Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)n1ncc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ncc2c(N)cccc21
Yield: 96.9 %

Procedure:
1,1-Dimethylethyl 4-nitro-1H-indazole-1-carboxylate (1.2 g) was dissolved in ethanol (150 ml) and stirred with 10% palladium on carbon (0.24 g) under an atmosphere of hydrogen (1 atmosphere pressure) for 18 h. The solution was filtered through a pad of celite and the filtrate concentrated in vacuo to give the title compound as a yellow-orange solid (1.03 g).
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:21][OH:22])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O>CN(C)C=O.CC(C)=O.O.CC(O)C>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:21]([OH:24])=[O:22])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(CO)cccc1OC
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: C=CCOP(=O)(OCC=C)OCc1c(OC)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
Diallyl 2-(hydroxymethyl)-6-methoxybenzyl phosphate (715.0 mg, 2.18 mmol) obtained from Example 21-(4) was dissolved in N,N-dimethylformamide (8 ml), and pyridinium dichromate (2.87 g, 7.63 mmol) was added thereto. After the mixture was stirred at room temperature for 12 hours, water (60 ml) was added thereto, and the product was extracted with diethyl ether. The organic layer was washed successively with water, a 2N aqueous solution of hydrochloric acid, and a saturated aqueous solution of sodium chloride, and then the solvent was distilled off under reduced pressure to give an oily residue. The residue was dissolved in acetone (5 ml), and Jones reagent (a mixture of chromic anhydride (5.34 g, 4 mmol) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 1.5 ml) was added thereto. The reaction mixture was stirred at room temperature for 1.5 hours, and then 2-propanol (1 ml) was added thereto to stop the reaction. The solid insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give an oily residue. The residue was dried using a vaccum pump, and then subjected to chromatography on a silica gel (25 g) column (eluent; ethyl acetate:dichloromethane=1:1) to afford the title compound (447.0 mg, 60% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](OC(OCC)OCC)C>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:17]=[N:16][N:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1OCc1ccccc1
Reactant: CCOC(OCC)OCC
Product: c1ccc(COc2cccn3cnnc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A flask was charged with 3-(benzyloxy)-2-hydrazinylpyridine (10.0 g, 46.5 mmol) and triethoxymethane (77.3 ml, 465 mmol). The mixture was heated at reflux for 1 hour and then stirred overnight at ambient temperature. The solids were filtered and rinsed with EtOH and dried on high vacuum to afford 8-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine (8.05 g, 35.7 mmol, 76% yield).
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CO>[C:22]([NH:26][CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[N:18]=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC2CO2)c1
Solvent: CO
Product: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Reaction time: 24 h
Yield: 71.5 %

Procedure:
A solution of 6-[2-(2,3-epoxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine (0.7 g, 0.0024 mole), t-butylamine (10.0 ml, 0.093 mole) in methanol (20 ml) was allowed to stand at room temperature for 24 hours. Evaporation of the solvent and crystallisation of the residue from ethyl acetate gave 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine (0.62 g, 70%, m.p. 114°-116°).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]3[CH2:25][CH2:24][C:23](=O)[C:21]3=2)[O:16][CH2:15]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]3[CH2:25][CH2:24][C:23](=[CH:5][C:3]#[N:4])[C:21]3=2)[O:16][CH2:15]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCc2cnc3c(c21)CCO3
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCc2cnc3c(c21)CCO3
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a suspension of 60% sodium hydride (137 mg, 3.42 mmol) in tetrahydrofuran (15 mL) was added diethyl cyanomethylphosphonate (600 μL, 3.71 mmol) under ice-cooling, and the mixture was stirred for 15 min. A solution of 1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-one (500 mg, 2.85 mmol) in tetrahydrofuran (15 mL) was added thereto, and the mixture was further stirred for 15 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (514 mg, yield 91%).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C(Br)Br.[CH:16]12CC(CC1)C=[CH:17]2>C1(C)C=CC=CC=1>[CH:10]1[C:9]2[NH:8][C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]=2[CH:16]=[CH:12][CH:11]=1
Reactant: c1ccc(-c2ccccn2)nc1
Reactant: C1=CC2CCC1C2
Solvent: BrCBr
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1ccccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To an ampoule, Cu(I)Br (1 mmol), 2,2′-bipyridine (1 mmol), norbornene methylene bromide (NBMBr) (1 mmol) and styrene(St) (100 mmol) were added in 10 mL toluene. The heterogeneous mixture was placed under vacuum and then degassed via a freeze-pump-thaw cycle thrice. After degassing, the reaction mixture in ampoule was stirred at 100° C. for 12 hrs. The macromonomer containing polystyrene segments (NBMPStBr) was precipitated from methanol. Polymer was dissolved in THF and reprecipitated from methanol three times. Number average molecular weight of (NBMPStBr) is 160000 and PDI is 1.28 (by GPC).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH:20]([C:22]2[S:26][C:25]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)[OH:21])([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]([C:22]2[S:26][C:25]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=2)=[O:21])([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC2CCOCC2)(C(O)c2cc3cccc(F)c3s2)C1
Agent: O=[Mn]=O
Product: CC(C)(C)OC(=O)N1CCC(CC2CCOCC2)(C(=O)c2cc3cccc(F)c3s2)C1

