Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CCOC(=O)CCCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 74.2 %

Procedure:
Ethyl 5-(6-cyano-2-pyridyl)valerate (0.34 g, 1.5 mmol) and methyl thiosalicylate (0.40 g, 2.4 mmol) were dissolved in toluene (2 ml), and triethylamine (0.43 ml, 3.1 mmol) was added thereto. The reaction mixture was refluxed for 14 hrs and subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethanol-hexane to give the titled compound (0.41 g, 76%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:32].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][CH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=3)=[CH:15][C:14]=2[CH3:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(C)[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc(CCl)nc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1.8 g (4.4 mmol) of 6-methyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide in 18 ml of methylene chloride was added dropwise a solution of 0.41 ml (1.13 eq) POCl3 in 4 ml of methylene chloride. After addition of 10% of POCl3 solution, triethylamine (0.54 ml; 1.1 eq) in 4 ml of methylene chloride was added portions. The exothermic mixture was stirred for 30 min, washed with saturated ammonium chloride solution, and the organic layer was separated and dried over sodium sulfate. The organic layer was concentrated in vacuo and purified by flash filtration through silica gel (hexane/ether, 2:1) to afford 0.59 g (31%) of 6-chloromethyl-3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyl-phenoxy]-propyl]-pyridine (BIL-1991-187), as a pale yellow oil which solidified upon standing, m.p. 79°-81° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:13])[N:9]1[CH:14]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:32]>CC#N>[C:1]([O:5][C:6]([C:8]1([CH3:31])[CH2:12][O:11][S:10](=[O:32])(=[O:13])[N:9]1[CH:14]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2S(=O)OCC2(C)C(=O)OC(C)(C)C)cc1
Solvent: CC#N
Product: COc1ccc(C(c2ccc(OC)cc2)N2C(C)(C(=O)OC(C)(C)C)COS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A solution of the diastereomeric sulfamidites 13a (97 mg, 0.22 mmol) in 4 mL of CH3CN was cooled in an ice bath and treated successively with 1.1 eq of NaIO4 (51 mg), a catalytic amount of RuO2.H2O (˜1 mg) and 2.4 mL of H2O. After 5 minutes of stirring the ice bath was removed, and the reaction was continued for 20 minutes. The reaction mixture was diluted in 10 mL of EtOAc and washed with 10 mL of saturated NaHCO3 solution. The aqueous layer was extracted with 2×10 mL of EtOAc, and the combined organic layers were washed with 10 mL brine followed by usual work up. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane) to provide the cyclic sulfamidate 14a as a light yellow solid (90 mg, 89%): mp 143.5-145 EC (EtOAc.hexane); 1H NMR (CDCl3) δ 1.29 (3H, s), 1.51 (9H, s), 3.77 (3H, s), 3.80 (3H, s), 4.16 (1H, d, J=8.8), 4.73 (1H, d, J=8.8), 5.98 (1H, s), 6.82-6.89 (4H, m), 7.38-7.44 (4H). Anal. (C23H29NO7S)C,H,N.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[O:17]=[C:18]1[N:22]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[NH:19]1>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[N:22]([CH:23]2[CH2:24][CH2:25][N:26]([CH2:2][C:3]3([CH3:16])[CH2:7][C:6]4[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=4[O:4]3)[CH2:27][CH2:28]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[NH:19]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: Cc1ccccc1C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(n3c(=O)[nH]c4ccccc43)CC1)O2
Temperature: 180 °C
Reaction time: 15 h
Yield: 57.9 %

Procedure:
In an autoclave, a suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g) and 4-(2-keto-1-benzimidazolinyl)piperidine (2.3 g) in xylene (20 mL) was stirred under nitrogen gas at 180° C. for 15 hours. The reaction mixture was then cooled, filtered, and washed with diethyl ether. The filtrate was washed with water and extracted with 1N-hydrochloric acid. The aqueous layer was neutralized with saturated aqueous NaHCO3 and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate (Na2SO4) and silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was crystallized from ethanol to give 1.2 g of 2-[[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 55%. This product was dissolved in tetrahydrofuran with heating and after the solution was diluted with methanol, a stoichiometric excess of 10% HCl/methanol was added. The resulting solution was concentrated under reduced pressure and cyrstallized from methanol/diethyl ether to provide the title compound.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Li].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9].Cl>CS(C)=O.C(OCC)C>[CH3:1][S:2]([NH:5][C:8]([C:7]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:12])=[O:9])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Agent: [Li]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CS(=O)(=O)NC(=O)c1ccccc1N
Temperature: 25 °C

