Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:25]=1>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 119.4 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (7.9 g, 42.5 mmol) and diisopropylethylamine (13.69 g, 106.1 mmol) in dichloromethane (80 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (7.9 g, 42.5 mmoL), and the reaction mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The reaction mixture was directly concentrated to afford ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (17 g, crude), which was directly used in the next step without further purification. MS (ES+) C16H24N4O4 requires: 336, found: 237, 281 [M-56+H]+.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[C:25]=4[C:35]([O:37][CH3:38])=[O:36])[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH3:38][O:37][C:35]([C:25]1[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:27][O:28][C:24]=1[C:22]1[O:21][N:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][N:10]3[CH2:11][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]3)=[CH:14][CH:15]=2)[N:23]=1)=[O:36]
Reactant: COC(=O)c1c(-c2ccccn2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(-c2ccccn2)noc1-c1nc(-c2ccc(CN3CC(C(=O)O)C3)cc2)no1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)isoxazole-4-carboxylate (79 mg, 0.153 mmol) in trifluoroacetic acid (2 mL) was allowed to stand at room temperature for 1 h. The volatiles were removed under reduced pressure, and the residue was suspended in water. The pH was adjusted to ˜4 with a 1N aqueous solution of sodium hydroxide, and the resulting suspension was allowed to stir briskly overnight. Filtration and drying afforded 1-(4-(5-(4-(methoxycarbonyl)-3-(pyridin-2-yl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (65 mg, 0.141 mmol, 92% yield) as a slightly off-white powder. HPLC retention time=2.51 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=462.18. 1H NMR (500 MHz, MeOD) δ ppm 3.61-3.68 (m, 1H), 3.98 (s, 3H), 4.30-4.37 (m, 4H), 4.50 (s, 2H), 7.53-7.56 (m, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.98-8.02 (m, 1H), 8.09 (d, J=7.7 Hz, 1H), 8.26 (d, J=8.8 Hz, 2H), and 8.69 (d, J=4.4 Hz, 1H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.[NH4+].[Cl-]>C1COCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])[CH:10]=1
Reactant: BrCCCCCCCCCCCBr
Reactant: Cc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: BrCCCCCCCCCCCCc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
LDA (2 M) (10.5 mL, 21.22 mmol) was added drop-wise to a solution of 3-picoline (2.17 g, 23.34 mmol) in THF (60 mL) at −78° C. The mixture was stirred for 30 min and then 1,11-dibromoundecane (10 g, 31.83 mmol) was added in one portion. The resulting mixture was warmed to 0° C. and stirred for 4 hrs. Fifty percent saturated NH4Cl was added to the reaction mixture. The aqueous phase was extracted with ethylacetate (2×40 mL), and the combined organic liquors were washed with 50% saturated brine (3×40 mL) and saturated brine (40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexanes:ethylacetate 4:1) to afford 4.47 g 12-(pyridin-3-yl)-1-bromododecane. Yield: 59%.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:13][C:11]([CH3:12])([CH3:14])[CH2:10][CH2:9][CH2:8][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7]
Reactant: C[C@H](CCCCO)CCCC(C)(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(CCCC=O)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
To a stirred solution of diol 14 (25 mg, 0.12 mmol) in anhydrous CH2Cl2 (3.5 mL) was added Dess-Martin reagent (73 mg, 0.15 mmol) at room temperature. The reaction was stirred at room temperature for 1.5 hours. Then, an aqueous solution of sodium thiosulfate (6 mL) and saturated NaHCO3 (6 mL) were added. The reaction was extracted with CH2Cl2, solvents were removed under reduced pressure, and the crude oil was purified on silica Sep-Pak using hexane/EtOAc (7:3) as an eluent to give an oily aldehyde 15 (16.5 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH2:12])[N:3]=1.CCN(CC)CC.[F:20][C:21]1([F:36])[O:25][C:24]2[CH:26]=[CH:27][C:28]([C:30]3([C:33](Cl)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:23]=2[O:22]1>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:33]([C:30]2([C:28]3[CH:27]=[CH:26][C:24]4[O:25][C:21]([F:36])([F:20])[O:22][C:23]=4[CH:29]=3)[CH2:32][CH2:31]2)=[O:34])[N:3]=1
Reactant: Nc1cc2ccccc2c(Br)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
To a solution of 1-bromoisoquinolin-3-amine (3.00 g, 13.5 mmol) and Et3N (3.8 mL, 27 mmol) in dichloromethane (50 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (4.18 g, 13.5 mmol) in dichloromethane (50 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then washed with 1N aqueous NaOH (2×200 mL), 1 N aqueous HCl (1×200 mL) and saturated aqueous NaHCO3 (1×200 mL). The organics were dried over sodium sulfate and evaporated. The resulting material was purified by silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to yield N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)cyclopropanecarboxamide (4.2 g, 70%). ESI-MS m/z calc. 446.0. found 447.1 (M+1)+. Retention time 2.39 minutes.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=[O:16])#[N:2].C([OH:22])C.[OH-].[K+]>O>[C:15]([C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3]=1[C:1]([NH2:2])=[O:22])([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnn(-c2cccc(C)c2)c1C#N
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-n2ncc(C(=O)O)c2C(N)=O)c1

