Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([CH:5](O)[C:6]([CH3:9])([CH3:8])[CH3:7])[C@H:3]1[C:11]([OH:13])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C@H:3]2[C@@H:4]1[C@H:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[O:12][C:11]2=[O:13]
Reactant: CC(C)(C)C(O)[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)[C@@H]1OC(=O)[C@@H]2[C@H]1C2(C)C
Reaction time: 0.25 h

Procedure:
A solution of 5 g of the product of Step A in 50 ml of benzene was heated to reflux and 20 mg of p-toluene sulfonic acid were added thereto and reflux was continued for 15 minutes. The mixture was cooled and was washed with aqueous sodium hydroxide and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 benzene-ethyl acetate mixture to obtain (1R,4R,5S) 6,6-dimethyl-4-(2-methyl-prop-2-yl)-3-oxa-bicyclo(3,1,0)hexan-2-one melting at 113° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:35][CH3:36])[CH2:5][CH2:6][N:7]([S:28]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:30])=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:3].ClCl.Cl.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:35]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]([S:28]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:30])=[O:29])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([Cl:1])=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:36]
Reactant: CCCCS(=O)(=O)N(CCN(CC)CC)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Reactant: Cl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)N(CCN(CC)CC)c1ccc(C(Cl)=C(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
N-(2-Diethylaminoethyl)-4'-(β-phenylstyryl)butanesulfonanilide hydrochloride (10.5 g., 0.02 mole, refer to Procedure 51) is dissolved in a mixture of 300 ml. of carbon tetrachloride and 20 ml. of chloroform. The mixture is stirred and 39 ml. of a carbon tetrachloride solution containing 1.4 g. (0.02 mole) of chlorine is added thereto during 30 min. The mixture is kept at room temperature for an additional 30 min. and then refluxed for 1 hr. Vigorous evolution of hydrogen chloride gas is apparent during this period. The reaction mixture is allowed to cool and then neutralized with 100 ml. of aqueous 5% sodium hydroxide. The organic layer is separated, dried over magensium sulfate, and the solvent evaporated yielding 11.0 g. of the desired product. The material is purified by chromatography on an alumina column having dimensions 1 inch by 15 inches and eluting sequentially with 1:1 benzene-octane; benzene; benzene-chloroform, and finally with chloroform and collecting the eluate in 20 fractions. Fractions 15-19 are combined and the desired product recovered as the citrate salt, m.p. 65°-70°C.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:17][CH:18](C)CCC1C=CC2OCC(=O)COC=2C=1>>[CH2:4]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:7]=2[CH:6]=1)[CH2:3][CH2:2][CH2:1][CH2:17][CH3:18]
Reactant: CC1CCc2cc3c(cc21)OCC(=O)CO3
Reactant: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Product: CCCCCCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, aquatic.—IR (film): ν=1502/1435/1580 cm−1 (ν C═C, Ar), 1265/1304/1201 cm−1 (ν ring), 1051 cm−1 (ν C—O—C), 1741 cm−1 (ν C═O).—1H-NMR (CDCl3): δ=0.88 (t, J=6.8 Hz, 3H, 6′-H2), 1.27–1.35 (m, 6H, 3′-H2-5′-H2), 1.57 (br. quint, J=8.0 Hz, 2H, 2′-H2), 2.51 (t, J=7.8 Hz, 2H, 1′-H2), 4.68 (d, J=8.0 Hz, 4H, 2-, 4-H2), 6.77 (dd, J=8.0, 4.0 Hz, 1H, 8-H), 6.81 (d, J=4.0 Hz, 1H, 6-H), 6.90 (d, J=8.0 Hz, 1H, 9-H).—13C-NMR (CDCl3): δ=13.96 (q, C-6′), 22.46 (t, C-5′), 28.77 (t, C-3′), 31.19/31.56 (2t,C-2′,-4′), 34.89 (t, C-1′), 75.35/75.63 (2t, C-2,-4), 120.31/120.47 (2d, C-6,-9), 123.50 (d, C-8), 138.85 (s, C-7), 146.03/147.83 (2s, C-5a,-9a), 204.73 (s, C-3).—MS (EI): m/z (%)=77 (16) [C8H6+], 91 (9) [C7H7+], 135 (9) [M+-C5H11—C2H2O], 149 (21) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (2) [M+-C4H9], 205 (3) [M+-C3H7], 248 (43) [M+].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[S:8].N12CCCN=C1CCCCC2.Cl>C(O)C>[C:4]([C:3]([C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=1)=[S:8])=[C:2]([OH:6])[CH3:1])#[N:5]