Procedure:
Lithium methanesulfonamidate (1.0 g, 10 mmol) and isatoic anhydride (1.63 g, 10 mmol) in dimethyl sulfoxide (5 mL) were heated at 80° C. for 30 min. The reaction was cooled down to room temperature and acidified with hydrogen chloride in diethyl ether. The ether was evaporated and water added. The precipitated oil was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (95:5). The desired material was obtained in a yield of 0.52 g.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](=[O:33])[C@H:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C@H:22]([CH2:26][CH:27]=[CH2:28])[C:23]([NH2:25])=[O:24])[C:3]1=[O:34].C1CC=CCC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20](=[O:33])[C@H:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C@H:22]([CH2:26][CH2:27][CH3:28])[C:23]([NH2:25])=[O:24])[C:3]1=[O:34]
Reactant: C=CC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CO
Product: CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C

Procedure:
The product of Example 6 was hydrogenated by dissolution in methanol (0.25M), addition of an equal amount by weight of Pearlman's catalyst [Pd(OH)2/C (20% Wt, Water % ≦50)] and 30 eq. of 1,4-cyclohexadiene at room temperature. The solution was heated to reflux for 1 hr, then cooled to room temperature. Removal of volatiles and purification by flash chromatography using 4% methanol in CH2Cl2 gave the title compound. MS (M+H)+=463.3; MS (M+Na)+=485.3.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].C(OCC)(=[O:35])C.C(OO)(=O)C>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][C:19]([OH:35])([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3CC[C@@]2(O)C1
Reactant: CCOC(C)=O
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)(C)O)CC[C@H]4[C@@H]3CC[C@@]2(O)C1

Procedure:
A solution of 50 g 3β-acetoxy-5-α-hydroxy-cholestane (II), in 25 ml. of ethyl acetate was treated with 100 ml. of peracetic acid (70%) in acetic acid and was irradiated with ultra-violet light of about 300 mμ wavelength for 12 hours. The resulting reaction mixture was washed with a solution of aqueous sodium bisulfite, sodium bicarbonate and then with water. After evaporation of the solvent in vacuo, the residue was chromatographed on a column of silica gel to give 10 g of the novel 3β-acetoxy-5α,25-dihydroxy cholestane (IV) which was recrystallized from methanol, m.p. 180°-182°C.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[F:8][C:7]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=[C:3]([F:12])[C:2]=1[C:23]1[N:19]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[N:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
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: COCCOC
Product: O=[N+]([O-])c1ccc(F)c(-c2ccnn2C2CCCCO2)c1F
Reaction time: 0.17 h

Procedure:
To a solution of tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.04 mmol) in dimethoxyethane (30 mL), 2-bromo-1,3-difluoro-4-nitrobenzene (2.38 g, 10 mmol) in dimethoxyethane (20 mL) was added and the mixture was insufflated with nitrogen for 10 min. To the solution, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4 g, 15 mmol) in dimethoxyethane (30 mL) was added and the mixture was insufflated with nitrogen for 2 min, then 2 M sodium carbonate solution (40 mL) was added and the mixture was refluxed for 4 h. The mixture was cooled and the organic phase was concentrated to oil. By addition of diethyl ether a precipitate was obtained, filtered off and discarded. The filtrate was concentrated and purified by flash chromatography (eluant: dichloromethane/ethyl acetate 20:1). The title compound was obtained as oil (1.27 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Li]CCCC.[C:18](=[O:20])=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1)[C:18]([OH:20])=[O:19]
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Temperature: -75 °C

