Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12](=O)[CH2:13]Br)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>COCCOC.C(O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]2[N:19]=[C:16]([CH3:17])[S:18][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)c1nc(N)sc1C(=O)CBr
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1nc(N)sc1-c1csc(C)n1
Yield: 64.8 %

Procedure:
A solution of ethyl 2-amino-5-(2-bromoacetyl)-4-thiazolecarboxylate (2.35 g) and thioacetamide (1.8 g) in a mixture of 1,2-dimethoxyethane (70 ml) and ethanol (70 ml) was refluxed for 7 hours and the reaction mixture was evaporated in vacuo. To the residue was added water, and the resulting mixture was adjusted to pH 8.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine, dried over magnesium sulfate, and evaported in vacuo. The residue was washed with diethyl ether and recrystallized from ethyl acetate to give ethyl 2-amino-5-(2-methyl-4-thiazolyl)-4-thiazolecarboxylate (1.4 g). mp 197°-199° C. (dec.)
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:30])[C@@H:5](/[CH:6]=[CH:7]\[C:8](=[O:10])[OH:9])[C@H:4]1[C:11]([O:13][CH:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12].C(O)(=O)C.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Ca+2]>C(Cl)Cl>[CH3:2][C:3]1([CH3:30])[C@@H:5](/[CH:6]=[CH:7]\[C:8](=[O:9])[O:10][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[C@H:4]1[C:11]([O:13][CH:14]([C:28]#[N:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]
Reactant: C1=COCCC1
Reactant: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A methanolic N hydrochloric acid solution was added dropwise at 15° C. with stirring to a mixture of 1.5 g of α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate solvated with one mole of acetic acid, 4.5 ml of dihydropyran and 10 ml of methylene chloride and the mixture was stirred at room temperature for 30 minutes. Calcium carbonate was added to the mixture which was then filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-ether mixture yielded 1.07 g of α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(tetrahydropyran-2-yloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47° (c=0.5% in benzene).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 0.20 g of 5'-O-acetyl-3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of dioxane were added 0.29 g of benzoyl chloride and 0.73 ml of triethylamine, and the mixture was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.2 g of the title compound as an oil in a yield of 78%.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 41 mg, 1.03 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (247 mg, 1.02 mmol) in THF (4 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (1.23 mmol, crude, prepared as in Example 69, step 4) in THF (3 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 30 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% →50% EtOAc/CH2Cl2, gradient) afforded 122 mg (31%) of the title compound.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O>C(OC(=O)C)(=O)C>[O:12]1[C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1=[O:10]
Reactant: O=C(O)CCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCCCC(=O)O1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of suberic acid (5.0 g, 28.7 mmol) in acetic anhydride (10 mL) was heated at reflux for 1 h. After cooling to RT, the solvent was removed in vacuo. The pale yellow residue was recrystallized from acetonitrile. After filtration and drying to the vacuum pump, the oxonane-2,9-dione was obtained as a white solid (2.26 g, 50.4% yield).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1.[Br:20][C:21]1[CH:22]=[C:23]2[C:29](I)=[N:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:29]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH:2]([F:1])[F:19])=[N:28][N:27]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:24]2=[N:25][CH:26]=1
Reactant: CC1(C)OB(c2ccccc2OC(F)F)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccccc2OC(F)F)c2cc(Br)cnc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
2-(2-difluoromethoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (208 mg, 0.77 mmol), 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (350 mg, 0.77 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (28 mg, 0.035 mmol) and aqueous solution of sodium carbonate (2 M, 0.77 mL) were suspended in anhydrous THF (7 mL) and acetonitrile (7 mL) under an atmosphere of nitrogen. The mixture was stirred at 60° C. for 12 h. The cooled mixture was applied to a Varian Chemelut cartridge and eluted with ethyl acetate. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 355 mg (0.75 mmol, 95%) of 5-bromo-3-(2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine as a white solid. MS: m/z 471 [MH+] which was directly used in the next step.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18](N1CCOCC1)=[O:19].Cl>C1COCC1.CC(OC)(C)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[O:19])=[CH:12][C:11]=1[F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=Cc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