Reactant: Cc1oncc1C(=S)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC(O)=C(C#N)C(=S)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of 7.0 grams of 5-methyl-4-(4-trifluoromethylphenyl)aminothiocarbonylisoxazole and 5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 50 ml of ethanol was heated at 80° C. for 8 hours. The reaction mixture was cooled to room temperature and acidified with 6N hydrochloric acid solution until pH 2. The mixture was then cooled in an ice-water bath for 30 minutes and the solid was filtered, washed with a chilled solution of ethanol and water (2:1) and dried by suction to provide 5.0 grams of 1-cyano-2-hydroxy-1-(4-trifluoromethylphenyl) aminothiocarbonylpropene.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]=[CH:5][CH2:4][O:3]1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].C(O)(=O)C>[Pd].CO>[C:14]([O:13][C:9]([NH:10][N:11]=[C:7]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH3:1])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1OCC=CC1=O
Reactant: CC(C)(C)OC(=O)NN
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC1OCCCC1=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A methanol (9 mL) solution of (±)-2-methyl-2H-pyran-3(6H)-one (370 mg, 3.30 mmol) was treated with a suspension of 10% palladium on carbon (185 mg) in methanol (3 mL). The mixture was sparged under hydrogen and stirred for 45 minutes at ambient temperature. The mixture was sparged under nitrogen, treated with tert-butyl carbazate (436 mg, 3.30 mmol, 1 equiv) and acetic acid (0.756 mL, 13.2 mmol, 4 equiv) and sparged under hydrogen. After stirring for 1 hour, the mixture was sparged under nitrogen and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with sodium bicarbonate (30 mL, saturated aqueous) and the organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 20:80; hexanes:ethyl acetate) to provide the titled compound.
Reaction SMILES: [NH:1]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:2]([C:30](ON1C(=O)CCC1=O)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH2:47][CH2:48][C:49]([OH:51])=[O:50].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH:1]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:2]([C:30]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)O
Reaction time: 24 h

Procedure:
To a solution of Boc—(D)—Arg(Cbz2)—OSu (1 g, 1.6 mmol) in dioxane (10 mL) was added a solution of Gly (300 mg, 4 mmol) and NaHCO3 (400 mg, 4.76 mmol) in water (10 mL). The solution was stirred for 24 h. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (20 mL) and 1 N HCl (6 mL). The separated organic layer was washed with sat. NaCl (10 mL), dried over MgSO4, filtered and evaporated to give a solid residue which was used directly without further purification. ES—MS (M+H)+=600
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]O)[CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:16].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:16][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccccc1OCC1CCC1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: BrCc1ccccc1OCC1CCC1
Temperature: 5 °C

Procedure:
A solution of {2-[(cyclobutylmethyl)oxy]phenyl}methanol (for a preparation see Intermediate 26) (0.5 g, 2.60 mmol) in anhydrous DCM (5 ml) was cooled to 5° C. under nitrogen. A solution of phosphorus tribromide (0.248 ml, 2.63 mmol) in anhydrous DCM (2 ml) was added dropwise. The reaction mixture was stirred allowing to warm up to ambient temperature for 1.5 h. The reaction mixture was then poured onto a mixture of ice/water (40 ml) and saturated sodium bicarbonate (15 ml). DCM (30 ml) was added and the layers were separated. The aqueous phase was extracted with DCM (20 ml). The combined DCM extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound as a pale yellow oil (0.50 g); LCMS: (System 4) tRET=3.61 min, no strong MH+ or (M-H)− detected.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.C([Li])(C)(C)C.C1C(=O)N([I:23])C(=O)C1>O1CCCC1>[I:23][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1
Reactant: Cn1cnc2ccccc21