Procedure:
To a stirred solution of 1.1 g of 2-chloro-4-iodo-6-trifluoromethyl-pyridine (3.58 mmol) in 15 ml THF under argon at −75° C., were added 2.2 ml of n-BuLi (1.6 M in hexane) within 15 min (temperature kept between −72° C. and −75° C.). After 5 additional min stirring at −75° C., the reaction mixture was poured on an excess of freshly crushed dry ice and stirred until RT was reached. The reaction mixture was then concentrated in vacuo, the remaining residue treated with 2M aqueous HCl and the resulting mixture was extrated with diethylether. The combined organic phases were washed with water, and then extracted with saturated NaHCO3 solution. The aqueous phase was then acidified with concentrated HCl, extracted twice with diethylether and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The remaining residue was recrystalized from 12 ml hot n-hexane, leading to 0.459 g (56%) of 2-chloro-6-trifluoromethyl-isonicotinic acid as an off-white solid. MS: 224.0 (M−H)−.
Reaction SMILES: [C:1]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:14]Br>C(O)(=O)C>[Br:14][C:2]([CH3:4])([CH3:3])[C:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)=[O:5]
Reactant: BrBr
Reactant: CC(C)C(=O)c1ccc(C#N)cc1
Solvent: CC(=O)O
Product: CC(C)(Br)C(=O)c1ccc(C#N)cc1
Reaction time: 72 h
Yield: 71.5 %

Procedure:
To a mixture of 4-isobutyrylbenzonitrile (2.4 g, 13.86 mmol) in acetic acid (50 mL) was added bromine (0.8 mL, 15.53 mmol). The mixture was stirred for 3 days and then concentrated in vacuo. The reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3. The organic layer was dried MgSO4, filtered, concentrated, and then purified on silica gel using an EtOAc/hexanes gradient to yield 2.5 g of 4-(2-bromo-2-methylpropanoyl)benzonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 8.00-8.07 (2H, m), 7.76-7.79 (2H, m), 1.24 (3H, s), 1.22 (3H, s).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[C:26]([Cl:34])[C:25]=1[N:35]=[C:36]=[O:37].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[C:26]([Cl:34])[C:25]=1[NH:35][C:36](=[O:37])[N:2]([CH3:1])[C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[N:6]=[CH:5][N:4]=1
Reactant: CNc1ncnc(Nc2ccc(N3CCN(C)CC3)cc2)n1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)N(C)c2ncnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)c1Cl
Reaction time: 3 h

Procedure:
To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogene atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol) is added. The mixture is stirred for 70 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is added portion-wise to a boiling solution of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3 h, another 2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are added and stirring is continued for totally 5 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM/MeOH/NH3aq, 97:3:0.2) gives the title compound: ESI-MS: 547/549 [MH]+; tR=3.5 min (purity: 100%, gradient J); TLC: Rf=0.40 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)[CH2:15][CH:16]=[CH2:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCSC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Reaction time: 17 h
Yield: 83 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (3.5 g, 1.78×10-2 mol, 100 M%) and 2-(3-butenylthio)-2-methylpropanal (4.23 g, 2.67×10-2 mol, 150 M%) were dissolved in 200 ml methanol. Glacial acetic acid (2.05 ml, 3.56×10-2 mol, 200 M%) and sodium cyanoborohydride (3.36 g, 5.35×10-2 mol, 300 M%) were then added. After 17 hours, the reaction was quenched by the addition of 100 ml 0.5 N HCl. The acidic solution was then extracted with 2×100 ml diethyl ether. The combined organic extracts were washed with 100 ml saturated NaHCO3, followed by 100 ml saturated NaCl. The ether layer was then dried over anhydrous Na2SO4. The solvent was removed on the rotary evaporator, and the residue was purified by filtration through a 600 ml sintered-glass funnel silica bed, using 90% hexane/diethyl ether as the eluting solvent, to give 5 g (84% yield) 1-[2-(3-butenylthio)-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)-benzene as a yellow oil.
Reaction SMILES: C1(O)C=CC=CC=1.[CH2:8]([O:15][CH2:16][CH2:17]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:19][CH2:20][CH2:21]/[C:22](/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[C:23](\[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:8]([O:15][CH2:16][CH2:17][O:36][C:33]1[CH:32]=[CH:31][C:30](/[C:23](/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:22](/[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)\[CH2:21][CH2:20][OH:19])=[CH:35][CH:34]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC/C(=C(/c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: BrCCOCc1ccccc1
Solvent: Oc1ccccc1
Product: OCC/C(=C(/c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
The alkylation of the starting phenol with benzyl-(2-bromoethyl)ether was carried out as described in Example 1 of the International Patent Application WO 96/07402 with the exception that now the starting compound was the other geometric isomer, E-4-(4-hydroxy-1,2-diphenyl-but-1-enyl)-phenol which was prepared by the method described in U.S. Pat. No. 4,996,225. The product was extracted to toluene. The toluene phases were combined, washed with water, dried and evaporated to dryness. The residue was recrystallized from a minor quantity of toluene and the precipitated product was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)C(C(O)=O)=[CH:20][CH:19]=[CH:18]3)[CH:9]=1.CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18]3)[CH:9]=1
Reactant: O=C(O)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 571 μl (6.66 mMol) oxalyl chloride in 15 ml CH2Cl2 is added to an ice-cooled solution of 1 g (3.33 mMol) 6-(6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (preparation see WO 2006/59234; Step 25.1) and 10 μl DMF in 30 ml CH2Cl2. The reaction mixture is stirred at room temperature for 1 h. The solvent is then evaporated off under reduced pressure to afford the title compound as a brown solid, which is used directly without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:6]1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH3:1][NH:2][CH2:3][CH:4]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:21]
Reactant: CNCC=C1CC2(CCCC2)c2ccccc21
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CNCC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 20 °C

