Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH3:3]>CCOC(C)=O>[ClH:1].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3]
Reactant: CCOc1ccccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1ccccc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Excess HCl in EtOAc was added dropwise to a solution of intermediate 30 (800 mg, 2.5 mmol) in EtOAc and the reaction mixture was stirred at rt for 1.5 h. Filtration gave 1-(2-ethoxyphenyl)-1,4-diazepane hydrochloride (intermediate 31) (382 mg, 59%) as a white solid.
Reaction SMILES: C1([CH:7]([N:14]2[CH2:17][CH:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[CH:20]3)[CH2:15]2)C2C=CC=CC=2)C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[N:19]1([CH2:18][CH:16]2[CH2:15][CH2:7][NH:14][CH2:17]2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1ccc(C(c2ccccc2)N2CC(Cn3ccnc3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1cn(CC2CCNC2)cn1
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of the title compound(1.7 g) from Step D and Pd(OH)2 on carbon (0.2 g) in EtOH (20 mL) was stirred at 50 psi under an atmosphere of hydrogen for 24 h. The catalyst was filtered to give the title compound (0.508 g, 66.8%). m/z=137 (MH+)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12](Br)=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:16]([NH2:18])=[O:17])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)c1cnc(N)c2c1sc1cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(N)c2c1sc1cc(-c3ccccc3)ccc12

Procedure:
To a suspension of 1-amino-7-bromo[1]benzothieno[3,2-c]pyridine-4-carboxamide (Example 12, Step 10) in DMF (0.1 M) was added phenylboronic acid (1.5 equiv). The mixture was degassed for 5 min, and 1 M Na2CO3 (3 equiv) and PdCl2dppf (0.1 equiv) were added. It was heated is the microwave reactor at 120° C. for 10 min. The reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated, dried over MgSO4, filtered, evaporated and purified by flash chromatography (EtOAc/MeOH) to provide the title compound.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]2[CH2:10][NH:11][C:12](=[N:15][OH:16])[CH2:13][S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:17]OS(OC)(=O)=O>C(O)C>[Cl:3][C:4]1[C:9]2[CH2:10][NH:11][C:12](=[N:15][O:16][CH3:17])[CH2:13][S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: ON=C1CSc2cccc(Cl)c2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1CSc2cccc(Cl)c2CN1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 10% aqueous solution of sodium hydroxide (4 ml) was added to a suspension of 6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.29 g, prepared as Example 26 above) in ethanol (150 ml). After 15 minutes dimethylsulphate (1.33 g) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 22 hours and then the solvent was removed by evaporation at reduced pressure. Purification of the residue by chromatography on a silica gel support using dichloromethane followed by dichloromethane/ethanol (97:3) as successive eluents gave 6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from n-hexane. Yield 1.21 g (m.p. 120°-121° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(Br)c1O
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1C=O
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
3-Bromo-2-hydroxy-benzaldehyde (27 g, 134 mmol), prepared as described in N. Hofsloekken, L. Skatteboel, “Convenient Method for the ortho-Formylation of Phenols”, Acta Chemica Scandinavica, 1999, v. 53, p. 258-262), was dissolved in dimethylformamide (150 mL) and then cesium carbonate (54.7 g, 170 mmol) was added to the solution portionwise. The mixture was stirred for 30 minutes and then methyl iodide (28.5 g, 201 mmol) was added. The mixture was stirred for 20 hours and poured into water. The product was extracted with ethyl ether and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-bromo-2-methoxybenzaldehyde (28 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:10]([C:14]1[CH:18]=[C:17]([NH2:19])[NH:16][N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[NH2:19][C:17]1[N:16]([C:2]2[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=2)[N:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:18]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1cc(N)n(-c2cc(O)cc(F)c2)n1
Temperature: 150 °C
Yield: 37.4 %

Procedure:
Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added to a mixture of 3-bromo-5-fluorophenol (1.00 g, 5.23 mmol), 3-tert-butyl-1H-pyrazole-5-amine (728 mg, 5.23 mmol), copper (I) iodide (50.0 mg, 0.26 mmol) and potassium carbonate (1.52 g, 11.0 mmol). Trans-N,N′-dimethylcyclohexanediamine (165 μL, 1.05 mmol) was added and the reaction heated to 150° C. for 3.5 h using microwave irradiation. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-75% EtOAc in cyclohexane, to give the title compound (488 mg, 37%). LCMS (Method 4): Rt 2.49 min, m/z 250 [MH+].
