Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([Br:4])(Br)[Br:2].[N:5]1([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>N1C=CC=CC=1>[Br:2][P:1]([Br:4])[C:15]1[CH:14]=[N:13][CH:12]=[CH:11][C:10]=1[N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: c1cc(N2CCCC2)ccn1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Product: BrP(Br)c1cnccc1N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of PBr3 (8.8 g, 32.5 mm) in 100 mL of pyridine was treated with 4-pyrrolidinopyridine (5.0 g, 33.7 mm) over a period of 5 min. The resulting mixture was then stirred at room temperature for 3 days to give the crude 3-dibromophosphino-4-pyrrolidinopyridine (31P NMR: δ152.2 ppm). This compound was used directly for the next step without further purification. Next, polymer-supported secondary amines from Example 1 (9.0 g, 1.1 mmol/g, 9.9 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was refluxed overnight before the solution was filtered off. The resin was washed with THF (2×50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported 3-P(Br)-4-(NC4H8)C5H3N. 31P NMR (202 MHz, CDCl3): δ168.4 ppm.
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>>[N+:22]([C:25]1[CH:30]=[C:29]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12]([C:14]4[S:15][C:16]([CH3:19])=[CH:17][CH:18]=4)=[O:13])=[N:7][C:6]=3[C:5]([O:20][CH3:21])=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2cccc([N+](=O)[O-])c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 42 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [7-(3-nitro-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (155 mg, 0.36 mmol) and 3-nitrophenylboronic acid (135 mg, 0.81 mmol) using the general procedure A as a light yellow crystalls in 42% yield. MS: m/e=425 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[C:7](C(C)(C)C)[CH:6]=[C:5](C(C)(C)C)[C:3]=1[OH:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(Cl)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Oc1cccc(O)c1Cl
Temperature: 210 °C
Yield: 91 %

Procedure:
A mixture of 2-chloro-4,6-di-tert-butylresorcinol (25.7 g, 100 mmol, prepared as described in Example 1A) and p-toluenesulfonic acid monohydrate (0.2 g, 1 mmol) is added to a flask--which is equipped with a gas withdrawing port leading to a dry ice cooled trap--heated at 210° C. for 2 hours, then allowed to cool. Recrystallization from toluene affords pure 2-chlororesorcinol (13.2-13.9 g, 91-96% yield). The yield of recovered isobutylene is >95%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(C#Cc2ccncc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C(#Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1

Procedure:
A mixture of 4-(2-(pyridin-4-yl)ethynyl)phenol (335 mg, 1.72 mmol), 2-(chloromethyl)quinoline hydrochloride (385 mg, 1.8 mmol), and cesium carbonate (2.2 g, 6.87 mmol) was stirred in dimethylformamide (8 mL) at 65° C. for 3 h. Water (20 mL) was added and the mixture was extracted with dichloromethane (3×15 mL). The organic layers were dried, concentrated, and the residue chromatographed on silica eluted with a gradient of 10% to 80% ethyl acetate-hexanes giving 450 mg (78%) of a yellow solid. 1H NMR (CDCl3, 400 mHz) δ 8.56 (m, 2H), 8.20 (d, 1H, J=8.7 Hz), 8.08 (d, 1H, J=8.3 Hz), 7.82 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H, J=8.4, 7, 1 Hz), 7.63 (d, 1H, J=8.7 Hz), 7.55 (ddd, 1H, J=8, 7, 1 Hz), 7.47 (m, 2H), 7.35 (m, 2H), 7.01 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 337 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:7])=[CH:4][C:3]=1[O:16][CH3:17].N1C=CC=CC=1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>ClCCCl.CN(C=O)C>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[O:7])=[CH:4][C:3]=1[O:16][CH3:17])=[O:28]
Reactant: COc1cc(C(=O)Nc2nccs2)ccc1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COc1cc(C(=O)Nc2nccs2)ccc1NC(=O)CC(C)(C)C
Reaction time: 2 h

Procedure:
To 200 μL of a 0.2 M stock solution of 4-amino-3-methoxy-N-thiazol-2-yl-benzamide in 1,2-dichloroethane/DMF, containing 1.2 mmol pyridine per mmol 4-amino-3-methoxy-N-thiazol-2-yl-benzamide, was added 0.05 mmol of 3,3-dimethyl-butyric acid chloride. The reaction mixture was incubated at ambient temperature for 2 h. Purification was performed by preparative HPLC-MS.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[OH:19])=[C:6]([CH:11]=1)[C:7](OC)=[O:8]>N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[C:12]3[C:13](=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[O:19][C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(N)cc(C)c1-c1ccc(F)cc1O
Solvent: c1ccncc1
Product: Cc1cc(N)cc2c(=O)oc3cc(F)ccc3c12
Yield: 94 %