Procedure:
N-Methyl-2-[spiro(cyclopentane-1,1'-indene)-3'-yliden]ethylamine (8.1 g; Swedish Pat. No. 7203905-0) in diethyl ether (100 ml) is treated with trifluoroacetic anhydride (8 ml) while being stirred with powdered anhydrous sodium carbonate (6 g). The solid is filtered off and the solvent is evaporated from the filtrate. The crude N-trifluoroacetyl-N-methylspiro(cyclopentane-1,1'-indan)-3'-ylideneethylamine is dissolved in dichloromethane (100 ml), added to sodium bicarbonate solution (40 ml; 0.5 M) and treated in portions with m-chloroperbenzoic acid (50%; 3.4 g) with stirring at about 20° C. After stirring for 2 hours, the solution is washed with saturated sodium carbonate solution and water, and dried with sodium sulphate. After filtration, the solvent is evaporated. The crude epoxy compound is dissolved in tetrahydrofuran (100 ml), and treated with perchloric acid (10 drops) at room temperature for 2 hours. After evaporation of the solvent the remaining crude 2-(N-methyltrifluoroacetamido)-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol is dissolved in a mixture of methanol (20 ml), water (50 ml) and potassium carbonate (10 g) and stirred overnight. The methanol is evaporated under reduced pressure and the free amine is extracted into dichloromethane. After drying with sodium sulphate the solvent is evaporated. The title compound is crystallized from diisopropyl ether; m.p. 134° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:10](OCC)=[O:11])[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][OH:11])[CH2:2]1
Reactant: CCOC(=O)C1CNc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CNc2ccccc21

Procedure:
0.79 g (3.5 mmol) ethyl 2,3-dihydro-1H-indole-3-carboxylate were added batchwise at RT to 7.8 mL (7.8 mmol) of a 1 molar lithium aluminium hydride-THF solution in 40 mL THF and the mixture was refluxed for 1 h. Then the reaction mixture was decomposed with water, while cooling, the precipitate formed was filtered off and the filtrate was evaporated down.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]([F:19])([F:18])[F:17])=[O:13])[CH:6]=[CH:5]2.[CH2:28]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[CH2:28]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]([F:17])([F:18])[F:19])=[O:13])[CH:6]=[CH:5]3)=[O:42])=[CH:39][CH:38]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc3cc(C(=O)OC(CCCCCCCC)C(F)(F)F)ccc3c2)cc1

Procedure:
To a solution of the 1,1,1-trifluoro-2-decyl-6-hydroxynaphthalene-2-carboxylate (0.5 g) obtained in (1) above, the 4-n-octyloxybenzoic acid (0.4 g) obtained in (2) above in tetrahydrofuran (40 ml) were added dicyclohexylcarbodiimide (0.45 g) and dimethylaminopyridine (0.05 g). The solution was stirred at room temperature overnight. The solution was distilled to remove the solvent. The residue was dissolved in dichloromethane (50 ml) and the solution was washed with dilute aqueous hydrochloric acid solution and water in this order. The organic layer collected was dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer : hexane/ethyl acetate =20/1) to obtain the titled compound (0.39 g) having specific rotation, [α]D20 =+45.79°.