Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][C:30](=[S:34](=[O:36])=[O:35])[CH2:31][CH2:32]Cl)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][C:30](=[S:34](=[O:36])=[O:35])[CH2:29][C:28]3[CH:37]=[CH:38][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(CC(CCCl)=S(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CC(CCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)=S(=O)=O)cc1
Yield: 54 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (10.0 g) as a starting compound, 3-(4-methoxybenzyl)-sulfonylpropyl chloride (8.50 g) and potassium carbonate (16.8 g) were reacted and purified in the same manner as in Example 199 to give 7.60 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-(4-methoxybenzyl)-sulfonylpropyl)piperidin-4-yl)methyl)benzamide, m.p. 111°-112° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl-].[Li+].[F:28][C:29]([F:41])([C:37]([F:40])([F:39])[F:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=O>C(#N)C.C(OC)(C)(C)C>[CH2:12]([O:14][C:15](=[O:25])/[CH:16]=[CH:35]/[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]([F:28])([F:41])[C:37]([F:38])([F:39])[F:40])[CH3:13]
Reactant: O=CCCCCCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C/CCCCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.08 mL, 7.26 mmol) was added to a solution of (diethoxy-phosphoryl)-acetic acid ethyl ester (1.57 mL, 7.87 mmol) and lithium chloride (359 mg, 8.47 mmol) in acetonitrile (60.5 mL) at 0° C., and the mixture was stirred at 0° C. for 10 minutes. A solution of 7,7,8,8,8-pentafluoro-octanal (1.32 g, 6.05 mmol) in acetonitrile (20.5 mL) was added dropwise to the reaction solution at 0° C., and the mixture was stirred for 10 minutes. Thereafter, the reaction mixture was stirred at room temperature for one hour and diluted with methyl tert-butyl ether (300 mL). The organic layer was sequentially washed with 2 N hydrochloric acid (50 mL), H2O (50 mL) and saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (E)-9,9,10,10,10-pentafluoro-dec-2-enoic acid ethyl ester (purity 80%) as a colorless oily substance (49.7 mg, 47%).
Reaction SMILES: [C:1]([CH:4]([NH:35]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][C@@H:8]([C:27]([NH:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31])=[O:28])[NH:9][C:10]([NH:12][CH2:13][CH:14]([C:24]([OH:26])=[O:25])[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([OH:3])=[O:2]>C(O)(C(F)(F)F)=O>[C:1]([CH:4]([NH2:35])[CH2:5][CH2:6][CH2:7][C@@H:8]([C:27]([NH:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31])=[O:28])[NH:9][C:10]([NH:12][CH2:13][CH:14]([C:24]([OH:26])=[O:25])[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([OH:3])=[O:2]
Reactant: CCCCCCC(=O)NC(CNC(=O)N[C@@H](CCCC(NC(=O)OC(C)(C)C)C(=O)O)C(=O)N[C@H](C)C(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC(=O)NC(CNC(=O)N[C@@H](CCCC(N)C(=O)O)C(=O)N[C@H](C)C(=O)O)C(=O)O

Procedure:
To 85.9 mg of 1b-5 under argon is treated with 500 μl of TFA according to Example 80. The volatiles are evaporated to a residue which is triturated with ether 3× and the ether is decanted. The residue is dried to give 77.9 mg of 1b-11 as a white solid. NMR(CD3OD) δ 0.80(t,3H), 2.16(t,2H), 3.22(br s,5H), 3.58(m,2H), 3.85(m,1H), 4.15(m,1H), 4.30(d,1H), 4.40(m,1H); MS(HR-FAB) m/z 526.2482 (M+H, calcd for C21H38N5O9 526.2489).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH:20]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[NH:21]2)=[CH:13][CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH3:37])[CH2:32]Cl.[O-]S([O-])(=O)=O.[Mg+2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH:20]2[C:24](=[O:25])[N:23]([CH2:32][C:31]3[CH:34]=[CH:35][C:36]([CH3:37])=[C:29]([CH3:28])[CH:30]=3)[C:22](=[O:26])[NH:21]2)=[CH:13][CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(CCl)cc1C
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCCC2NC(=O)NC2=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(CN2C(=O)NC(CCCc3ccc(OC(C)(C)C(=O)OC(C)(C)C)cc3)C2=O)cc1C
Yield: 53 %

