Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:11]=[N:12][C:13]([OH:16])=[N:14][CH:15]=1)([O-:3])=[O:2].[I-].C[N+]1C=CN([C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:12][CH:11]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1-c1cnc(O)nc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ncc(-c2ccccc2[N+](=O)[O-])cn1)c1ccccc1
Yield: 31.9 %

Procedure:
A solution of 5-(2-nitrophenyl)-pyrimidin-2-ol (0.35 g, 1.61 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (0.55 g, 1.61 mmol) and triethylamine (0.22 ml, 1.61 mmol) in acetonitrile (15 ml) was heated at 50° C. for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.18 g, 32% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>ClCCl>[CH2:1]([O:3][C:4]1[C:5]([OH:15])=[C:6]([N+:16]([O-:18])=[O:17])[C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=[O:10])[CH3:2]
Reactant: CCOc1cc(C=O)c([N+](=O)[O-])cc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Ethoxy-4-hydroxy-2-nitro-benzaldehyde (1.6 g) was dissolved in dichloromethane (30 ml) and a solution of nitric acid in dichloromethane (2M, 13 ml) was gradually added at a temperature under 30° C. The solution was stirred at room temperature for 10 min and then it was poured into ice-cold water. The organic phase was washed with water and then it was dried and evaporated.
Reaction SMILES: O.Cl[S:3]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)(=O)=O.Cl[Si](Cl)(C)C.S(Cl)(Cl)(=O)=O.O[CH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)=[N:35][C:34]=1[CH2:48][OH:49]>C(OC(C)C)(=O)C.[Zn].COCCOC>[OH:49][CH2:48][C:34]1[N:35]=[C:36]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=2)[S:37][C:33]=1[CH2:32][S:3][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: COCCOC
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of zinc dust (0.75 wt, 3.5 eq) in isopropyl acetate (5 vols), add a solution of DME (0.5 vol) and water (0.5 eq). Heat the resulting solution from room temperature to 40° C. Treat the reaction mixture with a solution of ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate (1.0 wt, 1.0 eq) and dichlorodimethylsilane (0.32 wt, 0.75 eq) in isopropyl acetate (3 vols) over a period of 2 h as this addition is mildly exothermic. After the addition is complete, increase the process temperature to 60° C. Treat the suspension at 60° C. slowly with neat dichlorodimethylsilane (0.95 wt, 2.3 eq) over a period of 1 h. When the reduction of the sulfonylchloride is deemed complete (by HPLC), treat the reaction mixture with {5-Hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol (1.04 wt, 1.1 eq) in one portion at 60° C. After the addition is complete, increase the process temperature to 89° C. and stir the reaction mixture at this temperature for 3 to 5 h then cool to ambient temperature. Filter the reaction mixture to remove unreacted zinc residue, wash the filtrate with water (2×8 vols) and concentrate the organic layer to about 3.5 volumes via vacuum distillation at 40–45° C. Dissolve the resultant, somewhat syrupy, residue in ethanol (2 vols) and treat the resulting solution with iso-octane (2 vols). Cool the clear yellow-tinted solution to ambient temperature to induce crystallization of the product. Collect the solid via filtration. Wash the wet cake with iso-octane/EtOH (9:1, 1 vol) and dry under vacuum (˜21 Torr) at 60° C. for 12 h to afford the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.O.[NH2:15][NH2:16]>O1CCOCC1>[NH:15]([C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1)[NH2:16]
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NN)c2cccc(O)c2n1

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (0.10 g, 0.51 mmol) and hydrazine monohydrate (0.75 mL, 15 mmol) in dioxane (10 mL) was heated to reflux for 4 d. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with DCM/methanol/conc. aqueous NH3 5:1:0.033) to give the title compound. MS (m/z): 190.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:13][CH2:14]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:24]([F:26])([F:25])[F:27]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 45 °C
Yield: 98.7 %

Procedure:
A stirred suspension of N-[5-bromo-2-nitro-4-(trifluoromethyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D54) (380 mg, 0.84 mmole) in ethanol (20 ml) at room temperature under argon was treated with Raney Nickel (20 mg) followed by the dropwise addition of hydrazine hydrate (0.25 ml, 8.0 mmole). The mixture was maintained at room temp. for 0.5 hr, then heated at 45° C. for 1 hr producing a grey solution, which was filtered through Kieselguhr and the filtrate concentrated under vacuum to afford the title compound as a pale yellow solid (350 mg, 99%). MH+=422, 424.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC2OC3C=CC=CC=3C=2C=1)(=O)C.[N:33]1[CH2:37][CH2:36][CH2:35][CH:34]=1.N1CCCCC=1>>[NH:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:2][C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)=[O:3]
Reactant: C1=NCCC1
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: C1=NCCCC1
Agent: CC(=O)c1ccc2oc3ccccc3c2c1
Product: O=C(CC1CCCN1)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
Following essentially the same procedure as in Example XI above, but substituting 2-acetylfluorene for the 2-acetyldibenzofuran above and substituting 1-pyrroline as the trimer for the 2,3,4,5-tetrahydropyridine (as α-tripiperidein) above results in the formation of 2-fluorenyl 2-pyrrolidinylmethyl ketone as the hydrochloride salt, and which when recrystallized from isopropyl alcohol has a M.P. of 234-44°C. (dec.)