Reaction SMILES: C(O)(=O)C.N1CCCCC1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[C:21]([O:27][CH3:28])(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>C(O)(C)C>[C:23]([C:22](=[CH:14][C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[Cl:11])[C:21]([O:27][CH3:28])=[O:26])(=[O:24])[CH3:25]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: COC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C(=Cc1ccc(F)cc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.7 ml of piperidine acetate are added to a solution of 50 g (315 mmol) of 2-chloro-4-fluorobenzaldehyde and 36.6 g (315 mmol) of methyl acetoacetate in 150 ml of isopropanol. Stirring at room temperature overnight is followed by dilution with dichloromethane and extraction with water, and the organic phase is dried over sodium sulfate and concentrated. The product is reacted further as a crude cis/trans mixture.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].C[O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14](Cl)[N:13]=1)=[O:11]>O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([OH:9])=[O:11])=[N:13][C:14]=1[O:7][CH2:6][CH2:5][O:4][CH3:3]
Reactant: COCCO
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOc1nc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (2.26 g, 66 mmol) was added in portions to a solution of 2-methoxyethanol (30 mL). The mixture was stirred for 30 min at room temperature. Then 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9 c, 3 g, 12 mmol) was added and the reaction mixture was heated to 100° C. overnight. The mixture was poured into water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed three times with brine, dried (sodium sulfate) and evaporated. The crude title compound (2.48 g, yellow solid) was used for the next reaction step without further purification; MS (EI): m/e 276.0 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[OH:17])[CH3:2].[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>O1CCCC1>[CH2:1]([N:3]1[C:4]2[CH:9]=[C:8]([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:7]([O:15][CH3:16])=[CH:6][C:5]=2[O:17][C:18]1=[O:19])[CH3:2]
Reactant: CCNc1cc(CC=C(C)C)c(OC)cc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCn1c(=O)oc2cc(OC)c(CC=C(C)C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
80 mg of 2-ethylamino-5-methoxy-4-(3-methyl-2-butenyl)phenol was dissolved in 5 ml of tetrahydrofuran under nitrogen atmosphere. Then, 0.11 g of 1,1′-carbonyldiimidazole was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the mixture was further stirred at 50° C. for 1 hour. The reaction solution was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 60 mg of the subject compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH2:14]Br.[CH3:17][NH2:18]>C1COCC1>[F:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]2[C:5]=1[CH2:14][N:18]([CH3:17])[C:3]2=[O:2]
Reactant: CN
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(F)c1CBr
Solvent: C1CCOC1
Product: CN1Cc2c(F)ccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
At room temperature, a solution of 2-bromomethyl-3-fluoro-6-nitro-benzoic acid methyl ester (4.48 g, 15.3 mmol) in THF (100 mL) is treated with 2M solution of methylamine in THF (23 mL, 46 mmol), and the mixture is stirred for 48 h at the room temperature. The reaction mixture is filtrated through a glass filter and the precipitates are collected and washed with ethyl acetate. The filtrate is washed with sat. aqueous solution of NaHCO3 and brine, dried over Na2SO4, and concentrated under reduced pressure to give 4-fluoro-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (1.6 g, 7.61 mmol 50%) as yellow solids. 1H-NMR (400 MHz, δ, ppm) CDCl3: 3.22 (s, 3H), 4.47 (s, 2H), 7.32 (dd, 1H), 7.84 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([C:19]1[N:23]2[CH:24]=[C:25]([O:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@@H:32]([NH2:39])[CH2:31][CH2:30]3)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:39][C@@H:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:29]([O:28][C:25]3[CH:26]=[CH:27][C:22]4[N:23]([C:19]([C@:3]5([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:14])[CH3:15])[CH:10]([CH3:11])[CH3:12])[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:20][N:21]=4)[CH:24]=3)[CH2:30][CH2:31]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OC[C@@]1(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCCN1C)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN5C)n4c3)c3ccccc32)cc1
