Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].C(OCC)(=O)C.O.[H+].[B-](F)(F)(F)[F:24]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([F:24])[CH:8]=1
Reactant: F[B-](F)(F)F
Reactant: Cc1cc(Br)cc(N)c1C
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Br)cc(F)c1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In 50 ml of 42% borofluoric acid was suspended 5.00 g of 5-bromo-2,3-dimethylaniline, followed by adding dropwise thereto 3.9 ml of an aqueous solution of 1.80 g of sodium nitrite under ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. The crystals precipitated were collected by filtration, dried under reduced pressure, and then heated at 60° C. on an oil bath. At the time when a theoretical amount of nitrogen was produced, the reaction mixture was cooled to room temperature and then added to a mixed solvent of 50 ml of ethyl acetate and 50 ml of water, and the organic layer was separated. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by a column chromatography (eluent; n-hexane:ethyl acetate=30:1) to obtain 2.90 g of 5-bromo-2,3-dimethylfluorobenzene as a colorless oil.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH:7]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C>CCO>[CH:7]1([CH:13]([OH:14])[CH2:6][N+:3]([O-:5])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C[N+](=O)[O-]
Reactant: O=CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC(O)C1CCCCC1
Reaction time: 0.17 h

Procedure:
10 M aqueous NaOH (8.31 mL, 83 mmol) was added dropwise via addition funnel to a solution of nitromethane (4.46 mL, 83 mmol) and cyclohexanecarboxaldehyde (10 mL, 83 mmol) in EtOH (20 mL) at 0° C. with vigorous stirring. The resulting white slurry was stirred 10 minutes and became a white solid. Acetic acid (4.76 mL, 83 mmol) was added and the reaction was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated in vacuo and dried under vacuum to afford 1-cyclohexyl-2-nitroethanol. The product was used directly for the next step without further purification.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11]CC2CCC[N+]2(C(C2C=CON=2)C(=O)N)C)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].O[CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][N+:39]1([CH2:44][C:45](=[O:52])[NH:46][C:47]1[CH:51]=[CH:50][O:49][N:48]=1)[CH3:43].[Br-].OC1CC[N+](CC(=O)NC2C=CON=2)(C)CC1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:42]2[CH2:37][CH2:38][N+:39]([CH2:44][C:45](=[O:52])[NH:46][C:47]3[CH:51]=[CH:50][O:49][N:48]=3)([CH3:43])[CH2:40][CH2:41]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC(O)CC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with 4-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate I).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=1>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:20][C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:34])[C:23]=3[CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc3c(c2)C(=O)c2ccccc2-3)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5 Step A and 2-hydroxy-9-fluorenone in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H20O5 [M−H]−: 411.2
Reaction SMILES: Br[C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)=[CH:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[BH4-].[Na+].N>FC(F)(F)C(O)=O>[CH3:26][N:6]1[C@H:5]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:17]=3[C@H:3]([CH2:4]2)[CH2:2][NH:16]4)=[CH:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7]1
Reactant: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)N[C@H]1C=C2c3cccc4c3[C@@H](CN4)C[C@H]2N(C)C1
Yield: 62.2 %

Procedure:
In an ice bath, 280 ml of trifluoroacetic acid is cooled and then successively combined, under inert gas, with 12.5 g of 3-(2-bromo-9,10-didehydro-6-methyl-8α-ergolinyl)-1,1-diethylurea (30 millimoles) and 7 g of sodium borohydride in tablet form. The mixture is stirred under ice cooling for 4 hours and, during this time, 2×3 g of sodium borohydride is added. Then the reaction mixture is poured on about 200 ml. of ice and, under ice cooling, gently neutralized with concentrated aqueous ammonia solution (32%). The mixture is extracted with methylene chloride, and the organic phase is then dried with magnesium sulfate and evaporated. The residue is crystallized from ethyl acetate and diisopropyl ether, thus obtaining 6.35 g of 3-(9,10-didehydro-2,3β-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea (62% of theoretical). From the mother liquor, another 1.0 g of compound is additionally crystallized. According to NMR analysis, the compound is solely a 3βH-compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S-:13].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:13][CH3:12]
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Na+]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A mixture of 3,4-difluoro-nitrobenzene (25 g, 0.157 mol) and sodium methanethiolate (10.5 g, 0.15 mol) was stirred at room temperature overnight. The reaction mixture was poured into water and extracted twice with ether. The extracts were combined, washed with water (twice) and brine, dried (sodium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 17% dichloromethane/hexanes to give 2-fluoro-1-methylsulfanyl-4-nitro-benzene (18.6 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.Cl.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][C:25]=1[O:33][CH3:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:12]([C:9]2([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:11][CH2:10]2)=[O:13])=[CH:26][C:25]=1[O:33][CH3:34])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1C1(C(=O)Cl)CC1
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CCNC(=O)C2(c3ccccc3OC)CC2)ccc1OCc1ccccc1
Reaction time: 72 h