Procedure:
3-(7-Fluoro-benzo[b]thiophene-2-carbonyl)-3-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 3-[(7-fluoro-benzo[b]thiophen-2-yl)-hydroxy-methyl]-3-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester by oxidation with MnO2 using the procedure of step 3 of Example 18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][N:29](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O.SCC(O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:44])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCN(S(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)n2cc1-c1ccc(Cl)cc1Cl
Agent: O=C(O)CS
Agent: O=C([O-])O
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCNCC3)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of {6-(2,4-dichloro-phenyl)-3-[4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-imidazo[1,2-a]pyridin-7-ylmethyl}-carbamic acid tert-butyl ester (2.9 g, 4.38 mmol, prepared following the procedure described for Example 6, Step 3.3 using the adequate cyclisation reagent), LiOH.H2O (1.11 g, 26.3 mmol) and mercaptoacetic acid (0.94 mL, 13.2 mmol) in DMF (20 mL) was stirred at RT for 30 min then poured into a saturated aqueous NaHCO3 solution (200 mL) and extracted with AcOEt (4×200 mL). The combined organic fractions were washed with brine (100 mL), dried over Na2SO4, filtered and evaporated to dryness. The remaining residue was purified by Combi-Flash CompanionT™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/[DCM/MeOH—NH3 9:1]95:5→100% [DCM/MeOH—NH3 9:1]) to yield the title compound (1.61 g, 3.38 mmol, 77%) as a yellow foam. MS: 477 [M+1]+; HPLC: AtRet=1.45; TLC: RF 0.33 (DCM/MeOH—NH3 9:1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].[N+]([C:14]1[CH:19]=CC=C[CH:15]=1)([O-])=O.B(O)(O)O.S(=O)(=O)(O)O>OCC(CO)O>[Cl:10][C:4]1[CH:5]=[C:6]([OH:9])[CH:7]=[C:8]2[C:3]=1[N:2]=[CH:19][CH:14]=[CH:15]2
Reactant: Nc1ccc(O)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: OCC(O)CO
Product: Oc1cc(Cl)c2ncccc2c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
In a 500 ml 3-necked flask equipped with a mechanical stirrer, a reflux condenser, were added in order ferrous sulfate (2.0 g), 4-amino-3-chlorophenol hydrochloride (6.4 g, commercially available), nitrobenzene (2.9 mL) and a solution of boric acid (3.0 g) in glycerol (16 g). Then concentrated sulfuric acid (9 mL) was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120° C. for 2 hours, then at 150° C. and kept stirring under this temperature for 20 hours. After cooling, the reaction was poured on crushed ice and the resulting solution was neutralized with K2CO3. The product separated as a light brown solid that was filtered off, washed with water and hexanes and dried in a vacuum oven (35° C.) overnight giving 7 g (77%) of the desired product. MS (ES) m/z (relative intensity): 180 (M++−H, 100).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[N:8]([CH3:33])[CH:7]=1)=[O:5])C.[OH-].[K+].[CH2:36](O)C>>[CH3:32][O:31][C:19]1[CH:20]=[C:21]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)[CH:22]=[CH:23][C:18]=1[NH:17][C:13]1[N:12]=[C:11]([C:9]2[N:8]([CH2:33][CH3:36])[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)cc1-c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2OC)n1
Yield: 100 %