25.9 g (1.07 mol) of magnesium turnings are initially introduced in 200 ml of THF, and a solution of 285.6 g (1.02 mol) of 1-benzyloxy-4-bromo-2-fluorobenzene in 700 ml of THF is added dropwise at such a rate that a gentle reflux is maintained after initiation of the Grignard reaction. When the addition is complete, the mixture is diluted with 1000 ml of THF, and the batch is heated at the boil for 1 h. The solution of the Grignard reagent is cooled to 0° C., and 118 ml (1.07 mol) of N-formylmorpholine in 100 ml of THF are added dropwise. After 1 h, the mixture is diluted with MTBE and hydrolysed using dilute hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with saturated sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is recrystallised from n-heptane:MTBE.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([N:15]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:17][C:16]2([CH3:28])[CH3:27])[N:3]=1.[CH2:29]([NH2:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:29]([NH:37][C:2]1[N:7]=[C:6]([N:8]([CH:9]([CH3:10])[CH3:11])[CH:12]([CH3:13])[CH3:14])[N:5]=[C:4]([N:15]2[C:16]([CH3:27])([CH3:28])[CH2:17][C:18]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:19][C:20]2([CH3:22])[CH3:21])[N:3]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCN
Reactant: CC(C)N(c1nc(Cl)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1)C(C)C
Solvent: O
Product: CCCCCCCCNc1nc(N(C(C)C)C(C)C)nc(N2C(C)(C)CC3(CC2(C)C)OCCO3)n1

Procedure:
15 g (36.4 mmol) of the product from Example 18 are heated to 120° for 3 hours together with 30 ml of octylamine. After cooling, 40 ml of water are added and the mixture is extracted three times using 30 ml of methylene chloride. The CH2Cl2 solution is washed with water, dried over Na2SO4 and evaporated. The oily residue is dissolved in hexane/acetone and purified chromatographically on an SiO2 column. The main fraction is a viscous material.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14](=[O:16])[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCCl>[CH2:9]1[C:8]2=[CH:7][C:1]3[C:6]([C:13]([C:14](=[O:16])[CH3:15])=[C:12]2[CH2:11][CH2:10]1)=[CH:5][CH:4]=[CH:3][CH:2]=3
Reactant: CC(=O)C#CCCC/C=C/c1ccccc1
Solvent: ClCCCl
Product: CC(=O)c1c2c(cc3ccccc13)CCC2
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
To a 0.5-2 mL microwave irradiation vial equipped with a stir bar was added enyne 5a (0.020 g, 0.094 mmol) in DCE (1.6 mL). The reaction was irradiated with stirring at 180° C. for 30 min until complete by TLC. The reaction turned golden in color. The reaction was then transferred to a vial, concentrated under reduced pressure, and dried under vacuum to yield naphthalene 6a as a black oil (0.020 g, quant.).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][OH:21])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl[C:23]([O:25][CH2:26][Cl:27])=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:23](=[O:24])([O:25][CH2:26][Cl:27])[O:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCCl
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a mixture of 2-(N-CBz-L-valyloxy)-ethanol (12.0 g, 40.6 mmol) and pyridine (19.7 mL, 0.24 mmol) in CH2Cl2 (300 mL) at 0° C., was added dropwise chloromethyl chloroformate (10.5 g, 81.2 mmol). After 30 min at 0° C., the reaction mixture was washed with H2O (200 mL). The H2O phase was washed with CH2Cl2 (100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was column chromatographed (silica gel, 0.5→1% MeOH in CH2Cl2), to give 8.26 g 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[OH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:20]=2)=[N:11][CH:10]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
5-Benzyloxy-2-(4-hydroxyphenyl)pyrimidine (2 g, 0.0072 moles, Example 30) was dissolved in 15 ml of N,N-dimethylformamide in a 50 ml flask and 0.2 g of dry sodium hydride was added. After stirring the mixture for 15 minutes, 1.39 g (0.0072 moles) of octylbromide was added and the mixture was heated to 100° C. for 2 hours. Upon cooling to room temperature, 15 ml of water was added. The resulting solid was collected by filtration and the solid was then slurried in boiling methanol, cooled to room temperature, and again collected by filtration. The solid was hydrogenated on a Parr Hydrogenator with catalytic 10% palladium on carbon in tetrahydrofuran under 413.7 kPa hydrogen pressure for about 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator to yield 1.62 g (75% yield) of 5-hydroxy-2-(4-(octyloxy)phenyl)pyrimidine.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22]Br.O>CN(C=O)C>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][O:4][CH2:3][C@@H:2]([NH:1][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]([OH:7])=[O:6]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