Procedure:
A solution of 1-(2-methoxyphenyl)cyclopropane carbonyl chloride (16 g) in ethyl acetate (50 ml) was added to a stirred solution of 4-benzyloxy-3-methoxyphenylethylamine hydrochloride (22.3 g) in ethyl acetate (250 ml) and triethylamine (30 ml). The mixture was stirred for 3 days then water was added. The organic layer was washed with 5M-HCl, then water, then 2M aqueous sodium hydroxide solution, and dried over sodium sulphate. Evaporation yielded N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-1-(2-methoxyphenyl)cyclopropane carboxamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[F:38][C:37]([F:39])([F:40])[O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1[N:29]=[C:17]([C:16]2[CH:20]=[CH:21][C:13]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)[O:19][N:27]=1
Reactant: O=C(O)c1ccc(N2CCCCC2)c(C(F)(F)F)c1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccccc1-c1noc(-c2ccc(N3CCCCC3)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 42 (137 mg; 0.5 mmol; 1 eq.), Intermediate 2 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from MeOH/water afforded the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]3[C:10]([CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:8]=[CH:7]3.N1CCCCC1>CN(C=O)C>[CH2:7]1[C:6]2=[C:5]3[C:4](=[CH:12][CH:11]=[C:10]2[NH:9][CH2:8]1)[NH:3][C:2]([C:13]([O:15][CH3:16])=[O:14])=[CH:1]3
Reactant: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c3c(ccc2[nH]1)NCC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 374.6 %

Procedure:
A solution of 3 (22 mg, 0.02 mmol) in DMF (2 mL) was treated with 5% piperidine in DMF (2 mL). The reaction mixture was stirred for 5 min at 25° C. The final product was purified by Prep HPLC (SymmetrPrep C18, 7 μm, 19×150 mm column), eluted at 10 ml/min (0.01% TFA in water/acetonitrile) with a gradient: 10% acetonitrile in 5 min, 10% to 50% acetonitrile in 15 min, maintaining 50% acetonitrile in 5 min, 50% to 100% acetonitrile in 5 min, to obtain 4 (16.2 mg, 93%). MS: calcd for C41H44BrN9O6 (M+H) m/z 838.26 found 839.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:82][C:83]1([C:86](O)=[O:87])[CH2:85][CH2:84]1>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:86]([C:83]5([CH3:82])[CH2:85][CH2:84]5)=[O:87])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)CC1

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.10 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.3 mL, 1.72 mmol), followed by 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (0.02 g, 0.12 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.12 mmol) and 1-methylcyclopropane-1-carboxylic acid (0.01 g, 0.12 mmol). The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 445.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[CH2:21][N:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1
Reactant: COC(=O)c1cc[nH]n1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(CC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.9 %