Reactant: O=C1CCC(=O)N1I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(I)nc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
In an oven dried nitrogen purged 3 neck 100 mL round bottom flask, 1.00 g (7.57 mmol) of 1-methylbenzimidazole in 20 mL of dry tetrahydrofuran is cooled to −78° C. 10.69 mL (18.17 mmol) of 1.7 M t-butyllithium in hexanes is added and the reaction mixture is stirred at −78° C. for 1 h. 2.55 g (11.36 mmol) of NIS in 20 mL of dry tetrahydrofuran is added. Reaction is removed from bath and stirred at room temperature for 1 hour, quenched with saturated aqueous solution of ammonium chloride, and diluted with dichloromethane. The layers are separated, the aqueous is extracted 3×100 mL dichloromethane, dried (MgSO4), and concentrated. The crude mixture is purified by chromatography using hexanes:ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.400 g of the title compound, 21% yield. MS, ES+=259.0 (M+1); 1H NMR (DMSO-d6) δ 7.580-7.552 (m, 2H); 7.228-7.129 (m, 2H); 3.750 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:18]([CH3:17])(=[O:20])=[O:19])=[C:5]([CH3:10])[CH:4]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 6.85 gm (50 mmol) 4-methoxy-2-methylaniline in 70 ml of methylene chloride was introduced 8.5 gm (ml; mmol) pyridine followed by dropwise addition of 6.87 gm (60 mmol) methanesulfonylchloride. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with 1N HCl and then with saturated aqueous brine. The organics were dried with sodium sulfate and then evaporated in vacuo. The residue was triturated in diethyl ether to afford 7.5 gm (79%) of a light purple solid. Mass spectrum APCI (m/z) 216 (p+1).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:2][C:1]1([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)[O:11][CH2:10][CH2:9][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccsc2)OCCO1
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of 3-acetylthiophene (20 g), ethyleneglycol (10.54 g), p-toluenesulfonic acid (0.15 g) and toluene (200 ml) was stirred for 16 hours under reflux with removing azeotropic water by Dean-Stark trap. The mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-methyl-2-(3-thienyl)-1,3-dioxolan (12.6 g). 2-Methyl-2-(3-methyl-2-(3-thienyl)-1,3-dioxolan (12.0 g) was dissolved in tetrahydrofuran (200 ml), and N,N,N',N'-tetramethylethylenediamine (1.3 ml) was added. The mixture was cooled to -78° C, and n-butyllithium (1.6M in hexane, 49 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and then warmed slowly to room temperature for a period of 2 hours with introducing carbon dioxide gas. The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid (200 ml) was added. The mixture was stirred for 3 hours, and precipitated crystals were collected by filtration, washed with water and dried to give 3-acetyl-2-thiophenecarboxylic acid (10 g) as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 90 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl(3S)-3-amino-1-piperidinecarboxylate as in Example 28 gave tert-butyl(3S)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 90% yield: 1H NMR (DMSO-d6) (rotamers) δ8.12-7.58 (m, 3H), 7.38 and 7.38 (2t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=7.8 Hz, 1H), 3.97 (s, 3H), 3.78-3.69 (m, 10H), 2.99-2.94 and 2.85-2.83 (2m, 2H), 1.97-1.93 and 1.78-1.76 (2m, 2H), 1.58-1.19 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCCCCCCO
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: CCCCCCCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and 1-heptanol according to Method E. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (t, J=6.98 Hz, 3H), 1.11-1.56 (m, 15H), 1.67-1.75 (m, 3H), 1.83 (ddd, J=25.98, 12.82, 3.89 Hz, 1H), 2.01-2.12 (m, 1H), 2.20-2.27 (m, 1H), 2.85-2.96 (m, 1H), 3.07-3.15 (m, 1H), 3.62 (ddd, J=13.76, 9.33, 4.56 Hz, 1H), 4.28 (t, J=6.58 Hz, 2H), 4.97 (dd, J=9.40, 5.64 Hz, 1H), 7.21 (dd, J=8.86, 2.15 Hz, 1H), 7.42 (d, J=2.15 Hz, 1H), 7.69 (d, J=8.86 Hz, 1H), 7.83 (dd, J=8.19, 1.48 Hz, 1H), 7.87 (s, 1H), 8.12 (d, J=8.32 Hz, 1H); ES-MS m/z 518 (M+H).