Procedure:
A 9 g. portion of ethyl 5-cyano-1-(3-methylphenyl)-4-pyrazolecarboxylate was dissolved in 200 ml. of ethanol, and 5.8 g. of potassium hydroxide was added. The mixture was stirred under reflux for 4 hours, and then was cooled, diluted with water and made acid. The mixture was filtered, and the solids were washed with ethyl acetate as shown above in Example 8 to obtain 3.8 g. of the desired product, m.p. 209°-211° dec. It was identified by elemental analysis.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:7]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:25]4[C:26]([CH3:30])=[C:27]([CH3:29])[S:28][C:24]=4[N:23]4[C:31]([CH3:34])=[N:32][N:33]=[C:22]4[C@H:21]([CH2:35][C:36]([OH:38])=[O:37])[N:20]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=[N:8]1)[CH3:6].[CH3:39][O:40][CH:41](O)[CH3:42]>>[CH2:5]([N:7]1[C:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:25]4[C:26]([CH3:30])=[C:27]([CH3:29])[S:28][C:24]=4[N:23]4[C:31]([CH3:34])=[N:32][N:33]=[C:22]4[C@H:21]([CH2:35][C:36]([O:38][CH2:42][CH2:41][O:40][CH3:39])=[O:37])[N:20]=3)=[CH:17][CH:18]=2)=[CH:10][CH:9]=[N:8]1)[CH3:6]
Reactant: CCn1nccc1Nc1ccc(C2=N[C@@H](CC(=O)O)c3nnc(C)n3-c3sc(C)c(C)c32)cc1
Reactant: COC(C)O
Solvent: O=S(Cl)Cl
Product: CCn1nccc1Nc1ccc(C2=N[C@@H](CC(=O)OCCOC)c3nnc(C)n3-c3sc(C)c(C)c32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thionyl chloride (230 μL) and the intermediate synthesized in Example 151, (S)-4-[4-(2-ethyl-2H-pyrazol-3-ylamino)phenyl]-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-acetic acid (500 mg), were successively added to methoxy ethanol (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 day. After completion of the reaction, the mixture was partitioned by adding water and ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol=100:1) to give the title compound (410 mg).
Reaction SMILES: [O:1]=[C:2](C)[CH2:3]CC(OCC)=O.BrBr.[C:13]([O:19]CC)(=[O:18])[CH2:14][C:15]([CH3:17])=O.C(OC)(=O)C=C>C(O)(=O)C>[O:1]=[C:2]([CH3:3])[CH2:17][CH2:15][CH2:14][C:13]([OH:19])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CCC(C)=O
Agent: BrBr
Solvent: C=CC(=O)OC
Solvent: CC(=O)O
Product: CC(=O)CCCC(=O)O

Procedure:
Appropriate α-bromoketone 21b was prepared by bromination of ethyl 4-oxopentanoate by bromine in acetic acid. α-bromoketone 21c was prepared according to literature (Lugtenburg J. et. al., Eur. J. Org. Chem. 2002, 189-2202) from ethyl acetoacetate and methyl acrylate in 1,4-addition reaction and subsequent decarboxylation under acidic conditions to give 5-oxohexanoic acid. Esterification and bromination gave α-bromoketone 21c (methyl 6-bromo-5-oxohexanoic acid) in 4 step procedure. α-Chloroketone 21a
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][C:15]#[N:16].N.[H][H]>CO.[Ni]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: [H][H]
Reactant: N#CCCNCC1CCc2ccccc2O1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCNCC1CCc2ccccc2O1
Yield: 90.8 %