Yield: 48 %

Procedure:
A solution of Intermediate 85j (230 mg, 0.418 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009. which is incorporated herein by reference in its entirety; 253 mg, 0.628 mmol) and DIPEA (215 mg, 1.67 mmol) in DMF (4 mL) was stirred at 50° C. for 1 h. The mixture was diluted with EtOAc, washed with water (2×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a white foam (250 mg, 48%). LCMS (Method 3): Rt 3.70 min, m/z 805 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH:19]=[O:20])=[CH:7]2.[CH3:21][Mg]Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH:19]([OH:20])[CH3:21])=[CH:7]2
Reactant: C[Mg]Cl
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C(C)O

Procedure:
Prepared according to Procedure K. To a mixture of 8-methyl-2-o-tolylquinoline-3-carbaldehyde (434 mg, 1.7 mmol) in THF (6 mL) at 0° C. was added dropwise a solution of MeMgCl (3M, 2 eq, 1.1 mL) and the reaction was stirred over night before quenched with NH4Cl saturated solution. The mixture was extracted with EtOAc (2×10 mL) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: EtOAc/hexane, 1/1) to provide 1-(8-methyl-2-o-tolylquinolin-3-yl)ethanol as a white solid. 1H-NMR (CDCl3) δ 8.34 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.19-7.27 (m, 4H), 2.69 (s, 3H), 2.08 (s, 3H), 1.30 (m, 3H). Mass Spectrum (ESI) m/e=278 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=[O:21].[OH-].[K+]>CO>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[NH:14][CH:15]=1)[OH:21]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: c1ccc(Oc2cnc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC(c1ccc(Cl)cc1Cl)c1c[nH]c2ncc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To [5-phenoxy-1H-pyrrolo[2,3-b]pyridine (P-0035, 80 mg, 0.38 mol) in methanol (2.0 mL), 2,4-dichloro-benzaldehyde (32, 133 mg, 0.76 mmol) and potassium hydroxide (74 mg, 1.3 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction mixture resulted in a precipitate, which was collected with vacuum filtration to provide the compound (33, 104 mg, 71%). MS (ESI) [M+H+]+=385.1 and 387.1.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]([NH:46][CH:47]1[CH2:50][N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:48]1)=[O:45]>O1CCOCC1>[C:16]([C:4]1[CH:3]=[C:2]([NH:42][CH2:43][C:44]([NH:46][CH:47]2[CH2:50][N:49]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:48]2)=[O:45])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=1)#[N:17]
Reactant: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cc(C#N)nc3ccc(C(F)(F)F)cc23)C1
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-(trifluoromethyl)quinoline-2-carbonitrile (2 g, 8.4 mmol) from above step D, in dry dioxane was added TEA (2.9 mL, 21 mmol) and PyBroP (4.75 g, 10 mmol) and stirred at 50 C for 2 hour. To this solution tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (2.9 g, 12.45 mmol) from example 1, step E, was added and stirred at room temperature for 48 h. The solution was concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The ethyl acetate was removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 80% EtOAc in hexane) to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[NH:3]1.Br[CH2:21][CH:22]([OH:25])[CH2:23][OH:24].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:5](=[O:7])[C:4]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[NH:3]1
Reactant: OCC(O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)N(CC(O)CO)C2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
A mixture of tert-butyl 2,4-dioxo-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (6.9 g, 25.6 mmol), 3-bromo-1,2-propanediol (4.4 g, 28 mmol), sodium iodide (1.5 g, 10 mmol), potassium carbonate (14 g) and DMF (25 mL) was stirred approximately 48 hours at 100° C. Additional 3-bromo-1,2-propanediol (1.5 g, 10 mmol) was added, and the stirring and heating continued for an additional 72 hours. After cooling, the mixture was filtered, the solvent removed from the filtrate under vacuum, and the residue was purified by chromatography eluting with ethyl acetate containing 0.5-1% acetic acid. The fractions containing the product were combined and concentrated, and the residue was treated with ethyl acetate to give tert-butyl 2,4-dioxo-3-(2,3-dihydroxypropyl)-1,3,8-triaza-8-spiro[4.5]decanecarboxylate (1.5 g, 4.4 mmol) as a white solid, m.p. 167°-170° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10]O)=[C:4]([O:12][CH3:13])[CH:3]=1.[BrH:14]>C(Cl)Cl>[Br:14][CH2:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[O:12][CH3:13]