Reaction SMILES: C[O-].[Na+].[N+:4]([CH:7]=[C:8](SC)[S:9]([CH3:11])=O)([O-:6])=[O:5].Br.[Br:15][CH2:16][CH2:17][NH2:18]>CO>[N+:4]([CH:7]=[C:8]([S:9][CH3:11])[NH:18][CH2:17][CH2:16][Br:15])([O-:6])=[O:5]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCCBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSC(=C[N+](=O)[O-])NCCBr
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
(b)(i) A solution of sodium methoxide (sodium (0.3 g, 0.013 mol) in methanol (10 ml)) was added dropwise, over a period of 10 minutes to a stirred mixture of 1-nitro-2-methylthio-2-methylsulphinylethylene (2 g, 0.011 mol) and 2-bromoethylamine hydrobromide (2.7 g, 0.013 mol) in methanol (25 ml), cooled to 0°. The solution was stirred at 0° for a further 15 minutes, and then it was allowed to attain room temperature. After 1 hour, the solvent was removed in vacuo, and the semi-solid residue was extracted with hot chloroform (2×25 ml). The extracts were combined and concentrated in vacuo. The solid residue was recrystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(2-bromoethylamino)ethylene (1.85 g, 71%) m.p. 123°-126°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5]O.P(Br)(Br)[Br:24]>COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH2:5][Br:24]
Reactant: COc1ccc(Oc2c(C)cc(CO)cc2C)cc1C(C)C
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: COc1ccc(Oc2c(C)cc(CBr)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl alcohol (1.0 g, 3.4 mmol) in DME (10 mL) at 0° C. was added phosphorous tribromide (1.8 g, 0.5 mL, 6.8 mmol). The reaction mixture was stirred at 0° C. for 5 h, quenched with methanol (2 mL) and stirred for 30 min. The reaction mixture was poured into ice water and extracted with ether (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide as an oil (1.02 g, 82%): 1H NMR (300 MHz, CDCl3): δ 7.15 (s, 2 H), 6.81 (d, J=3.0 Hz, 1 H), 6.67 (d, J=9.0 Hz, 1 H), 6.34 (dd, J=3.0, 8.7 Hz, 1 H), 4.51 (s, 2 H), 3.80 (s, 3 H), 3.40-3.25 (m, 1 H), 2.15 (s, 6 H), 1.20 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:4); Rf=0.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[S:3]1)[S:11][C:10]([CH3:15])([CH3:14])[S:9]3.[CH3:17][S:18]SC>>[CH3:17][S:18][C:13]1[C:4]2[S:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:9][C:10]([CH3:15])([CH3:14])[S:11][C:12]=12
Reactant: CSSC
Reactant: CC1(C)Sc2cc3c(cc2S1)SC(C)(C)S3
Product: CSc1c2c(cc3c1SC(C)(C)S3)SC(C)(C)S2

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole is lithiated with n-BuLl in diethyl either and then reacted with dimethyl disulfide to give 4-methylthio-2,2,6,6-Tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole. This compound can then be reacted with n-butyl glyoxalate (0.5 eq.) in a solvent consisting of a mixture of concentrated sulfuric acid and glacial acetic acid (1:10) (analogously to: G. Werber, Ann. Chim. 49, 1898 (1959)). After work-up, including neutralization and extraction the product is purified by preparative HPLC. The n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo[1,2-d;5,4-d']bis-(1,3)dithiole]acetate