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1)([OH:8])(=[O:7])=[O:6]>CCOCC.CN(C)C=O>[S:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([Cl:3])=[O:19])=[CH:12][CH:11]=1)([OH:8])(=[O:7])=[O:6]
Reactant: O=C(O)Cc1ccc(CS(=O)(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(CS(=O)(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of thionyl chloride in 20 ml of anhydrous ether is added p-sulfomethylphenylacetic acid. The mixture is stirred at room temperature until gas evolution ceases. Two drops of dimethylformamide is added, and the resulting mixture is stirred at 40° C. for 2.5 hours. The title compound is obtained after filtration and evaporation of the reaction mixture. The infrared spectrum of the product shows a characteristic acid chloride absorption at 1830 cm-1 whereas the starting acid shows a carbonyl absorption at 1740 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][C:14]([CH3:17])=[CH:15][CH3:16]>[OH-].[K+].CO.CO.[Pd]>[OH:1][C:2]1[C:7]([CH2:16][CH2:15][CH:14]([CH3:17])[CH3:13])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CC=C(C)CBr
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(O)c(CCC(C)C)c1O

Procedure:
2′,4′-Dihydroxyacetophenone (manufactured by Wako Pure Chemical Industries, Ltd.) was treated with 1-bromo-2-methyl-2-butene (manufactured by Aldrich) in 2 M KOH/methanol solution under ice-cooling, and thereafter the treated solution was hydrogenated in methanol, in the presence of palladium black (manufactured by Nakalai Tesque, Inc.), to give 2′,4′-dihydroxy-3′-(3-methylbutyl)acetophenone. Subsequently, 2′,4′-dihydroxy-3′-(3-methylbutyl)acetophenone and 4-hydroxybenzaldehyde (manufactured by Aldrich) were subjected to Claisen condensation, to give a yellow substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2].[C:43](=[O:46])([O-])[O-:44].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:25]=[C:24]([C:9]3[CH:14]=[CH:13][C:12]4[O:44][CH2:43][O:46][C:11]=4[CH:10]=3)[CH:23]=2)[C:10]=1[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:2]
Reactant: CCCS(=O)(=O)c1cc(Br)cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)c1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc3c(c2)OCO3)c1
Yield: 86.2 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-{6-[3-bromo-5-(propane-1-sulfony)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (208 mg, 0.31 mmol), 3,4-(methylenedioxyphenyl)boronic acid (103 mg, 0.62 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg, 0.046 mmol), and cesium carbonate (205 mg, 0.62 mmol) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(propane-1-sulfonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (95 mg, 43%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C39H50O10S (M+Na)+ 733.3017, found 733.3011.