Procedure:
Compound 2-{4-[3-(2,5-dioxo-imidazolidin-4-yl)-propyl]-phenoxy}-2-methyl-propionic acid tert-butyl ester (0.29 g, 0.770 mmol) in DMF (10 mL) was treated with 3,4-dimethyl benzyl chloride (0.131 g, 0.847 mmol), MgSO4 (0.185 g, 1.54 mmol) and then 325 mesh K2CO3 (0.213 g, 1.54 mmol). The resultant mixture was heated to 50° C. under N2 for 4 h. The reaction mixture was cooled and quenched with 1N HCl (8 mL) and then extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give a crude product which was purified by flash chromatography using a gradient of 4:1 then 1:1 hexanes:EtOAc to afford 0.202 g (53%) 2-(4-{3-[1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester. MS (ES+) Calc'd for C29H39N2O5 (M+1) 495. Found m/z 495 (100%). 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1.O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])=[CH:18][N:17]=1
Reactant: CN(C)c1ccc(N)cn1
Reactant: CN1CC(=O)NC1=NC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(N(C)C)nc1

Procedure:
A mixture of 8.1 g (35 mM) of the phenyl carbamate 8 and 2.5 g (23 mM) of 5-amino-2-dimethylaminopyridine in 50 ml of anhydrous DMF was heated at 55° for 3.5 hrs. and then cooled and poured into 200 ml of water. The resulting mixture was extracted with three 100 ml portions of ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated to a volume of 50 ml. The precipitate which formed was collected and recrystallized from acetone to give 0.84 of the above urea as tan crystals, m.p. 212°-213° C.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-])=O)=[CH:29][CH:28]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]2[N:9]2[CH2:10][CH2:11][C:6]3([C:4](=[O:5])[NH:33][CH2:32][CH:31]3[C:30]3[CH:36]=[CH:37][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[CH2:7][CH2:8]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC1
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1
Product: COc1ccc(C2CNC(=O)C23CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC3)cc1
Yield: 52 %

Procedure:
As described for example 1b, cis-rac-1-[2-(4-fluoro-phenyl)-cyclohexyl]-piperidine-4-carboxylic acid ethyl ester (800 mg, 2.4 mmol) (using 4-methoxy-beta-nitrostyrene instead of trans-beta-nitrostyrene) was converted to the title compound (642 mg) 52%) which was obtained as a light yellow foam. MS: m/e=513.4 (M+H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].C(O[CH2:20][C:21]([F:35])=[CH:22][C:23]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)(=O)C>O1CCCC1>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2([CH:22]=[C:21]([F:35])[CH2:20][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=3)[CH2:24][CH2:25]2)=[CH:27][CH:28]=1)[CH3:34]
Reactant: CCOc1ccc(C2(C=C(F)COC(C)=O)CC2)cc1
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc(C2(C=C(F)Cc3cccc(Oc4ccccc4)c3)CC2)cc1
Yield: 40.6 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 3-phenoxyphenyl bromide (2.35 g), tetrahydrofuran (10 ml) and magnesium (0.21 g) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-ethoxyphenyl)cyclopropane (Example 18) (0.6 g). The residue after evaporation was purified by column chromatography (solvent: diethyl ether/hexane; 5:95) to afford 1-(4-ethoxy-phenyl)-1-(2-fluoro-3-(3-phenoxyphenyl)prop-1-enyl)cyclopropane (0.34 g, 41%)
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:13]>Cl.C(O)C>[CH3:11][N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[N:13]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(N=CC=Cc1ccccc1)c1ccccc1

Procedure:
6.6 g of cinnamaldehyde and 6.1 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude cinnamaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 6.8 g (57.6%) of light yellow needle-like crystals which melt at 113.5°-114.5° C.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[CH2:13]([N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C@@H:21]1[C:26]([NH:28][CH:29]([CH:37]([OH:44])[C:38]([NH:40][O:41][CH2:42][CH3:43])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.ClCCl>[CH2:13]([N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C@@H:21]1[C:26]([NH:28][CH:29]([C:37](=[O:44])[C:38]([NH:40][O:41][CH2:42][CH3:43])=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCONC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 3 %