Procedure:
5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (160 mg, 0.355 mmol) was suspended in ethanol (13 mL) and treated with a 1.5 M solution of potassium hydroxide in ethanol (2.4 mL, 10 eq.) at reflux temperature for 3 hour. Solvent was evaporated to dryness and the residue dissolved in water. After treatment with acetic acid and the resulting precipitate was collected by filtration to give the title compound (150 mg, 100% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:15][CH3:16])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:15][CH3:16])[C:10]([NH:19][NH2:20])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(OC)c1ccc(N(C)C)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(C(=O)NN)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 38.8 %

Procedure:
To a solution of ethyl 2-(4-(dimethylamino)phenyl)-2-methoxyacetate (0.675 g, 2.84 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (0.8 mL, 16.4 mmol) and the mixture was heated at reflux for 22 hours. Additional hydrazine hydrate (1.0 mL, 20.6 mmol) was added and the heating continued for 7 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The solid product was stirred with hot diethyl ether then hexanes were added. After cooling to room temperature, the solids were collected on a Büchner funnel and rinsed with 50% diethyl ether-hexanes then dried under vacuum to give 2-(4-(dimethylamino)phenyl)-2-methoxyacetohydrazide as an orange solid (0.246 g). Additional product was isolated from the mother liquor by chromatography (80-100% EtOAc-hexanes, then 5% methanol-EtOAc) to give an off-white solid (0.173 g, 66% yield total).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[CH:18]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH2:25][C:24](=[O:33])[NH:23][C:22]=2[N:21]=[CH:20][CH:19]=1.O>CN(C)C=O.[I-].[Na+].C(OCC)(=O)C>[Si:11]([O:10][CH2:9][CH2:8][N:23]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:28]=2[C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[CH2:25][C:24]1=[O:33])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C1Cc2ccccc2-c2cccnc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 102.8 %

Procedure:
Add cesium carbonate (186.6 g, 572.7 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (88.0 mL, 409.1 mmol), and sodium iodide (6.1 g, 40.9 mmol) to a suspension of 5,7-dihydropyrido[2,3-d][3]benzazepin-6-one (86.0 g, 409.1 mmol) in dimethylformamide (860 mL) and stir at 70° C. for 20 hours. Cool mixture to ambient temperature, pour over ice and water (100 mL), add ethyl acetate (200 mL). Filter mixture through Celite®, then wash with ethyl acetate (100 mL). Separate layers of filtrate, extract from aqueous with ethyl acetate (2×50 mL). Wash combined organics with water (2×100 mL), brine (100 mL), dry over sodium sulfate and concentrate. Dissolve material in tetrahydrofuran (1.28 L), add Silia® bond palladium scavenger (16.7 g) and stir at ambient temperature for 20 hours. Filter through a pad of silica, wash with tetrahydrofuran (200 mL) and concentrate to obtain the title compound (155 g, 420.6 mmol) as a light brown oil that crystallizes in quantitative yield. MS (m/z): 369 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]([O:21]CC)=[O:20])[C:10]2=[O:24])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([C:19]([OH:21])=[O:20])[C:10]2=[O:24])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2cccnc2n(-c2ccc(OC)nc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-n2c(=O)c(C(=O)O)cc3cccnc32)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.5 %