Procedure:
Methyl 1H-pyrazole-3-carboxylate (1.0 g, 7.94 mmol) was dissolved in DMF (25 mL) and cesium carbonate (12.9 g, 39.7 mmol) was added. The mixture was cooled to 0 C and 2,2,2-trifluoroethyl methanesulfonate (2.4 mL, 19.8 mmol) was gradually added. The mixture was warmed to room temperature and stirred for 16 h. Water was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (3×10 mL) and concentrated under vacuum. The residue was purified by FCC, eluting with hexane followed by 0.5% MeOH in DCM to afford the title compound as a yellow oil (0.312 g, 19%). Method D HPLC-MS: MH+ requires m/z=209 Found: m/z=209, Rt=2.08 min (98%).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[N+:11]([C:8]1[CH:7]=[C:3]([C:4]([O:6][CH3:18])=[O:5])[C:2](=[O:1])[NH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 2-hydroxy-5-nitronicotinic acid (0.80 g, 4.35 mmol, Combi-Blocks) in methanol (10 mL) at 0° C. was added thionyl chloride (1 mL) dropwise. The mixture was stirred at 0° C. for 1 h, then at 60° C. for 2 h. The excess methanol was removed under reduced pressure and the residue was neutralized with aqueous sodium bicarbonate solution. The solid was collected, washed with water and dried to afford the title compound (0.85 g, 99%). 1H NMR (DMSO-d6) δ 8.44 (s, 1H), 8.34 (s, 1H), 3.67 (s, 3H); MS(ESI+) m/z 199 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[N:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH:21][C:22]2[C:23]([NH:32][C:33](=[O:44])[C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[CH:26][CH:27]=2)=[O:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O1CCOCC1.[OH-].[Na+]>O>[CH2:49]([O:48][C:46]([NH:45][C:12](=[N:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH:21][C:22]2[C:23]([NH:32][C:33](=[O:44])[C:34]3[CH:35]=[CH:36][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:38][CH:39]=3)=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=2)=[O:20])[CH2:14]1)=[O:47])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: COC(=O)c1ccc(NC(=O)C2CCCN(C(=NC(=O)OCc3ccccc3)NC(=O)OCc3ccccc3)C2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(C(=O)O)ccc2NC(=O)C2CCCN(C(=NC(=O)OCc3ccccc3)NC(=O)OCc3ccccc3)C2)cc1
Reaction time: 48 h
Yield: 91.3 %

Procedure:
To a solution of N1-[[1-(benzyloxycarbonylamino-(benzyloxycarbonylimino)methyl)piperidin-3-yl]carbonyl]-N2-(4-t-butylbenzoyl)-4-methoxycarbonyl-1,2-benzenediamine (0.7 g, 0.94 mmol), CH3OH (10 mL), dioxane (10 mL), and water (6 mL) was added 1 N NaOH (3.7 mL, 3.7 mmol) The reaction was stirred for 48 h and was concentrated. The residue was partitioned between H2O (100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (100 mL), acidified to pH, 2.5 with 5 N HCl and extracted with EtOAc (3×200 mL). The combined EtOAc layers were washed with water, MgSO4 dried, concentrated and crystallized at 0° C. overnight to give the title compound as a solid (0.63 g, 92%); TLC: Rf=0.38 (1:15:135 acetic acid:methanol:chloroform); NMR (CDCl3) δ1.35 (s,9H), 1.50-2.05 (m, 8H), 3.20-3.40 (m, 1H), 3.60-4.05 (m, 3H), 5.05 (s, 4H), 7.20-7.35 (m, 12H), 7.40-7.50 (m, 2H), 7.55-7.65 (m, 1H), 7.90-8.00 (m, 2H), 8.05-8.15 (m, 1H); MS(FAB): 734 (MH+).
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][N:12]([C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:11]1=[O:29])C1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.Cl.[CH2:53]([O:60][NH2:61])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CO.[Pd].ClCCl.[OH-].[Na+].ClCCl>[CH2:53]([O:60][N:61]=[CH:9][C@@H:10]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][N:12]([C@@H:19]([C:25]([CH3:27])([CH3:26])[CH3:28])[C:20]([N:22]([CH3:23])[CH3:24])=[O:21])[C:11]1=[O:29])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NOCc1ccccc1
Reactant: CCCC[C@H]1CN([C@H](C(=O)N(C)C)C(C)(C)C)C(=O)[C@@H]1COCc1ccccc1
Agent: [Pd]
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCC[C@H]1CN([C@H](C(=O)N(C)C)C(C)(C)C)C(=O)[C@@H]1C=NOCc1ccccc1
Reaction time: 8 h
Yield: 60.2 %