D-serine (25 g, 238 mmol) and triethylamine (35 mL, 250 mmol) were dissolved in water (400 mL), and Boc2O (50 g, 230 mmol) was added thereto and stirred at room temperature for 20 hours. The reaction mixture was washed with ethyl acetate (200 mL×2). The aqueous layer was acidified with 2 mol/L HCl to pH 2 and extracted with ethyl acetate (200 mL×5). The organic extract was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give Boc-D-Ser (44.4 g, 91%) as a colorless oil. Resulting Boc-D-Ser (44.4 g, 216 mmol) was dissolved in DMF (500 mL) and the mixture was cooled in an ice bath to 0° C. and then, NaH (18.4 g, 460 mmol) was added thereto in several portions. The mixture was stirred at 0° C. for 2 hours, and a solution of 3,5-bis(trifluoromethyl)benzyl bromide (42 mL, 230 mmol) in DMF (100 mL) was added dropwise thereto for a period of 30 min. After stirring at 0° C. for 2 hours and at room temperature for 20 hours, the reaction was stopped by adding water (1 L) thereto. The mixture was washed with hexane (250 mL×2) and acidified with 2 mol/L HCl to pH 2. After extracting with ethyl acetate (250 mL×4), the organic extract was washed with water and saturated brine in order and dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation under reduced pressure to give (2R)-3-(3,5-bis(trifluoromethyl)benzyloxy)-2-tert-butoxycarbonylaminopropionic acid (76.6 g, 82%) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:34])[C:15]([C:17]1[O:18][C:19]3[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=3[C:21]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])=[CH:7]2.Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][O:12][C:11]1[CH:10]=[CH:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([CH2:13][N:14]([CH3:34])[C:15]([C:17]3[O:18][C:19]4[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=4[C:21]=3[CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:16])[CH:7]=2)[C:2]=1[Br:1]
Reactant: COC(=O)CBr
Reactant: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2cc(CN(C)C(=O)c3oc4ccccc4c3CCc3ccccc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 3-phenylethyl-benzofuran-2-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide, prepared in step 4 of Example 45, methyl bromoacetate (260 μL, 2.75 mmol) and potassium carbonate (1.58 g, 11.96 mmol) in 25 mL of DMF was stirred under nitrogen at room temperature 16 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give (1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (1.29 g, 96%) as a light brown foam, MS m/z: 586 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:60]([CH3:62])[CH3:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:60]([CH3:62])[CH3:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (110 mg in 1.5 ml 33% methylene chloride in cyclohexane), isopropyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifiuoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compounds (15 mg 4"-ether; 16 mg 3"-ether).
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[C:1]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-naphtoic acid (commercially available) (15 g) in acetic acid (37 ml) was added dropwise bromine (4.5 ml). The reaction mixture was heated at reflux for 4 hours. The reaction mixture was then cooled to ambient temperature and stored at ambient temperature for 16 hours. The solids were isolated by filtration and washed with acetic acid and then ethanol to give 5-bromo-1-naphtoic acid (10.8 g) as a white solid. 1H-NMR (DMSO, 400 MHz): 8.85 (d, 1H), 8.40 (d, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.76 (m, 1H), 7.55 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:30][CH:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:27]([CH3:28])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:29]
Reactant: Cc1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C1CCNCC1)N1C(=NNC(=O)C1C)CO2
Yield: 97 %

Procedure:
A solution of 4-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.015 g, 0.036 mmol) in DCM (6 mL) and trifluoroacetic acid (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 4,7-dimethyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (0.015 g, 97%). LC/MS (Table 1, Method 5) Rt=1.939 min.; MS m/z: 315 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[CH:10]=3)[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[C:10]=3[F:50])[CH2:2][CH2:3]1
Reactant: CC(C)[Si](Oc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)cc1)(C(C)C)C(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2F)cc1)(C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (218 mg) in THF (2.5 mL) was added dropwise a THF solution (1.11 M, 0.59 mL) of lithiumdiisopropylamide at −78° C. under an argon atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added N-fluorobenzenesulfonimide (236 mg) at −78° C., and the mixture was stirred at 0° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (110 mg).