Procedure:
Methyl 5-amino-2-(4-fluoro-2-hydroxyphenyl)-3-methylbenzoate (Reference Compound No. 1-4-(5), 7.40 g, 26.9 mmol) was dissolved in pyridine (250 mL) and then the reaction mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, then ethyl acetate-hexane (1:1) was added to the obtained residue, and then filtered to give the titled reference compound (6.15 g) as a pale yellow solid. (Yield 94%)
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(CNc2ncns2)c(OC)c1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
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: CN(C)/[CH:3]=[CH:4]/[C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=1[N+:14]([O-])=O.C(O)(=O)C>O1CCCC1.[Pd]>[S:9]1[C:5]2[CH:4]=[CH:3][NH:14][C:6]=2[CH:7]=[C:8]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc2[nH]ccc2s1
Yield: 84.9 %

Procedure:
A solution of methyl (E)-5-(2-dimethylaminovinyl)-4-nitrothiophene-2-carboxylate (20 g, 78 mmol), 5% palladium/carbon (2 g) and acetic acid (20 ml) in tetrahydrofuran (300 ml) was stirred under hydrogen atmosphere (3.5 atm) at room temperature for 16 hr. The reaction mixture was filtered through celite and concentrated under reduced pressure. Diethyl ether (300 ml) was added to the residue. The mixture was washed successively with 1N hydrochloric acid (100 ml×2), water (100 ml), saturated aqueous sodium hydrogen carbonate solution (100 ml×2) and saturated brine (100 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave methyl 4H-thieno[3,2-b]pyrrole-2-carboxylate (12 g, yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].C([Mg]Cl)(C)C.CN([CH:27]=[O:28])C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:27]=[O:28])[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(Br)n1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester (0.25 g, 0.74 mmol) (as prepared in the previous step) in THF (3 mL) at −40° C. was added dropwise a solution of 2M i-PrMgCl in THF (0.37 mL, 0.74 mmol). The reaction was allowed to stir for 10 min at −40° C. and then cooled to −78° C. and DMF (0.3 mL) was added. The reaction was allowed to attain RT and stirred for 1 h. The reaction was quenched with saturated NH4Cl, diluted with EtOAc (10 mL) and washed with brine (2×10 mL) and the organic layer was concentrated. The title compound was eluted from a 10-g SPE cartridge (silica) with 50% EtOAc/hexane to give 0.11 g (53%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H20N2O4Si, 285.1 (M+H), found 284.7.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2=[N:26][N:27]=[C:28]([C:29]3[CH:33]=[C:32]([CH3:34])[O:31][N:30]=3)[N:18]2[N:17]=1>>[CH3:34][C:32]1[O:31][N:30]=[C:29]([C:28]2[N:18]3[N:17]=[C:16]([O:14][CH2:13][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[N:12]=4)[C:25]4[C:20]([C:19]3=[N:26][N:27]=2)=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:33]=1
Reactant: OCc1cccc(N2CCOCC2)n1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cccc(N5CCOCC5)n4)nn23)no1

Procedure:
The reaction was carried out according to Example 1 step 4 using (6-(morpholin-4-yl)pyridin-2-yl)methanol (96 mg, 0.49 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (141 mg, 0.49 mmol). The crude residue was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 to yield, after recrystallisation from CH2Cl2/iso-hexanes, the desired phthalazine (101 mg, 46%). 1H NMR (360 MHz, CDCl3) δ 8.70 (1H, d, J=8.1 Hz), 8.31 (1H, d, J=8.0 Hz), 8.00-7.91 (1H, m), 7.85-7.78 (1H, m), 7.58-7.50 (1H, m), 6.97 (1H, d, J=7.2 Hz), 6.80 (1H, s), 6.61 (1H, d, J=8.5 Hz), 5.60 (2H, s), 3.82 (4H, t, J=5.1 Hz), 3.54 (4H, t, J=5.1 Hz), 2.57 (3H, s). m/z (ES+) 444 (M+H+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16]Cl)=[CH:10][CH:9]=1>C(O)(=O)C>[Br:7][C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[C:14](=[O:18])[CH2:15][CH2:16]2
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCc2cc(Br)ccc21
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
A mixture of 448 g of AlCl3 (335.98 mmol) and 112 g of NaCl is brought to 180° C. in a reactor. The mixture is stirred whilst introducing the compound obtained in Step A (44.77 g, 180.9 mmol) slowly using a spatula. The temperature is maintained at 180-220° C. The reaction continues for 30 minutes. Hydrolysis over 4.5 kg of ice in the presence of 135 ml of acetic acid yields a dark brown precipitate, which is filtered off, washed with water and dried in vacuo. The title compound is isolated by recrystallisation from methanol.
Reaction SMILES: [CH3:1][C:2]([O:16][C:17](=[O:24])[CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([N:19]([CH2:22][CH3:23])[C:18]1[C:17](=[O:24])[O:16][C:2]([CH3:15])([CH3:1])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:21]
Reactant: CCN(CC)CC(=O)OC(C)(C)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Yield: 31 %