Procedure:
IBX (2-iodoxybenzoic acid 432 mg, 0.694 mmol) was added to a solution of (2R)-1-benzyl-N-(4-(ethoxyamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (218 mg, 0.496 mmol) in DMSO (2 ml). After stirring for 2 h at room temperature more IBX (123 mg, 0.198 mmol) was added and the stirring was continued overnight. Saturated aqueous NaHCO3 solution was added and the reaction mixture was diluted with water and dichloromethane. The precipitate formed was filtered off, the organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with water and dried (MgSO4). The solvent was removed in vacuo, the resulting residue was redissolved in a small amount of dichloromethane and diethylether was added. The white precipitate formed was filtered, washed with diethylether and dried in vacuo. The crude product was dissolved in dichloromethane and treated with three drops of aqueous HCl (4M in dioxane). Removal of the solvent provided the title compound (8.2 mg, 0.015 mmol, 3.02% yield). ESI-MS [M+H]+=438.2
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(S(C)(=O)=O)C3)cc1
Reaction time: 1 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.122 mmol) in dry N,N-Dimethylformamide (0.60 mL, 7.7 mmol) was added N,N-Diisopropylethylamine (0.0636 mL, 0.365 mmol) followed by Methanesulfonyl chloride (0.01410 mL, 0.1822 mmol). The reaction mixture was stirred for 1 hour then submitted for purification. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.16 (d, J=8.7, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.32 (dd, J=36.6, 17.0, 2H), 4.01 (s, 1H), 3.85 (d, J=10.7, 1H), 3.79 (d, J=11.4, 1H), 3.68 (dd, J=20.5, 8.8, 2H), 3.59-3.49 (m, 2H), 3.43 (t, J=11.0, 1H), 3.26-3.17 (m, 1H), 3.16-3.06 (m, 2H), 3.02 (s, 3H), 2.94-2.81 (m, 1H), 2.77-2.63 (m, 1H), 1.88-1.69 (m, 2H), 1.06 (t, J=7.2, 3H), 0.83 (t, J=7.4, 3H). LC/MS-m/z+489.2 (M+H)+.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](F)=[CH:13][CH:12]=1)#[N:10]>N1C=CC=CC=1>[CH:5]12[N:8]([C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)c2ccccc12
Solvent: c1ccncc1
Product: N#Cc1ccc(N2C3CCCC2CC3)c2ccccc12
Yield: 3.8 %

Procedure:
Alternatively, the title compound was also obtained using the following procedure: 8-Azabicyclo[3,2,1]octane (20 mg, 0.18 mmol), 1-cyano-4-fluoronaphthalene (46 mg, 0.27 mmol) and pyridine (0.5 mL) were heated overnight at 100° C., concentrated in vacuo and the residue purified by preparative TLC (dichloromethane, 3× eluted) to afford the title compound (1.8 mg, 4.0%) as a yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([N:12]1[CH2:16][C@H:15]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[O:14][C:13]1=[O:26])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][C@@H:15]1[O:14][C:13](=[O:26])[N:12]([C@H:10]([CH3:11])[CH2:9][OH:8])[CH2:16]1
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 98.2 %

Procedure:
A procedure similar to that described in Preparation 5(b) was repeated, except that 3.25 g of 3-[2-t-butyldimethylsilyloxy-1(R)-methylethyl]-5(R)-(3-chlorophenoxymethyl)oxazolidin-2-one (prepared as described in Preparation 43), 24 ml of tetrabutylammonium fluoride (26% w/v in tetrahydrofuran) and 30 ml of anhydrous tetrahydrofuran were used, to give 2.28 g of the title compound, melting at 76° C. to 78° C. and having [α]D =-65.4° (methanol, c=1.060).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reaction time: 72 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO is added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 3-pyridylboronic acid (4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture is stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture is concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 5-(5-Nitro-pyridin-2-yloxy)-1-pyridin-3-yl-1H-indazole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][CH2:3][CH:4]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl [3-hydroxy-1-(3-nitrophenyl)propyl]carbamate (4.00 g; 13.50 mmol; 1.00 eq.) in anhydrous DCM (15 mL) and N,N-diethylethanamine (2.82 ml; 20.25 mmol; 1.50 eq.) at 0° C. was added dropwise 4-methylbenzenesulfonyl chloride (3.09 g; 16.20 mmol; 1.20 eq.). The mixture was stirred at room temperature for 15 h. After workup, the crude product was purified by flash chromatography on silica gel (EtOAc:Hex from 10:90 to 20:80) to provide 5.5 g of the 3-[(tert-butoxycarbonyl)amino]-3-(3-nitrophenyl)propyl 4-methylbenzenesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:26](Br)[C:27]#[CH:28]>CN(C=O)C>[CH2:28]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:27]#[CH:26]
Reactant: COc1ccc(-c2cc(C=O)ccc2O)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C=O)cc1-c1ccc(OC)cc1
Yield: 5.9 %