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([S:7][C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:11])[CH3:6].[C:27](=O)(O)[O-].[Na+]>C1COCC1>[CH2:5]([S:7][C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([N:12]([CH3:27])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][N:14]=1)=[O:11])[CH3:6]
Reactant: CCSc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCSc1ccccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.03 g of 60% sodium hydride (oil-based) and 0.14 g of methyl iodide were added to a mixture of 0.15 g of 2-ethylsulfanyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide and 2 mL of THF, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.10 g of 2-ethylsulfanyl-N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:17][CH2:16][C:14]1[CH:13]=[C:12]([CH:25]=[CH:26][C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[CH:30]=[CH:31][CH:32]=2)[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=1
Reactant: CC(C)(O)CCCCc1cccc(C=Cc2cc(CO[Si](C)(C)C(C)(C)C)cc(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCc1cccc(C=Cc2cc(CO)cc(CO)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 858 mg (1.47 mmol) of 6-(3-{2-[3,5-bis-(tert-butyldimethylsilanyloxymethyl)phenyl]vinyl}phenyl)-2-methylhexan-2-ol with 3.25 ml of tetrabutylammonium fluoride 1M/THF, after purification on a silica column (ethyl acetate), a white paste (m=460 mg; Y=88%) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[H-].[Na+].[CH3:22][O:23][CH:24]([O:27][CH3:28])[CH2:25]Br>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:25][CH:24]([O:27][CH3:28])[O:23][CH3:22])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: COC(CBr)OC
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 27.1 g. (0.1 mole) of 7-chloro-1,3 -dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 300 ml. of dry dimethylformamide was added 4.6 g. (0.11 mole) of 57% sodium hydride in mineral oil, under nitrogen and with continuous stirring. After stirring one hour at room temperature, 25.4 g. (0.15 mol) of redistilled bromoacetaldehyde dimethylacetal in 10 ml. of dimethylformamide was added and the reaction mixture is kept at 100° C. with stirring during 16 hours. The mixture was then concentrated in vacuo to one-half the volume, well shaken with ice water and extracted with methylene chloride. The extract was washed with water, dried over Na2SO4 and evaporated at 25° C. and 0.2 mm.Hg pressure giving a brown oil which was crystallized from 2-propanol yielding 26.2 g. (73% of light brown crystals m.p. 115-117° C. A sample chromatographed on silica gel, eluted with 2% methanol-98% chloroform, evaporated in vacuo, and crystallized from 2-propanol gave 7-chloro -1,3-dihydro-1-(2,2-dimethoxyethyl)-5-phenyl-2H-1,4 -benzodiazepine-2-one of melting point 117° to 119° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([OH:36])[CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][C:29]=2[OH:36])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: OB(O)c1ccc(Cl)cc1O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P([c-]1ccc(Cl)c1Cl)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1O)CCCC3
Temperature: 105 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
To a solution of Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 200 mg, 422 μmol) in dioxane (4 mL) was added (4-chloro-2-hydroxyphenyl) boronic acid (Preparation 17, 191 mg, 761 μmol), Dichloro [1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (II)™ (Pd-118) (Johnson-Matthey, 27 mg, 10 mol %, 42.2 μmol), potassium phosphate (180 mg, 844 μmol) and water (1 mL). The resulting mixture was stirred at 105° C. in a sealed tube for 18 hours. A further portion of Pd-118 (10 mg, 3.7 mol %, 15.6 μmol) was added and the mixture stirred at 105° C. for 72 hours. The reaction mixture was cooled to room temperature and filtered through a short pad of silica, washing with ethyl acetate. The solvent was removed in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate/heptane (0-10%) to yield the title compound as a brown solid, 37.5 mg, in a 19% yield. Material obtained was a mixture of atropisomers, in a ˜2:1 ratio and was carried on to hydrolysis step 2 without further purification.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH2:30])[CH3:29]>>[CH3:12][C:8]1([CH3:11])[CH2:9][O:10][C:5]2([CH2:13][CH2:14][C:2]([CH2:15][CH2:16][NH:30][C@H:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[CH3:29])([OH:1])[CH2:3][CH2:4]2)[O:6][CH2:7]1
Reactant: C[C@H](N)c1ccc2ccccc2c1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc2ccccc2c1