Procedure:
4.1 g (13 mmol) of ethyl (6-methoxy-3-pyridinyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (60 mL), and 2.6 g (19 mmol) of potassium carbonate and 100 mL of water were added thereto at room temperature. The resulting mixture was stirred for 3 hours at 60° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was dissolved in water and washed with chloroform. Concentrated hydrochloric acid was added to the aqueous phase to make the aqueous phase acidic, and the mixture was extracted with chloroform. The organic phase was dried and concentrated. Thus, 1.45 g of the title compound was obtained as colorless crystals (yield: 39%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N1C=CN=C1.[CH3:19][CH:20]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21]>CN(C=O)C.CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:19])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: OCc1cc(Br)cc2ccccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(Br)cc2ccccc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of (3-bromonaphthalen-1-yl)methanol in DMF (100 mL) was added imidazole (6.4 g, 93 mmol), DMAP (0.57 g, 4.7 mmol), and TIPSCl (15 mL, 70 mmol). The resulting solution was stirred at room temperature for 12 h, diluted with a saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with water then brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (3-10% EtOAc/hexanes) to yield the title compound (17.9 g, 96%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-bromo-benzylamine (0.8 g, 2.807 mmol) in anhydrous DME (12 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol), pyridine-4-boronic acid (0.513 g, 4.211 mmol), and a 2M aqueous Na2CO3 solution (2.8 mL, 5.614 mmol). Heat the reaction overnight at 70° C. Cool the mixture to ambient temperature, dilute with EtOAc, and filter over Celite®. Wash the organic fraction with water, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give the title compound as an oil (0.295 g, 37%). GC-MS m/z: 284 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)NCC(OC)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of (3-methoxy-phenyl)-acetyl chloride (40 g, 0.22 mol) in chloroform (100 mL) was added dropwise to a solution of 2,2-dimethoxy-ethylamine (25 mL, 0.23 mol) and triethylamine (34 mL, 1.1 eq) in chloroform (400 mL) at 0° C., and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water, aqueous 1N HCl, and then again with water, dried (MgSO4), filtered and concentrated to provide N-(2,2-dimethoxy-ethyl)-2-(3-methoxy-phenyl)-acetamide (53.8 g, 98%). 1H-NMR (CDCl3) δ 7.27 (t, J=8.8 Hz, 1H), 6.84 (s, 1H), 6.81 (d, J=8.8 Hz, 2H), 5.66 (br s, 1H), 4.31 (t, J=5.2 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 2H), 3.35 (t, J=5.2 Hz, 2H), 3.33 (s, 6H); LC/MS (ESI+): 222.15 [(M-MeOH)+H].
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10]3([CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13][CH2:12]3)[O:9][C:8]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([N:7]2[CH2:11][C:10]3([CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[O:9][C:8]2=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CN(c1ccccc1)C(=O)O2
Agent: [Pd]
Solvent: CCO
Product: O=C1OC2(CCNCC2)CN1c1ccccc1
Reaction time: 6 h
Yield: 113.7 %

Procedure:
A mixture of 3.4 g 3-phenyl-8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 50 ml ethanol and 0.4 g, 10% palladium on carbon is hydrogenated at room temperature and 60 psi for 6 hours. Filtration and removal of solvent affords 2.45 g 3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, a pasty solid; m/e=232 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][CH2:34][OH:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[F-].[K+].[CH3:38][CH2:39]N(CC)CC>CN(C=O)C.CO>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:38]#[CH:39])[CH:3]=[CH:4][C:5]=3[O:32][CH2:33][CH2:34][OH:35])[C:21]2=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2OCCO)N1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.11 mmol) prepared in example 181b in DMF (2 mL), Et3N (0.3 mL), PdCl2(Ph3P)2 (Aldrich, 15 mg) were added and the mixture was purged with nitrogen and sealed. The vessel was heated on a microwave reactor for 25 min. and the mixture was poured into water. The mixture was extracted with EtOAc. The extracts were combined and dried with sodium sulfate and dried to give a brown oil, which was purified by chromatography on an ISCO machine (30-100% EtOAc/Hexanes) to give a foam. 45 mg. The foam was then dissolved in methanol (4 mL) and KF (Aldrich, 53 mg) was added. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partioned between EtOAc/water. The organic layer was dried and concentrated and the residue was purified by chromatography on ISCO machine (30-100% EtOAc/Hexane) to give an off-white solid. 25 mg.