Procedure:
A solution of 4-hydroxy-3-(4-methoxyphenyl)benzaldehyde (1.14 g, 5 mmol) in DMF (10 mL) was treated with potassium carbonate (2.48 g, 18 mmol), potassium iodide (10 mg) and propargyl bromide (0.67 mL, 6 mmol). The mixture was heated at 80 C for 3 days, then cooled and the solvent removed under reduced pressure. The residue was redissolved in ethyl acetate and washed water then brine. The organic layer was dried over sodium sulphate then the solvent removed under reduced pressure and the residue purified by column chromatography (3/1 hexane/ethyl acetate) to afford 0.078 g of title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36]/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[C:31]([CH3:42])[CH:30]=1.[NH2:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:57][C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH:47]=[CH:48][CH:49]=1.C(N(CC)CC)C>C(#N)C>[CH2:61]([O:60][C:58]([NH:57][C@@H:50]([C:46]1[CH:47]=[CH:48][CH:49]=[C:44]([NH:43][C:39](=[O:41])/[CH:38]=[CH:37]/[CH2:36][C:32]2[C:31]([CH3:42])=[CH:30][C:29]([Br:28])=[CH:34][C:33]=2[CH3:35])[CH:45]=1)[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:59])[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: Cc1cc(Br)cc(C)c1C/C=C/C(=O)O
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)/C=C/Cc2c(C)cc(Br)cc2C)c1
Temperature: 0 °C
Reaction time: 15 h
Yield: 53.9 %

Procedure:
BOP (1.3 g, 3.0 mmol) was added to a solution of 53C (675 mg, 2.5 mmol), 39C (1.0 g, 2.75 mmol) and triethylamine (5.0 mmol) in acetonitrile (25 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at ambient temperature for 15 h. The mixture was concentrated in vacuo and purified by flash chromatography (0% to 60% EtOAc in hexanes) to afford 53D (800 mg, 54%) as a white solid. MS (ESI) m/z 593.3/595.3 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][C:14]([CH2:16][CH2:17][C:18]([CH3:20])=O)=O>C(O)(=O)C.C(Cl)Cl>[CH3:20][C:18]1[N:1]([N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])[C:14]([CH3:13])=[CH:16][CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(C)n1N1C(=O)c2ccccc2C1=O
Yield: 98 %

Procedure:
A mixture of N-amino-phthalimide (50 g) and 2,5-hexadione (35.2 g) in 400 ml acetic acid was refluxed for 48 hours, stripped of solvent, slurried in methylene chloride and filtered. The filtrate was washed with saturated sodium bicarbonate solution, dried and stripped to yield N-(2,5-dimethylpyrrol-1-yl)-phthalimide (98%).
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([CH2:20]Cl)[CH2:8][N:7]4[CH3:22])=[CH:3]1.[C-:23]#[N:24].[Na].[C-]#N.[K+]>CS(C)=O>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([CH2:20][C:23]#[N:24])[CH2:8][N:7]4[CH3:22])=[CH:3]1
Reactant: CO[C@]12C[C@@H](CCl)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Reactant: [C-]#N
Agent: [K+]
Agent: [Na]
Solvent: CS(C)=O
Product: CO[C@]12C[C@@H](CC#N)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13

Procedure:
The starting material for preparing compounds of the present invention is, preferably, 1-methyl-lumilysergol-10-methylether or 1,6-dimethyl-8β-hydroxymethyl-10α-methoxyergoline (I), described and claimed in the Bernardi et al. U.S. Pat. No. 3,228,943. It is reacted at a temperature between 40° and 50° C with the chloride of an aryl- or alkylsulphonic-acid, such as tosyl chloride or mesyl chloride, in pyridine and in the presence of pyridinium chloride, to give the corresponding 8-chloromethyl derivative. This compound, that is, 1,6-dimethyl-8β-chloromethyl-10α-methoxyergoline (II), is treated with an alkaline cyanide, such as sodium or potassium cyanide in a suitable solvent, such as dimethylsulphoxide, at the temperature of 100°-120° C for a period between 4 and 8 hours. The product thus formed, that is, 1,6-dimethyl-8β-cyanomethyl-10α-methoxyergoline (III), is isolated and characterized: it has never been described in the previous literature. This product is subjected to alkaline hydrolysis, preferably with potassium hydroxide in water/ethanol/dioxan solution, under reflux conditions for a few hours.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1.O.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: O
Product: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution (80 mL) of [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7.1 g) in acetonitrile were added tetra-n-propylammonium perruthenate (0.63 g), N-methylmorpholine N-oxide hydrate (4.2 g) and molecular sieves 4 A powder (3.5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 4.6 g, 71%).