Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]3[CH2:12][CH2:13][CH2:14][C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Cl:20]C1C=CC=C(Cl)C=1S[S:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37].Cl>>[ClH:20].[C:1]1([CH:7]2[CH2:11][N:10]3[CH2:12][CH2:13][CH:14]([S:29][C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccc(Cl)c1SSc1c(Cl)cccc1Cl
Reactant: c1ccc(C2CN3CCCC3=N2)cc1
Agent: Cl
Agent: [Li]CCCC
Product: Clc1cccc(Cl)c1SC1CCN2CC(c3ccccc3)N=C12
Yield: 40.7 %

Procedure:
2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with 2 equivalents of n-BuLi and 1 equivalent of 2,6-dichlorophenyldisulfide according to the general procedure A above except that when the reaction mixture was poured into the aq HCl solution, the HCl salt of the desired product precipitated. It was collected, washed well with cold H2O, then Et2O and dried in vacuo; yield 40.7%; m.p. 96°-99°. Neutralization of the acidic filtrate with NaHCO3, followed by extraction with Et2O, yielded an additional amount of the desired product as the free base (39.2%).
Reaction SMILES: [OH:1][NH:2][C:3]([C@H:5]([C@@H:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16]([NH:18][N:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25])=[O:17])[CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]>C(O)(=O)C.[Pt](=O)=O>[CH:9]1([CH2:8][CH2:7][CH2:6][C@@H:5]([C@@H:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:16]([NH:18][N:19]2[CH2:23][C:22](=[O:24])[NH:21][C:20]2=[O:25])=[O:17])[C:3](=[O:4])[NH:2][OH:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)C[C@@H](C(=O)NN1CC(=O)NC1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C(=O)NN1CC(=O)NC1=O)[C@H](CCCC1CCCCC1)C(=O)NO
Yield: 57.1 %

Procedure:
A solution of 0.134 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,4-dioxo-1-imidazolidinyl)valeramide (prepared as described in Example 35) in 10 ml of acetic acid was hydrogenated for 1.66 hours in the presence of 0.015 g of platinum (IV) oxide. The catalyst was removed by filtration and evaporation gave a residue which was triturated with diethyl ether to give 0.078 g of 2(R)-[4-cyclohexyl-1(S)-(hydroxycarbamoyl)butyl]-4-methyl-N-(2,4-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12.[H-].[Na+].Cl[C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:20]4[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]5[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=5[N:21]=4)=[CH:14][CH:15]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(C2CCCn3ccnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(C3CCCn4ccnc43)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of 4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)phenol (0.13 g) in DMF (10 ml) was added sodium hydride (60% in oil, 0.024 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.17 g) obtained in Example 1, step A), and the mixture was stirred under microwave irradiation at 150° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.19 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@H:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]([CH2:5][C:6](OS(C(F)(F)F)(=O)=O)=[CH:7]2)[CH2:3]1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[CH2:9][C@H:8]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]([CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2)[CH2:3]1
Reactant: CN1C[C@H]2CC(OS(=O)(=O)C(F)(F)F)=C[C@@H](C1)N2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C[C@H]2CN(C)C[C@@H](C1)N2C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
To a solution of (1R,5S)-tert-butyl 3-methyl-7-(((trifluoromethyl)sulfonyl)oxy)-3,9-diazabicyclo[3.3.1]non-6-ene-9-carboxylate (14 g, 36 mmol) and diisopropylethylamine (9.47 mL, 54.3 mmol) in methanol (100 mL) and DMF (100 mL) was triphenylphosphine (0.95 g, 3.62 mmol) and palladium (II) acetate (0.407 g, 1.81 mmol). The mixture was stirred under carbon monoxide atmosphere for 24 h. The mixture was concentrated and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, concentrated and the residue was purified on silica gel using ethyl acetate and hexane as eluting solvents to give the title compound. LC/MS: (M+1)+: 297.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10](O)[CH3:11])=[CH:4][CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]([N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)C#Cc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#Cc1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-but-3-yn-2-ol (3 g, 16.6 mmol), phthalimide (3.7 g, 25.2 mmol, 1.5 eq.) and PPh3 (4.8 g, 18.3 mmol, 1.1 eq.) in 100 mL of THF cooled to 0° C. with an ice bath was added dropwise DEAD (i.e., diethyl azodicarboxylate) (3.1 mL, 19.9 mmol, 1.2 eq.). The ice-bath was removed and the mixture was stirred overnight at room temperature. The THF was evaporated and the residue was stirred with 200 mL of 1:1 ether-hexane mixture for 1 hr. The precipitate was filtered off and the filtrate was concentrated and chromatographed with 15% ethyl acetate-hexane to provide 4.1 g of 2-[3-(4-chloro-phenyl)-1-methyl-prop-2-ynyl]-isoindole-1,3-dione.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[CH2:21]1)(=O)=O.C(#N)C>>[CH3:44][O:43][C:37]1[CH:36]=[C:35]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:34])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:21]2)[CH:40]=[CH:39][C:38]=1[O:41][CH3:42]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1ccc([C@@]2(CCOS(C)(=O)=O)CCN(C(=O)c3ccccc3OC)C2)cc1OC
Solvent: CC#N
Product: COc1ccc([C@]2(CCN3CCC(N4CCCCC4)CC3)CCN(C(=O)c3ccccc3OC)C2)cc1OC

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dimethoxyphenyl)-1-(2-methoxybenzoyl)pyrrolidine (3.17 g), prepared essentially as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH2:17])[C:6]([O:8]CC)=[O:7].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:37][C:38](O)=[O:39])[CH:23]=[CH:24][C:25]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])=[O:28].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][C:38](=[O:39])[CH2:37][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[O:28])=[C:20]([O:19][CH3:18])[CH:21]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OCCN)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2OC)ccc1NC(=O)Nc1ccccc1C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-(2-aminoethoxy)benzoate (250 mg, 1.04 mmol) and pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (500 mg, 1.04 mmol) was added Et3 N (210 μl, 3.01 mmol), and the resulting mixture was stirred for 2 days. 0.25 N NaOH (20 mL) and THF (20 mL) was added to the mixture and the resulting mixture was heated under reflux overnight. After cooling, the mixture was evaporated and the residue was acidified by the addition of 1 N HCl. The mixture was extracted with CHCl3, and the extract was washed with brine, dried over Na2SO4, and evaporated. The obtained crude solid was recrystallized from CHCl3 to give 110 mg (20% for 2 steps ) 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 255 as a white crystalline powder. mp 180–181° C.; IR (KBr) 1687 cm−1; 1H-NMR (DMSO-d6) δ 2.24 (s, 3 H), 3.37 (s, 2 H), 3.38 (s, 2 H), 3.41–3.50 (m, 2 H), 3.81 (s, 3 H), 3.83 (s, 3 H), 4.06–4.08 (m, 2 H), 6.76–8.55 (series of m, total 12 H); MS (FAB) m/z 508 (M++1); Anal. Calcd for C27H29N3O7.1/2H2O: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.46; H, 5.69; N, 8.03.
Reaction SMILES: COC(=O)[N:4]([CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH3:13])[CH2:5][CH2:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9].[Br-].[CH2:23]1[CH2:27]OC[CH2:24]1>>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]([NH:4][CH2:5][CH2:6][C:7]([OH:11])([CH2:27][CH:23]=[CH2:24])[CH:8]([CH3:9])[CH3:10])[CH3:13])=[CH:19][CH:18]=1
Reactant: COC(=O)N(CCC(=O)C(C)C)C(C)c1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CCC(O)(CCNC(C)c1ccc(Br)cc1)C(C)C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-bromo-phenyl)-ethyl]-(4-methyl-3-oxo-pentyl)-carbamic acid methyl ester (1.78 g, 5 mmol) in dried THF (20 mL) was added allymagnesium bromide (1 M, 25 mL, 25 mmol) dropwise at −78° C. The mixture was stirred overnight. The reaction was quenched with aqueous sat. NH4Cl. The mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, and condensed to give 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.O>O1CCOCC1>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(Nc2cc(N3CCCCC3)cc(-c3ccc(F)cc3)n2)cc1
Yield: 60.5 %

Procedure:
To a solution of 4-(6′-chloro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-ylamino)-N-methyl-benzenesulfonamide (70 mg, 0.18 mmol) in 1,4-dioxane (8 mL) was added sodium carbonate (1N, 80 mg, 0.72 mmol), and tetrakis(triphenyl-phosphine)palladium(0) (21 mg, 0.018 mmol), followed by 4-fluorophenyl boronic acid (49 mg, 0.36 mmol). This reaction was refluxed for 8 hours, after which time water (100 mL) added to the reaction mixture, and the product was extracted with ethyl acetate (100 mL×3). The organic layer was dried over sodium sulphate, filtered, and the filtrate was and concentrated under vacuum. The resulting product was purified through column chromatography using 230-400 mesh silica gel (5% methanol in dichloromethane) to afford the desired compound as A yellow solid (48 mg, Yield 60%). Purity: 98.2%.
Reaction SMILES: Cl[C:2]1[CH:40]=[CH:39][C:5]([C:6]([NH:8][C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:37])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]6([C:35]#[N:36])[CH2:34][CH2:33]6)[CH:27]=5)[CH:19]=4)=[N:13][N:12]3[CH:38]=2)=[O:7])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH3:46][N:47](C)C=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[C:46]([C:2]1[CH:40]=[CH:39][C:5]([C:6]([NH:8][C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:37])[C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([C:32]6([C:35]#[N:36])[CH2:34][CH2:33]6)[CH:27]=5)[CH:19]=4)=[N:13][N:12]3[CH:38]=2)=[O:7])=[CH:4][N:3]=1)#[N:47]
Reactant: CN(C)C=O
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccc(Cl)nc6)cn5n4)c3)c2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Product: N#Cc1ccc(C(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)ccc3n2)cn1
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 6-chloro-N-[6-(3-{[3-(1-cyanocyclopropyl)benzoyl]amino}phenoxy)imidazo[1,2-b]pyridazin-2-yl]nicotinamide (120 mg, 0.201 mmol), tetrakis(triphenylphosphine)palladium (0) (58 mg, 50.4 mol), zinc cyanide (26 mg, 0.225 mmol) and N,N-dimethylformamide (2.5 mL) was stirred with heating under an argon atmosphere at 100° C. for 6.5 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→100/0) to give the title compound (51 mg, 47%) as a yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][OH:9])[CH2:6][CH:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17])[CH3:2].[OH:18]P([O-])(O)=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.Cl([O-])=O.[Na+].Cl[O-].[Na+].ClCl.S([O-])([O-])=O.[Na+].[Na+].Cl>C(#N)C>[CH2:1]([N:3]1[C:4](=[O:17])[CH:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C@H:7]1[C:8]([OH:18])=[O:9])[CH3:2]
Reactant: CCN1C(=O)C(Cc2ccccc2)CC1CO
Reactant: O=P([O-])(O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: ClCl
Solvent: CC#N
Product: CCN1C(=O)C(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
1-Ethyl-5-(hydroxymethyl)-3-(phenylmethyl)-2-pyrrolidinone (0.748 g, 3.21 mmol) was dissolved in acetonitrile (5 ml) and a 1M aqueous sodium phosphate monobasic buffer solution (3.69 ml, 3.69 mmol), a few crystals of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), and sodium chlorite (0.580 g, 6.41 mmol) were added and the mixture was warmed to 40° C. Approximately 1 drop of bleach (sodium hypochlorite solution, available chlorine >12%) was then added to the mixture and stirring continued at 40° C. for 3 hrs. The mixture was then poured onto ice-water containing 1% w/w sodium sulphite and the resulting mixture was adjusted to pH2 using 5N aqueous hydrogen chloride and then extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulphate and concentrated to give 1-ethyl-5-oxo-4-(phenylmethyl)proline (0.807 g) as a solid which was used without additional purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[Li]CCCC.Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].[NH4+].[Cl-]>C1COCC1.O.C(Cl)Cl>[O:20]([CH2:19][CH2:18][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
A suspension of compound 2.2 from Step A (2.0 g, 8.6 mmol) in THF (40.0 mL) was cooled to −78° C. under an argon atmosphere. n-BuLi (1.6M in hexanes, 13.4 mmol) was then added over 1.0 hr via syringe. A suspension formed and (2-bromoethoxy)-tert-butyldimethylsilane (7.4 mL, 34.4 mmol) was added via syringe while maintaining the reaction mixture at −78° C. The reaction mixture was allowed to slowly reach −30° C. and stirred for 2 h, then −30 to −10° C. for 1 h, and −10 to 0° C. for 1 hr. The reaction mixture became dark brown in color, was treated with NH4Cl, CH2Cl2 and water. The reaction mixture was extracted with CH2Cl2 and the extracts were dried over Na2SO4, filtered and evaporated. The beige residue was purified by flash column chromatography using 23% EtOAc in hexanes as eluent to give the desired compound 2.3 (1.16 g, 43%) as a white solid. (Brown, D. M. et al., J. Chem. Soc. PT-1, 3565-3570.)
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:32]=[N:33][C:34]4[C:39]([CH:40]=3)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=4)=[O:30])[CH2:25][CH2:24]2)[CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:41][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[CH2:16][NH2:8])[CH2:24][CH2:25]1)=[O:30])=[CH:40]2
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cnc4ccc(Cl)cc4c3)CC2)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(C2CCN(C(=O)c3cnc4ccc(Cl)cc4c3)CC2)c1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
N,N-bis-(tert-butoxycarbonyl)-3-[1-(6-Chloroquinoline-3-carbonyl)-piperidin-4-yl]benzylamine (0.055 g, 0.095 mmol) was treated with a solution of 15% trifluoroacetic acid in methylene chloride (5 ml) at 0° C. The reaction was warmed to ambient temperature over 2.5 hr and the solvents were removed in vacuo. The residue was triturated with ether to yield the title compound (0.033 g, 0.087 mmol) as an amorphous solid. 1H NMR[(CD3)2SO, 500 MHz]: δ 8.95 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.07 (d, 1H), 7.84 (d, 2H), 7.23-7.40 (m, 4H), 4.67 (m, 1H), 7.34 (m, 3H), 4.75 (br m, 1H), 4.05 (m, 2H), 3.75 (br m, 1H), 3.30 (br m, 1H), 2.80-3.00 (br m, 2H), 1.90 (br m, 1H), 1.6-1.8 (br m, 3H). MS(EI): 380(M++H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[CH2:14][C@:13]4([CH:19]5[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]5)[CH2:15]4)[O:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[Br:22]Br>CN(C=O)C.C(Cl)(Cl)Cl>[Br:22][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]2[CH2:14][C@:13]3([CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[O:12][C:9]2=[N:10][CH:11]=1
Reactant: BrBr
Reactant: c1cc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)co1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Brc1occc1-c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
(2′R)-5′-(Furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (102 mg, 0.37 mmol), was stirred with bromine (65 mg, 0.41 mmol) in DMF (3 ml) at room temperature for 1 h. Vaccum was applied, and the mixture was stirred for a further 30 min. The reaction mixture was diluted with chloroform, and washed with aqueous sodium hydroxide, then the organic layer was dried, filtered and evaporated. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound (28 mg) as a pale solid; m/z 361, 363 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]3[CH:12]([CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH:15]1[C:14]2[CH2:13][CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:2]
Reactant: COc1ccc2c(c1)CC1CCCCC21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1)CC1CCCCC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To 7-methoxy-2,3,4,4a,9,9a-hexahydro-1H-fluorene (1.95 g, 9.65 mmol) in CH2Cl2 (20 mL) was added BBr3 (1M in CH2Cl2, 24 mmol) dropwise at 0° C. This mixture was stirred at 0° C. for one hour. The reaction mixture was then quenched with MeOH (5 mL). Aqueous sodium hydrogen carbonate (10 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated. Silica gel chromatography (EtOAc/heptane) provided 1.48 g of 5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-ol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:10]2[S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C2CN(C(=O)OC(C)(C)C)CCS2(=O)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2CNCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
In a 150 mL round-bottomed flask, 2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholine-4-carboxylic acid tert-butyl ester (435 mg, 1.27 mmol) was combined with dichloromethane (15 ml) to give a light yellow solution. To that was added 4 mL TFA. The resultant reaction mixture was stirred at room temperature for 1 h. Reaction was complete by LCMS. Reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, poured onto 10% NaHCO3 and extracted 3 times with dichloromethane. Combined organic layers were washed with water, dried over Na2SO4, filtered and filtrate concentrated in vacuo to afford 2-(3-methoxyphenyl)-thiomorpholine 1,1-dioxide (252 mg) which was used as is in the next step. (M+H)+=242 m/e.
Reaction SMILES: [C:1]([NH:6][C:7](=O)[O:8]CC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][OH:16])[CH3:13]>C1(C=CC(O)=CC=1)O>[C:1]([NH:6][C:7](=[O:8])[O:16][CH2:15][CH:14]([CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH3:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)NC(=O)OCC
Reactant: CCCCC(CC)CO
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)NC(=O)OCC(CC)CCCC
Temperature: 120 °C
Yield: 72.2 %

Procedure:
A reaction vessel was charged with 15.7 g of ethyl N-methacryloylcarbamate and 52 g of 2-ethylhexyl alcohol, to which 0.1 g of hydroquinone was added and heated at 120° C. for one hour. The resulting mixture was condensed under reduced pressure and isolated by column chromatography to obtain 17.4 g of 2-ethylhexyl N-methacryloylcarbamate having a viscosity of 800 cp.