Reactant: Br
Reactant: COc1cc(CO)c(OC)cc1Cl
Solvent: ClCCl
Product: COc1cc(CBr)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
(Bloomer et al., Tetrahedron Lett. 1989, 30, 1201-1204.) To a stirred solution of 2 (5.00 g, 24.7 mmol, 1 equiv) in CH2Cl2 (125 mL) at 0° C. was added dropwise HBr (47-49% solution; 4.13 mL, 74.0 mmol, 3 equiv). The resulting solution was allowed to slowly warm to room temperature and stir overnight (˜16 h). The following morning a second batch of HBr (47-49% solution; 4.13 mL, 74.0 mmol, 3 equiv) was added to the reaction mixture, which was allowed to stir for an additional 4 h. The crude mixture was extracted with Et2O (×2), washed with water, a saturated aqueous solution of NaHCO3, brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 6.55 g (100% yield) of 3 as a white solid: Mp 85-88° C.; Rf 0.31 (EtOAc/hexanes, 3:7); IR (neat) 2962, 2947, 2844, 1732, 1582, 1495, 1458, 1443, 1389, 1301, 1204, 1182, 1033, 882 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.91-6.90 (m, 2 H), 4.50 (s, 2 H), 3.84 (s, 3 H), 3.82 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 151.3, 148.9, 125.1, 123.2, 114.6, 113.6, 56.6, 56.2, 28.2.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)=O.CC(O)C.C([Li])CCC.CCCCCC.Cl[Si:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([Si:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
Dibenzo[b,d]furan (5.00 g, 29.7 mmol) was dissolved in THF (150 mL), and cooled in the CO2/i-PrOH bath. n-Butyllithium solution in hexane (2.5 M, 12.49 mL, 31.2 mmol) was added dropwise by syringe. After addition, it was stirred at room temperature for 2 hours, and cooled again in the CO2/i-PrOH bath. Chlorotriphenylsilane (8.77 g, 29.7 mmol) in ether (50 mL) was added dropwise into the reaction solution. The reaction was gradually warmed to room temperature and stirred overnight. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel with DCM/hexane (1/9, v/v) as eluent to yield dibenzo[b,d]furan-4-yltriphenylsilane (8.2 g, 65%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].Cl>C(OCC)(=O)C.O.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Oc1ccccc1)c1cc(Cl)c2ccccc2c1O
Temperature: 10 °C
Reaction time: 48 h

Procedure:
To a 500-mL, three-neck, nitrogen-purged flask was added 17.9 g (0.10 mole) of 4-chloro-1-naphthol, 100 mL of methylene chloride, 15 g (0.11 mole) of anhydrous aluminum chloride, and 15 mL (0.12 mole) of phenyl chloroformate. This mixture was heated to reflux. After 48 hours, the mixture was cooled to 10° C. and 200 mL of water and 15 mL of 37% hydrochloric acid were added. To this mixture was added 100 mL of ethyl acetate. The layers were separated and the organic layer was washed with two 100-mL portions of 5N hydrochloric acid. The organic layer was dried with anhydrous magnesium sulfate, filtered, then the solvent stripped off under vacuum. The resulting oil solidified and the crude product was recrystallized from isopropyl alcohol. The yield of phenyl 4-chloro-1-hydroxy-2-naphthoate (off-white, m.p. 102°-104° C.) obtained was 54%.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC.CC(C)=O.CCOCC>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][C:3]3[O:7][N:6]=[C:5]([C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)=[O:9])[CH:4]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(CBr)on1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(c1ccc(F)cc1)c1cc(CN2CCN(c3ccccc3)CC2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 115.6 %

Procedure:
A solution of 3.7 g of (5-bromomethylisoxazol-3-yl)-4-fluorophenylmethanone in 100 ml of Et2O was added dropwise to a solution of 5.2 g of N-phenylpiperazine in 400 ml of 20% acetone/Et2O. The resulting mixture was stirred at room temperature for 24 hours. This mixture was filtered and the solution was washed with water (2×200 ml) and saturated NaCl, and dried over MgSO4. Concentration of the product gave 5.5 g of a solid which was dissolved in 100 ml of CH2Cl2 and stirred with 5 g of SiO2. This mixture was filtered, the silica washed with CH2Cl2, and the organics were evaporated to give 3.7 g of a solid. The amine was recrystallized from 135 ml of 8% toluene/hexane to yield 2.5 g (53%) of needles, m.p. 94°-95°.