Yield: 78 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-naphthalen-2-yl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 78% of theory; LC (method 6): tR=1.27 min; Mass spectrum (ESI+): m/z=398 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([SH:18])[N:15]([CH3:19])[N:14]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([S:18][CH3:22])[N:15]([CH3:19])[N:14]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A suspension of 0.5 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5-mercapto-1-methylpyrazole (2), 2.3 g of methyl iodide and 0.4 g of anhydrous potassium carbonate in 10 ml of acetonitrile was refluxed overnight with stirring. The reaction mixture was cooled to room temperature and filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to obtain 0.51 g of the desired product in the form of white crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.Br[CH2:17][CH2:18][C:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9]([I:15])=[CH:10][C:11](=[O:14])[N:12]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=1
Reactant: O=c1cc(I)c(F)c[nH]1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reaction time: 8 h
Yield: 34.9 %

Procedure:
Cesium carbonate (2.01 g, 6.16 mmol) was added to a solution of the 5-fluoro-4-iodopyridin-2(1H)-one (491 mg, 2.06 mmol) and ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (767 mg, 2.67 mmol in THF (30 mL). The resulting suspension was heated to reflux and stirred at this temperature overnight. The reaction was filtered through celite (˜1 inch), and the filter pad was washed with ethyl acetate (2×30 ml). The combined filtrates were concentrated and the crude was purified via flash chromatography on an Analogix SF15-12 g column and an eluant of ethyl acetate in heptane (30-100%) to afford the title compound as a white gum (319 mg, 34.9%). LC-MS m/z 446.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.12 Hz, 3H) 1.75 (s, 3H) 2.40-2.58 (m, 2H) 3.10 (s, 3H) 3.87-3.99 (m, 1H) 4.16-4.25 (m, 1H) 4.29 (q, J=7.22 Hz, 2H) 7.15 (d, J=5.85 Hz, 1H) 7.20 (d, J=3.32 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.[N-:16]=[N+]=[N-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH2:16])[N:7]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CN)no2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-chloromethyl-5-(4-methoxy-phenyl)-[1,2,4]oxadiazole (8.90 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (17.8 mmol). This mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (3×). The combined organic extracts were combined and washed with water (2×), dried over anhydrous sodium sulfate, and evaporated. Then clear oily residue was placed under high vacuum and gently warmed for 18 hours. Upon cooling the material solidified. This solid was dissolved in tetrahydrofuran (15 mL) and treated with triphenylphosphine (9.0 mmol). Bubbling was immediately evident. This mixture was stirred for 16 hours and then treated with water (3.0 mL). This was heated in a 45° C. oil bath for 3 hours. The product was purified by flash chromatography (silica gel; 2:1 ether/dichloromethane), m.p. 66-68° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.FC(F)(F)C([O-])=O.[NH:18]1[CH2:22][CH2:21][N:20]=[C:19]1[C:23]1[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:36])[C:27]=2[CH:26]=[CH:25][CH:24]=1>ClCCl.O.C(N(CC)CC)C>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:36])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2-c2c1cccc2C1=NCCN1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2-c2c1cccc2-c1ncc[nH]1
Temperature: -65 °C
Reaction time: 0.17 h

Procedure:
In a 100 mL three-necked flask under an argon atmosphere, cool to −65° C., a solution of 0.65 mL of oxalyl chloride in 5 mL of dichloromethane, then add, dropwise, 0.94 mL of dimethylsulphoxide on 3A molecular sieve. Stir for 10 minutes, then add, dropwise, a solution of 1.65 g of trifluoroacetate of 4-(4,5-dihydro-1H-imidazol-2-yl)-fluoren-9-one acid in 15 mL of dichloromethane then 5 mL of triethylamine. Stir at −65° C. for one hour, then leave to return to room temperature and stir for 2 hours. Pour the reaction mixture into water, and extract with dichloromethane. Wash the organic phases with a saturated aqueous solution of sodium chloride, dry over magnesium sulphate and evaporate to dryness at reduced pressure. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (98/2 by volume), we obtain 560 mg of 4-(1H-imidazol-2-yl)-fluoren-9-one in the form of a yellow powder to be used as it is in the next stage, and having the following characteristics: