Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:30])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:38]1([CH2:41][NH:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH2:39]1>C(O)C>[CH:38]1([CH2:41][N:42]([CH2:43][CH2:44][CH3:45])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:30])=[O:9])[CH:3]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CCCNCC1CC1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of tert-butyl 3-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate (Intermediate 34, 140 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate which was used directly without any further purification. The residue was redissolved in DCM (4.5 ml) and treated with TFA (0.5 ml). After stirring at RT for 2 hours the solvent was removed in vacuo to give the title compound as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]([F:22])=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][NH:25][CH3:26]>>[F:22][C:15]1[CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]2[O:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:25]([O:24][CH3:23])[CH3:26])=[CH:4][CH:5]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Reactant: CNOC
Product: COC(=O)c1cc(F)cc2nc(-c3ccc(CN(C)OC)cc3)oc12
Yield: 84 %

Procedure:
Following the experimental procedure as described in Example 144 C, and replacing methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate with methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate and substituting dimethylamine with methoxy(methyl)amine, methyl 5-fluoro-2-(4-((methoxy(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (Yield: 84%. LC-MS (ESI) m/z: 345 (M+1)+) was made.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37]Br)=[CH:31][CH:30]=1>>[CH3:26][O:27][C:28](=[O:39])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:25])[CH3:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccc(F)cc2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 57 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one (296 mg, 0.809 mmol) was alkylated with 4-(3-bromo-propyl)-benzoic acid methyl ester (276 mg, 1.07 mmol) over 72 h. Purification by medium pressure chromatography (1:1 hexanes:EtOAc) provided 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (250 mg). 1H NMR (CDCl3) (selected peaks) δ7.92 (d, 2H), 7.21 (d, 2H), 7.05 (m, 2H), 6.92 (m, 2H), 3.86 (s, 3H), 3.76 (m, 1H), 3.62 (m, 1H), 3.45 (m, 1H), 0.81 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH2:18]1[CH:26]2[N:21]([CH2:22][CH2:23][C:24](=O)[CH2:25]2)[CH2:20][CH2:19]1>[OH-].[K+].O>[CH2:18]1[CH:26]2[N:21]([CH2:22][CH:23]=[C:24]([C:4]3[CH:5]=[C:6]([CH:17]=[C:2]([OH:1])[CH:3]=3)[CH2:7][N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)[CH2:25]2)[CH2:20][CH2:19]1
Reactant: Oc1cccc(Cn2ccc3ccccc32)c1
Reactant: O=C1CCN2CCCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1cc(Cn2ccc3ccccc32)cc(C2=CCN3CCCC3C2)c1

Procedure:
A mixture of 5-hydroxybenzyl-1H-indole (3.69 g, 16.5 mmol) and 7-octahydroindolizinone (2.98 g, 21.5 mmol) in methanolic potassium hydroxide (10% potassium hydroxide in methanol, 50 ml) was heated to reflux for 3.5 hours. The reaction was diluted with water and the precipitate was collected by filtration. The filter cake was triturated with hot diethyl ether and filtered. The filter cake was recrystallized from methanol and dried to give 1.45 g of tan flakes. (25.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:61][CH3:62])=[C:33]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[C:38](=[O:60])[NH:37][N:36]=2)[CH:34]=1>C1COCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:61][CH3:62])=[C:33]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([N:6]([CH2:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[O:2][CH3:1])[C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:47])=[O:46])=[CH:42][CH:43]=3)[C:38](=[O:60])[NH:37][N:36]=2)[CH:34]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (70.7 mg, 0.282 mmol) and THF (938 μl). The resulting solution was cooled to −78° C. for 10 min. Then lithium bis(trimethylsilyl)amide (1M in THF) (413 μl, 0.413 mmol) was added drop wise. The vial was removed from the cold bath temporarily to ensure complete deprotonation of PMB-aminothiadiazole. When the suspension became homogenous, the reaction was cooled back down to −78° C. Then perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (100 mg, 0.188 mmol) in 0.5 mL of THF was added drop wise. LCMS after 15 min showed complete conversion of SM to product. The reaction was warmed to rt, quenched with 1 mL of MeOH and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 33.7% yield) as white solid. m/z (ESI) 600.0 (M+H)+, 622.0 (M+Na)+. 1-(5-Chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (38 mg, 0.063 mmol) was dissolved in DCM (633 μl, 0.063 mmol) and then TFA (24.4 μl, 0.317 mmol) was added. After 30 min at rt, LCMS showed a complete conversion of SM to product. Purification was done with 0.1% NH4OH in ACN and water as mobile phase to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide (17 mg, 59.7% yield) and NH4OH as a triplet at ˜7.07 ppm. To remove NH4OH, the product was dissolved in MeOH (1 mL) and loaded onto a 2 g SCX column. The product was flushed out with MeOH. Concentration afforded 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydrophthalazine-6-sulfonamide as white solid. m/z (ESI) 450.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[H-].[Na+].C[O:15][CH2:16][CH2:17]OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH2:17][C:16](=[O:15])[N:8]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOC
Reactant: COc1cccc(C(N)=O)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(C2=NC(=O)CO2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
2 g (1 eq) of 3-methoxybenzamide was mixed with 3.1 ml (2.7 eq) of chloroacethylchloride and the resulting mixture was heated at 110° C. for 1 h. After cooling, the resulting solid was recrystallized in CHCl3. The resulting solid was added to a suspension of NaH (489 mg, 1.1 eq) in DME at 0° C. After 30 min, the resulting mixture was refluxed for 5 h, cooled to RT and hydrolyzed, extracted with AcOEt, washed with NaCl salt and dried. The resulting solid was recrystallized in a mixture hexane/AcOEt giving 16 as a white solid in 26% yield.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:31])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[N:23]=[C:17]3[N:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:31])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:27]=[CH:28][CH:29]=4)[N:23]=[C:17]3[N:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(Br)c3)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(-c4ccccc4)c3)nc2n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of argon, in a 25 mL round-bottomed flask, 4-(azetidine-1-carbonyl)-N-(2-(3-bromophenyl)imidazo[1,2-a]pyrimidin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (85 mg, 177 μmol, Eq: 1.00, example 117), phenylboronic acid (43.2 mg, 354 μmol, Eq: 2), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (14.5 mg, 17.7 μmol, Eq: 0.1) and potassium carbonate (73.4 mg, 531 μmol, Eq: 3) were combined with DMF (2 ml) and water (0.2 ml) to give a brown solution. The reaction was stirred for 1 h at 100° C. The HPLC-MS showed complete conversion. The reaction mixture was poured into 20 mL water and extracted with EtOAc (2×25 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. After the addition of 2 ml Methanol the desired product crystallized. The suspension was filtered off and washed with 0.5 ml MeOH. The residual solvent was removed under vacuum. The title compound was obtained as a light brown solid (42 mg, 49.7%). 4-(Azetidine-1-carbonyl)-N-(2-(3-bromophenyl)imidazo[1,2-a]pyrimidin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide was prepared in analogy to example 29, using 2-(3-bromo-phenyl)-imidazo[1,2-a]pyrimidin-7-ylamine in the first step. 2-(3-Bromo-phenyl)-imidazo[1,2-a]pyrimidin-7-ylamine can be prepared in analogy to example 1, step 1, from 2-bromo-1-(3-bromo-phenyl)-ethanone.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH2:5][CH2:4][CH:3]=[CH:2]1.F>C(#N)C>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1C=CCC1
Agent: F
Solvent: CC#N
Product: OCCCCC1C=CCC1

Procedure:
The procedure followed is the same as that described in Example 23 substituting 3-(5-[(1,1-dimethylethyl)dimethylsiloxyl]but-1-yl)cyclopentene {[4-(2-cyclopenten-1-yl)butoxy](1,1-dimethylethyl)dimethylsilane} (100 g, 0.407 moles), 5% hydrofluoric acid (78 ml), and acetonitrile (1500 ml). The crude product is kugelrohred under reduced pressure leaving a clear, colorless oil (51 g, 0.36 moles).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOCC.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>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)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: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(-c2cncc(Br)c2)cc1
Temperature: 150 °C
Yield: 9.3 %

Procedure:
3,5-Dibromopyridine (4.4 mmol), 4-trifluoromethoxyphenyl boronic acid (5.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 mmol), 2 M potassium carbonate (8.44 mmol) and dioxane (21 mL) were combined in a vial and heated by microwave for 10 min at 150° C. The reaction mixture was taken up in ether and washed with brine. The ether layer was dried over magnesium sulfate, was filtered and the solvent removed in vacuo. The crude mixture was purified by silica gel chromatography to yield 130 mg of 3-bromo-5-(4-trifluoromethoxy-phenyl)-pyridine as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.71 (m, 2H), 8.00 (t, J=2.1 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H); EIMS 317 m/z (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][C:7](=[O:14])[CH2:6]1)=[O:4].[CH2:15](O)[CH2:16][OH:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:15]1[CH2:16][O:17][CH:6]2[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH:7]2[O:14]1
Reactant: OCCO
Reactant: COC(=O)C1CC(=O)CC1C(=O)OC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1CC2OCCOC2C1C(=O)OC
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
In 250 ml of dichloromethane were dissolved 124 g of 3,4-dimethoxycarbonylcyclopentanone and 155 g of ethylene glycol and to the solution was added dropwise 94 g of boron trifluoride ethyl etherate at 0° - 5°C. After completion of the addition, the reaction mixture was stirred for 2 hours at 10° - 16°C and next for 1.5 hours at 16° - 23°C. After completion of the reaction, the reaction mixture was added dropwise to 1.5l of a saturated aqueous sodium bicarbonate containing pieces of ice in order to decompose the excess of the boron trifluoride etherate. The mixture was extracted three times with 1 l of ether. The extract was washed with a saturated aqueous sodium chloride and a saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract to give 135.7 g of the desired product as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:8]([CH3:15])=[C:9]2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C)C=O>O1CCCC1>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:7]1[C:8]([CH3:15])=[C:9]([C:12]([Cl:24])=[O:13])[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)O)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)Cl)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carboxylic acid (500 mg, 1.81 mmol) in anhydrous tetrahydrofuran (10 mL), was added oxalyl chloride (250 μL) and N,N-dimethylformamide (30 μL). The resulting mixture was stirred at 60° C. for 2 hours, and concentrated in vacuo to afford (4-chlorocarbonyl-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (526 mg, 99%) as a light yellow solid, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]([CH:9]=[O:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:11]=[N+:12]=[N-:13].[Na+]>C(COC)OC.O>[N:11]([C:2]([CH:9]=[O:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(C)(Br)C=O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)(C=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl α-bromo-α-formylpropionate (20 g.) in dimethoxyethane (200 ml.) is added a solution of sodium azide (8 g.) in water (40 ml.) and the mixture is stirred at room temperature for 5 hours. The dimethoxy ethane is removed under reduced pressure and the residue is taken up in a mixture of ether and water. The ethereal phase is separated, washed with water, dried over anhydrous sodium sulfate and evaporated yielding ethyl α-azido-α-formylpropionate which is purified by vacuum distillation.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[CH:6]2.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: COc1ccc2c(cnn2C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(O)ccc21
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a solution of (2t) (0.99 g, 6.1 mmol) in toluene (30 mL) was added AlCl3 (2.44 g, 18.3 mmol) at room temperature, upon which a purple colored mixture formed. After refluxing for 20 minutes, an olive colored mixture formed. The mixture was refluxed for 2 hours, allowed to cool to room temperature and poured into an ice-water bath. The insoluble solids were collected by filtration (398 mg). The filtrate was extracted with DCM, filtered through 1PS paper, evaporated in vacuo and purified on the Biotage eluting with (1:9) then (3:7) Et2O/DCM and finally (1:1) DCM/Et2O. The product fractions were evaporated in vacuo affording compound (3t) as a brown foam (122 mg). Total combined yield, 520 mg (58%). 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H); MS (ESI+) m/z 149 (M+H) detected.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[F:9][C:10]([F:40])([F:39])[C:11]1[CH:12]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=C)[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=[O:5])[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:12]=[C:11]([C:10]([F:39])([F:40])[F:9])[CH:16]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
N-Methylmorpholine N-oxide (1 g, 8.6 mmol) and osmium tetroxide (2 ml, 2.5% solution in tert-butanol) were added to a solution of (2R,3R,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran (see Example 147 in WO 00/56727; 2 g, 4.3 mmol) in tetrahydrofuran (25 ml) and water (10 ml). The mixture was stirred at room temperature for one hour before sodium periodate (9 g, 43 mmol) was added. This mixture was stirred for 45 minutes and then filtered through Celite™. The filtrate was diluted with ethyl acetate (50 ml) and washed with brine. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/iso-hexanes to give the title compound (1.6 g, 80%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]3[C:20]4[C:25]([CH:26]=[CH:27][C:12]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:8]=[CH:9][CH:10]=1)=[NH:4].C1CCN2C(=NCCC2)CC1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[S:40].Cl>C(#N)C>[S:40]=[C:39]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([N:11]3[C:17](=[O:18])[CH2:16][C:15](=[O:19])[NH:14][C:13]4[C:20]5[C:25]([CH:26]=[CH:27][C:12]3=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:8]=[CH:9][CH:10]=2)[NH:4]1
Reactant: N=C(NO)c1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CC(=O)N(c2cccc(-c3noc(=S)[nH]3)c2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.6 %

Procedure:
To an ice-cold solution of 5-[3-(N-hydroxyamidino)phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (310 mg, 0.94 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (561 □L, 3.75 mmol) in acetonitrile (5.7 mL) was added dropwise, a solution of thiocarbonyldiimidazole (251 mg, 1.41 mmol) in acetonitrile (6 mL). The mixture was stirred at room temperature for 1.5 hours, to which was added 1M hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-0/1), to give the titled compound (161 mg, yield 41%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:6][CH:7]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Yield: 88 %

Procedure:
Using N-(3-(4-bromophenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 254, the title compound was synthesized in the same manner as in Example 271. Yield: 88%. Melting point: 171-172° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]([CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])[CH:26]=[CH:25][N:24]=2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Product: CC1(C)Oc2ccc(C#N)cc2C(n2ccnc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:25])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:4]1([CH2:1][C:2](=[O:25])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH3:18]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CC)CCc2cc(OC)ccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: CCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-allyl-2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (931 mg, 3.82 mmol) in acetonitrile (11 mL) was treated with benzoquinone (619 mg, 5.73 mmol), palladium(II) acetate (172 mg, 0.76 mmol), water (0.56 mL, 31 mmol), and perchloric acid (70%, 0.15 mL, 1.74 mmol). The resulting mixture was stirred overnight at room temperature, then filtered through a small plug of silica gel. The filtrate was diluted with CH2Cl2, washed with water, and the aqueous phase was back-extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to afford crude 2-ethyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone as an orange oil.