Procedure:
A mixture of intermediate (16-c) (0.12 mol) in methanol saturated with ammonia (500 ml) was hydrogenated with Raney nickel (6 g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by distillation, yielding 24 g (90.8%) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3-propanediamine (interm. 17-c).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:37][CH:38]=1)([O-])=O>>[NH2:30][C:33]1[CH:34]=[CH:35][C:36]([N:39]([CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[N:24]=[CH:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:21][CH2:22]2)[C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[N:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Product: CC(C)(C)OC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(N)cn1

Procedure:
The title compound was synthesized by procedure analogous to Step 2 and 3 of Example 28 from 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and tert-butyl (5-nitropyridin-2-yl)carbamate from Step 1 of this example.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>ClCCl.N1C=CC=CC=1>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:22]([CH3:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C)c(C)c2)cc1C
Yield: 16.8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.12 g, 3.26 mmol) in 25 mL of dichloromethane and 3,4-dimethylaniline (0.79 g, 6.52 mmol) in 8 mL of pyridine. The crude product was triturated with ethyl ether and filtered to yield 0.28 g of the title compound, mp 224-227° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[F:20][C:21]1[CH:22]=[C:23]([C@H:27]([NH2:29])[CH3:28])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:29][C@@H:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=2)[CH3:28])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1cccc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Yield: 96.6 %

Procedure:
Following a similar procedure to that described in Example (1a), 880 mg of 4-chlorophenyl 3-nitrophenyl ketone, 886 mg of (R)-1-(3-fluorophenyl)ethylamine hydrochloride, 2.58 ml of triethylamine, 0.44 ml of titanium tetrachloride, 890 mg of sodium cyanoborohydride and 0.29 ml of acetic acid were reacted, to obtain 1.25 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:25]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nccc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Temperature: 25 °C

Procedure:
252 mg (1.15 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 2 mL dry dimethylacetamide under argon atmosphere, and 56 mg (2.31 mmol) NaH is added. 100 mg (0.77 mmol) 2-amino-4-chloro-pyrimidine (2) is added and the solution stirred at room temperature over night. 1 mL water is added carefully to quench all excess NaH and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (ethyl acetate:cyclohexane 1:1). Yield: 160 mg (63%). ESI-MS m/z 327.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH3:39][O:38][C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[C:3]([Se:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:37]
Reactant: COC(=O)CCCCCCCBr
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCCCCCC(=O)OC)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to that of Example 51, by reaction of 370 mg (0.86 mmol) of ethyl 4-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 2-naphthylselanyl)benzoate with 408 mg (1.72 mmol) of methyl 8-bromooctanoate and 238 mg of potassium carbonate in MEK (10 ml), 502 mg (99%) of a yellow oil are obtained.
Reaction SMILES: [CH3:1][S:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[N:4][CH3:5])=[O:3].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.CCCCCC.[C:42]1([C:47]([CH2:49][S:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH:43]=1.[Cl-].[NH4+]>C1COCC1>[C:51]1([S:50][CH2:49][C:47]([OH:48])([C:42]2[CH2:46][CH2:45][CH2:44][CH:43]=2)[CH2:1][S:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[N:4][CH3:5])=[O:3])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CN=S(C)(=O)c1ccccc1
Reactant: O=C(CSc1ccccc1)C1=CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Product: CN=S(=O)(CC(O)(CSc1ccccc1)C1=CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of S-methyl-N-methyl-S-phenyl-sulfoximine (2.04 g, 12 mmol) and triphenylmethane (5 mg) in dry THF (20mL) is added dropwise to a solution of n-butyllithium (1.6 mol) in hexane (7.5 mL, 12 mmol) at 0° C. A solution of phenylthio-methyl cyclopent-1-enyl ketone (2.18 g, 10mmol) in dry THF (10 mL) is then added slowly during a period of 10 minutes. After stirring at 0° C. for 30 minutes, the mixture is poured into a 5% ammonium chloride aqueous solution (50 mL) and extracted with dichloromethane (40 mL×3). The combined extracts are washed with H2O, dried (Na2SO4), and evaporated in vacuo to dryness. The thin layer chromatography (TLC, SiO2, toluene/EtOAc, 9:1 v/v) of the mixture showed that it contains a mixture of diastereomers in a syrup, 2.70 g (70%) (Rf=0.43 and 0.37), which are isolated by liquid chromatography (SiO2, touene/EtOAc, 9:1 v/v) and used directly in the next step without further separation.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl.ClCCl>[CH2:38]([N:29]1[C:10]2[C@:9]3([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:18](=[O:19])[N:30]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Nc1ccccc1F
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.8 %