formed can be hydrolyzed with a 10% solution of sodium hydroxide and transferred into other esters, amides, thioesters and anhydrides etc. by standard procedures. If n-butyl bis[8-(methylthio-2,2,6,6-tetramethylbenzo-[1,2-d;5,4-d']bis-(1,3)dithiole] acetate is treated with n-BuLi (3 eq.) in tetrahydrofurane at ambient temperature and exposed to oxygen, the initially formed enolate anion is oxidized to the stable title radical (analogously to P. O'Neill and A. F. Hegarty, J. Org. Chem. 52, 2113 (1987)).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[CH2:11][CH3:12]
Reactant: O=C=Nc1cccnc1
Reactant: CCc1cc2c(cc1Cl)NCC2
Product: CCc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 59 %

Procedure:
6-Chloro-5-ethylindoline (D52) (0.42 g, 2.33 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.42 g, 59%) as a white crystalline solid m.p.=227° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:29])[C:11]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:30][O:31][C:32]1[CH:58]=[CH:57][C:35]([CH2:36][N:37]2[CH2:41][CH:40]([CH2:42][CH2:43]OS(C3C=CC(C)=CC=3)(=O)=O)[N:39]([CH3:55])[C:38]2=[O:56])=[CH:34][CH:33]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:29])[C:11]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:20])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:43][CH2:42][CH:40]2[CH2:41][N:37]([CH2:36][C:35]3[CH:57]=[CH:58][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:38](=[O:56])[N:39]2[CH3:55])=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Yield: 92.4 %

Procedure:
Cesium carbonate (8.23 g, 25.3 nmol) is added to a solution of 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (2.68 g, 8.43 mmol) and toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.88 g, 9.27 mmol) in DMF (30 mL). The resultant mixture is stirred at 65° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed with 1N HCl, water, and brine. The organic layer is dried, concentrated in vacuo, and purified by flash chromatography (17% acetone in hexanes) to provide the title compound (4.4 g, 93%). 1H NMR 400 MHz, CDCl3): δ 7.19-7.15 (m, 4H), 7.06-7.01 (m, 1H), 6.97-6.87 (m, 3H), 6.83 (d, 2H, J=8.6 Hz), 6.74 (d, 2H, J=8.6 Hz), 4.31, 4.27 (ABq 2H, J=14.8 Hz), 4.21, 4.17 (ABq, 2H, J=7.2 Hz), 3.96-3.92 (m, 2H), 3.76 (s, 3H), 3.60-3.53 (m, 1H), 3.33 (t, 1H, J=8.6 Hz), 3.25, 3.13 (ABq 2H, J=13.8 Hz), 2.994-2.83 (m, 2H), 2.82 (s, 3H), 2.24-2.16 (m, 1H), 1.89-1.80 (m, 1H), 1.37 (s, 3H), 1.22 (t, 3H, J=7.2 Hz). MS [EI+] 565 (M+H)+. Rf=0.56 in 50% acetone in hexanes.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C=O)C>[C:19]1(=[O:29])[N:23]([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(O)(CCN1C(=O)c2ccccc2C1=O)c1ccccc1-c1ccccc1

Procedure:
A mixture of 2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol, 2.04 g of potassium phthalimide and 40 ml of DMF is heated at 110° for 1.5 hours. After cooling, the mixture is worked up in the customary manner to give 1-phthalimido-3-p-biphenylyl-butan-3-ol, m.p. 153° - 155°.