of methylene chloride was dissolved 87.9 g (1.407 moles) of diketene. The solution was cooled to -35° C. and 74.2 g (1.045 moles) of chlorine gas was bubbled into the solution at -35° to -30° C. for about 2 hours to prepare a methylene chloride solution of 4-chloroacetoacetyl chloride. Separately, 100 g (0.805 mole) of methylsulfonylethanol was dissolved in 130 ml of methylene chloride followed by addition of 63.7 g of pyridine. To this solution was added the above methylene chloride solution of 4-chloroacetoacetyl chloride at -5° to 0° C. dropwise over a period of about 1.5 hours. The mixture was then stirred for 30 minutes and poured in water, and 800 ml of methylene chloride was added to extract the reaction product. The water layer was further extracted with methylene chloride and the organic layers were combined and washed with water. The organic solution was concentrated to dryness and the concentrate was dissolved in 50 ml of methylene chloride and crystallized by addition of 200 ml of isopropyl ether to give 156.3 g (yield: 80% based on methylsulfonylethanol) of methylsulfonylethyl 4-chloroacetoacetate as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:8][O:9][N+:10]=2[O-:11])[N:5]=[CH:6][N:7]=1.[H-].[Li+].[CH3:14]I>C1COCC1.C(OCC)(=O)C>[CH3:14][N:7]1[C:2](=[O:1])[C:3]2=[N+:10]([O-:11])[O:9][N:8]=[C:4]2[N:5]=[CH:6]1
Reactant: CI
Reactant: [O-][n+]1onc2ncnc(O)c21
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cnc2no[n+]([O-])c2c1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A solution of 3.0 g (20 mmol) of 7-hydroxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (C. Temple, C. L. Kussner, J. A. Montgomery, J. Org. Chem. 33 (1968) 2086) in 30 ml of THF is added dropwise to a suspension of 0.18 g (22.5 mmol) of lithium hydride in 20 ml of THF. The mixture is heated at 40° C. for 30 minutes, then 11.5 g (80 mmol) of methyl iodide in 10 ml of THF are added dropwise at room temperature and it is allowed to stand for 2 days. The mixture is diluted with 300 ml of ethyl acetate, washed three times with water, dried over magnesium sulphate and concentrated in vacuo. After recrystallisation from isopropanol, 1.9 g (57%) of 6-methyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-7(6H)-one-1-oxide are obtained.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH2:15][CH:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.C(O)C>CCCCCCC>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH2:15][C@@H:14]([CH:16]([CH3:17])[CH3:18])[NH:13][C:12]1=[O:19])[CH2:10]2.[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH2:15][C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:13][C:12]1=[O:19])[CH2:10]2
Reactant: CC(C)C1CN(C2C3CC4CC(C3)CC2C4)C(=O)N1
Solvent: CCCCCCC
Solvent: CCO
Product: CC(C)[C@@H]1CN(C2C3CC4CC(C3)CC2C4)C(=O)N1
Product: CC(C)[C@H]1CN(C2C3CC4CC(C3)CC2C4)C(=O)N1

Procedure:
Racemic 1-adamantan-2-yl-4-isopropyl-imidazolidin-2-one (320 mg, example 51) was subjected to preparative HPLC (Column: Chiralpack AD; Eluent: 15% ethanol in heptane; Flow: 35 mL/min; Detection: UV 220 nm) to give (R)-1-adamantan-2-yl-4-isopropyl-imidazolidin-2-one (136 mg, tRet=45 min) and (S)-1-adamantan-2-yl-4-isopropyl-imidazolidin-2-one (115 mg, tRet=64 min). Absolute configurations are tentatively assigned.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:24][CH2:25][CH:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=3)[CH2:21][CH2:22]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Temperature: 80 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (500 mg, 3.2 mmol) and 4-(3-trifluoromethyl-phenyl)-piperidine hydrochloride in DMF (15 mL) was added diisopropylethylamine (1.70 mL, 9.60 mmol). The mixture was heated in a sealed tube at 80° C. for 24 hours. The mixture was concentrated to dryness and triturated in methanol to give 5′-nitro-4-(3-triflouromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][CH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6]1)[CH:2]=C.I([O-])(=O)(=O)=[O:24].[Na+].C(OC)(C)(C)C>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[CH2:21]([CH:13]([CH2:12][CH2:11][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([O:4][CH2:1][CH:2]=[O:24])[CH2:6]1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:22]
Reactant: C=CCO[C@@H]1CCC[C@H](CCC(CC)C(=O)OC(C)(C)C)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CCC(CC[C@H]1CCC[C@@H](OCC=O)C1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 9 h

Procedure:
770 mg of tert-butyl 4-(cis-3-allyloxycyclohexyl)-2-ethylbutyrate are dissolved in 50 ml of diethyl ether, and 1.59 g of sodium periodate, dissolved in 50 ml of water, are added. At 0° C., 2.56 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 9 hours, a further 12.8 ml of the osmium tetroxide solution are added, and stirring at room temperature is continued for a further 3 hours. 200 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 710 mg of tert-butyl 2-ethyl-4-[cis-3-(2-oxoethoxy)cyclohexyl]butyrate as a yellow-brown oil. C18H32O4 (312.45), Rf(n-heptane:ethyl acetate=5:1)=0.15.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([C@@H:31]([NH2:40])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@@H:31]([NH:40][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Product: Cc1ccc(C[C@H](NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 58 %

Procedure:
The title compound was prepared in a yield of 58% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and (S)-1-phenyl-2-(4-methylphenyl)ethylamine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][CH2:20][Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:11])[CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=CCCCc1ccccc1
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 700 mg (4.7 mmol) of 4-phenyl-1-butanal (119) in 5.0 mL of THF at 0° C. was added 10.0 mL (5.0 mmol) of 3-phenyl-1-propylmagnesium bromide (120) and the resulting mixture was stirred at 0° C. for 0.5 h. The mixture was then quenched by the dropwise addition of saturated NH4Cl and diluted with ether. The phases were separated and the organic layer was washed with water and brine and then dried over MgSO4. Concentration gave 1.12 g of the alcohol 121 as an oil. 1H NMR spectrum was consistent with the structure.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][S:14][C@@H:15]2[CH2:19][N:18]([CH3:20])[C@H:17]([C:21](=[O:24])[NH:22][CH3:23])[CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[S:2]([F:1])([O-:5])(=[O:4])=[O:3].[CH3:20][N+:18]1([CH3:6])[CH2:19][C@@H:15]([S:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:26][CH:25]=2)[CH2:16][C@H:17]1[C:21](=[O:24])[NH:22][CH3:23]
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)C[N+]1(C)C
Product: O=S(=O)([O-])F
Reaction time: 0.5 h

Procedure:
280 μl of methyl fluorosulfonate were added, whilst ice-cooling, to a solution of 210 mg of (2S, 4S)-4-(4-methoxybenzylthio)-1-methyl-2-methylcarbamoylpyrrolidine [prepared as described in step (5) above] dissolved in 30 ml of dry methylene chloride. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed repeatedly by decantation with diethyl ether and dried under reduced rpessure, to afford 281 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16](SC)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:35]1C=CC=C(C(OO)=O)C=1.[S:45]([O-:49])([O-])(=[O:47])=S.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:32])([F:31])[F:33])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[O:19])=[C:16]([S:45]([CH3:35])(=[O:49])=[O:47])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C

Procedure:
In a solution of 0.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylthio-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-322) synthesized similarly to Synthetic Example 13 in 6 ml of dichloromethane, 0.17 g of 3-chloroperbenzoic acid was added with stirring at room temperature, and stirred at the same temperature for 3 days. After the completion of the reaction, the reaction mixture was poured in 30 ml of sodium thiosulfate aqueous solution, and extracted with chloroform (10 ml×3). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with chloroform, and 0.20 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][NH:27][CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:31]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=[O:41])([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([C:40]([C@@H:39]5[CH2:43][CH2:44][CH2:45][N:38]5[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:41])[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C2
Reaction time: 16 h
Yield: 78.7 %

Procedure:
4-(Benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (50 mg, 0.12 mmol) was stirred in DMF (1 mL) and saturated Boc-L-proline (30 mg, 0.14 mmol), HATU (68 mg, 0.18 mmol) and Et3N (36 mg, 0.36 mmol) were added. After 16 h, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 25 mL/min) to provide the title compound (55 mg, 78%) as a colorless oil: ESI MS m/z 583 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:22])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:7][CH:6]=1)[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCCC>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[O:22])=[CH:9][CH:10]=1)[CH3:25]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc3cccnc23)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc3cccnc23)cc1
Reaction time: 24 h
Yield: 60.2 %

Procedure:
16 (3.0 g, 9.0 mmol) was dissolved in CH2Cl2 (25 mL) and powdered pyridinium dichromate (PDC) (5.0 g, 13 mmol) was added portionwise at 25° C. Two more portions of PDC (0.5 g) were added after 3 h and 12 h. After 24 h, the solution was diluted with heptane and filtered through silica gel. Elution with EtOAc and evaporation in vacuo gave 17 (1.8 g, 60%). MS: 332, 303, 275, 260, 232, 204, 176, 156, 128, 115. 1H NMR (CDCl3): δ 1.1, 1.3 (2m, 6H), 3.22, 3.55 (2m, 4H), 7.39 (d, J=8 Hz, 2H), 7.43 (m, 1H), 7.65 (m, 1H), 7.75 (m, 1H), 7.86 (d, J=8 Hz, 2H), 7.98 (m, 1H), 8.23 (m, 1H), 8.83 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33]>C1C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(F)c(Cl)c2)C1=O
Yield: 25 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (112 mg) and tetrakis(triphenylphosphine)palladium(0) (54 mg) in 7 ml benzene and 1 ml ethanol, were added 2 M aqueous sodium carbonate (0.22 ml) and (3-chloro-4-fluorophenyl)boronic acid (82 mg). The reaction solution was kept at reflux for 24 hours. Then the solvent was evaporated off under reduced pressure. The resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 32 mg of 4-(3-chloro-4-fluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 162-164° C. NMR: δ1.58 (s, 6H), 3.09 (s, 3H), 7.13 (m, 2H), 7.40 (d, J=6.6 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.1 Hz, 2H). IR (cm−1): 2930, 1700, 1587, 1503, 1404, 1317, 1150, 1068, 913, 771, 744.