Procedure:
Triethylamine (440 μL, 3.2 mmol) was added dropwise to a solution of (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 25; 318 mg, 1.5 mmol) in 1,2-dichloroethane (4 mL) over 1 min. Then a solution of N-benzyl-N′-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (242 mg, 0.77 mmol) in 1,2-dichloroethane (8 mL) was added over 2 min. The reaction mixture was stirred at room temperature for 15 min and then heated in an oil bath at 100° C. for 45 min. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 1 h. A further portion of HCl in dioxane (4 M; 2 mL, 8 mmol) was added and the mixture was heated in an oil-bath at 100° C. for 2 h. The reaction mixture was allowed to cool to room temperature and dichloromethane (100 mL) was added. The mixture was washed with 1:1 water/brine (20 mL), dried (magnesium sulfate), filtered, evaporated, and purified on an ISCO system using a 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated with diethyl ether and petroleum ether, and then dried under high vacuum at 90° C. to give (4R,7S)-1-benzyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (40 mg, 14%) as a pale yellow solid. ES(+)-MS (M+H) 377.
Reaction SMILES: [OH2:1].P(Cl)(Cl)(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:17]2[C:18]3=[C:18]4[C:17](=[CH:15][CH:14]=[CH:13]3)[C:16](=[O:1])[CH2:15][CH2:14][CH:13]4[CH2:16]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O
Reactant: c1ccccc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Product: O=C1CCC2CC(c3ccccc3)c3cccc1c32
Reaction time: 1.5 h

Procedure:
3-(3-Phenyl-1-indan)propionic acid (32 g, 0.12 mol) was dried by refluxing in C6H6 (200 ml) with removal of azeotroped H2O. The solution was added to a stirred suspension of PCl5 (29 g, 0.14 mol) in C6H6 (50 ml) and stirred for 1.5 hours. The solution was then added to a cooled, stirred suspension of AlCl3 (29 g) in C6H6 and stirring continued at room temperature for 3 hours. The mixture was poured into ice and HCl and extracted with Et2O. The Et2O was washed (NaHCO3 solution), dried (Na2SO4) and evaporated to give the title compound (25.7 g), m.p. 99° C. (MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]1[CH2:12][CH2:13][NH2:14].Cl[C:20]1[NH:21][C:22]2[C:27]([C:28](=[O:30])[CH:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]1[CH2:12][CH2:13][NH:14][C:20]1[NH:21][C:22]2[C:27]([C:28](=[O:30])[CH:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: NCCC1CC=CCN1Cc1ccc(Cl)c(Cl)c1
Reactant: O=c1cc(Cl)[nH]c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(NCCC2CC=CCN2Cc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12
Temperature: 110 °C

Procedure:
A mixture of 2-[1-(3,4-dichlorobenzyl)-1,2,3,6-tetrahydropyridin-2-yl]ethylamine (284 mg, 1 mmol), 2-chloro-1H-quinolin-4-one (184 mg, 1.03 mmol) and diisopropylethylamine (0.18 mL, 1.03 mmol) was heated at 110° C. After 56 h the mixture was cooled and the residue chromatographed over silica gel eluting with dichloromethane and increasing amounts of methanol containing 10% concentrated aqueous ammonia to yield the title compound as a pink foam. δH (CD3OD) 1.59-1.69 (1H, m), 1.83-2.10 (2H, m), 2.21-2.42 (1H, m), 2.90-3.15 (4H, m), 3.67 (2H, s), 5.55-5.64 (1H, s), 5.66 (1H, s), 5.72-5.87 (1H, m), 7.18-7.58 (6H, m), 8.10 (1H, d, J=6.67 Hz); MS (ES+) 426 (100%) MH+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[CH2:15]([B-](F)(F)F)[CH2:16][CH2:17][CH3:18].[K+]>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(Br)cc2o1
Reactant: CCCC[B-](F)(F)F
Agent: [K+]
Product: CCCCc1ccc2cc(C(=O)OC)oc2c1
Yield: 66.8 %

Procedure:
Methyl-6-butylbenzofuran-2-carboxylate was synthesized as in Example 3.1 using methyl-6-bromobenzofuran-2-carboxylate (195 mg, 0.76 mmol) in place of 5-bromo-2-formylfuran and potassium butyltrifluoroborate (188 mg, 1.15 mmol) in place of hexylboronic acid to give methyl-6-butylbenzofuran-2-carboxylate (118 mg, 67%). Used without further characterization.