Procedure:
(S)-2-[(3S,4R)-3-Benzyloxymethyl-4-butyl-2-oxopyrrolidin-1-yl]-3,3, N,N-tetramethyl butyramide (0.08 g, 0.2 mmol) was dissolved in methanol (2 mL) and stirred overnight under a hydrogen balloon in the presense of palladium on activated carbon (15 mg). Filtration followed by concentration provided a crude alcohol (58 mg) which was dissolved in dichloromethane (5 mL) and treated with Dess-Martin periodinane (0.13 g, 0.3 mmol) at 0° C. After warning up to rt, the reaction was stirred overnight and the solvent was removed under vacuum. The residue was then dissolved in pyridine (5 mL) and benzyloxyamine hydrochloride (0.064 g, 0.4 mmol) was added. After 1 h, the reaction mixture was condensed to dryness, the residue was dissolved in 1 N aq. NaOH/dichloromethane (2:3, 15 mL). The organic phase was separated, the aqueous phase was extracted with dichloromethane (5 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification of the residue by HPLC afforded (S)-2-[(3S,4R)-3-benzyloxyiminomethyl-4-butyl-2-oxopyrrolidin-1-yl]-3,3,N,N-tetramethyl butyramide as a colorless oil (0.05 g, 61%). MS(ES) m/e 416 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.Cl[CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]2[CH:45]=1>O>[N:38]1[C:37]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:6][CH:7]=2)=[CH:45][N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 78.9 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.5 g, 8.06 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 min, upon which 2-(chloromethyl)imidazo[1,2-a]pyridine (2.4 g, 12.0 mmol) was added. The mixture was heated at 80° C. for 4 h (reaction was monitored by TLC). The reaction mixture was allowed to cool to RT, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.8 g, 77.7%,) as Off-white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H) 3.85 (s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=441.2. HPLC: (97.3%, Condition-A).
Reaction SMILES: C([O:14][C:15]1[C:16]2[C:44](=[O:45])[N:43]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)[CH2:42][C:17]=2[C:18]([O:25][S:26]([CH2:29][CH2:30][N:31]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:41])(=[O:28])=[O:27])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(C1C=CC=CC=1)C1C=CC=CC=1.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].C([SiH](CC)CC)C>ClCCl>[F:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][N:43]2[C:44](=[O:45])[C:16]3[C:15]([OH:14])=[C:24]4[C:19]([CH:20]=[CH:21][CH:22]=[N:23]4)=[C:18]([O:25][S:26]([CH2:29][CH2:30][N:31]4[C:39](=[O:40])[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]4=[O:41])(=[O:28])=[O:27])[C:17]=3[CH2:42]2)=[CH:52][CH:51]=1.[C:56]([OH:58])([C:55]([F:60])([F:59])[F:54])=[O:57]
Reactant: O=C1c2c(c(OS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(c(OS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c3cccnc3c2O)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 268 (12.2 mg, 0.017 mmol) dissolved in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reaction mixture was stirred at room temperature for ½ hours under an inert atmosphere then concentrated in vacuo. The residue was triturated with diethyl ether/hexane (1/1) to afford 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 269, TFA salt, (9.0 mg, 76%) as a yellow solid: 1H NMR (CDCl3) δ 9.0 (d, 1H), 8.5 (dd, 1H), 7.9 (m, 2H), 7.8 (m, 2H), 7.7 (m, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.6 (s, 2H), 4.4 (q, 2H), 3.9 (q, 2H); MS: 562 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH2:23][CH2:24][CH3:25])[C:13]=3I)[N:9]([CH3:27])[CH2:8]1)=[O:5])[CH3:2].[CH2:30](N(CC)CC)[CH3:31].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Si](C)(C)C)=C>CN(C)C=O.[Pd](Cl)Cl>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH2:23][CH2:24][CH3:25])[C:13]=3[CH:30]=[CH2:31])[N:9]([CH3:27])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCCn1c(I)c2c3c(cccc31)[C@H]1C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C2
Agent: Cl[Pd]Cl
Agent: C=C[Si](C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: C=Cc1c2c3c(cccc3n1CCC)[C@H]1C[C@H](NC(=O)N(CC)CC)CN(C)[C@@H]1C2

Procedure:
In a small autoclave, 1.15 g of 1,1-diethyl-3-(2-iodo-1-propyl-6-methyl-8α-ergolinyl)urea is heated under argon for 3 hours to a bath temperature of 115° C. in 10 ml of dimethylformamide with 10 ml of triethylamine, 53.5 mg of triorthotolylphosphine, 39.4 mg of palladium(II) chloride and 1.34 ml of vinyltrimethylsilane. After evaporation, the mixture is distributed in methylene chloride/sodium bicarbonate solution. The organic phase is evaporated and chromatographed over silica gel with ethyl acetate: ethanol=3:1 as the eluent, thus obtaining 218 mg of 1,1-diethyl-3-(2-trimethylsilylvinyl-1-propyl-6-methyl-8α-ergolinyl)urea and 230 mg of 1,1-diethy-3-(2-vinyl-1-propyl-6-methyl-8α-ergolinyl)urea as oils.