Procedure:
Sodium hydride, 60% dispersion (0.478 g, 11.96 mmol) was washed in hexane and suspended in DMF (5 mL). This suspension was added to a 0° C. solution of 2-(diethyl amino) acetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (1.70 g, 4.78 mmol) in DMF (20 mL). The resulting mixture was warmed to RT for 15 minutes. The mixture was diluted with ethyl acetate and quenched with water. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The residue was purified by swishing in ether/hexanes to give 500 mg of crystalline solid on filtration.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.[Li]CCCC.[CH:33]1([CH:39]=[C:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]C1>C1COCC1>[CH:40]1([C:39]2([C:11]3[C:10]4[CH2:9][C:8]5[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=5)[C:15]=4[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]2)[CH:41]=[CH:42][CH:43]=[CH:44]1
Reactant: C1=CC(=CC2CCCCC2)C=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C3(C4C=CC=C4)CCCCC3)c1C2
Yield: 43.8 %

Procedure:
In a 200 ml two-necked flask purged with nitrogen, 1.96 g (7.04 mmol, 1 eq) of 3,6-di-tert-butylfluorene was placed at room temperature. Then, 40 ml of dehydrated THF was added, and the mixture was stirred by a magnetic stirrer to give a solution. The solution was cooled with an ice bath (colorless transparent solution). To the solution, 5.0 ml (8.15 mmol, 1.16 eq) of a hexane solution of n-BuLi was dropwise added over a period of 5 minutes. Then, the ice bath was removed, and the solution was stirred at room temperature for 21 hours (red solution). After the olution was cooled with an ice bath, a solution of 1.37 g (9.37 mmol, 1.33 eq) of 6-cyclohexylfulvene in 5 ml of dehydrated THF was dropwise added over a period of 10 minutes. The ice bath was removed, and the solution was stirred at room temperature for 42 hours. The resulting brownish red solution was poured into 50 ml of a diluted hydrochloric acid solution to perform quenching. The soluble component was extracted from the aqueous layer with 100 ml of diethyl ether, and the organic phase was washed with 80 ml of a saturated saline solution. The dispensed organic phase was dried over MgSO4, then the MgSO4 was filtered off, and from the filtrate the solvent was vacuum distilled off by a rotary evaporator to obtain a brownish yellow solid. The solid was purified by silica gel column chromatography (developing solvent: hexane) to obtain 1.31 g of a white solid (yield: 44%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[O:30][CH:31]=[CH:32][N:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[O:30][CH:31]=[CH:32][N:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ncco4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ncco4)CC3)cnc12
Yield: 44.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(oxazol-2-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.17 mmol) obtained in step 2 and methanesulfonamide (0.081 g, 0.850 mmol), the title compound (0.04 g, 46%) was obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH:15]=[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17]4)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>CO.[H][H].O=[Pt]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17]4)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(c1ccc2c(c1)OCCO2)N1C2C=C(c3ccccc3)CC1CC2
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(c1ccc2c(c1)OCCO2)N1C2CCC1CC(c1ccccc1)C2

Procedure:
PtO2 (40 mg) is added to a solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-phenyl-8-aza-bicyclo[3.2.1]oct-2-en-8-yl)-methanone (0.40 g) in methanol (5 mL). The resulting mixture is shaken in hydrogen atmosphere (1 bar) at room temperature for 6 h. Then, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→9:1) to give the title product as a ca. 1:1 mixture of endo and exo isomer.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O1CCOCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(N3CCOCC3)c12
Temperature: 85 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (190 mg, 0.5 mmol) was added K3PO4 (159 mg, 0.75 mmol), morpholine (52 mg, 0.6 mmol), Pd(OAc)2 (10 mg) and 4 mL of dioxane. The mixture was heated and stirred in an 85° C. oil bath overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave the crude product, which was purified by column chromatography to give 96 mg of 3-methyl-4-morpholin-4-yl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: [CH:1]1([C:9]([O:11]CC)=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[OH-].[Na+]>O>[CH:1]1([C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC=CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCC=CCCC1

Procedure:
After 2 hours reaction, the autoclave was allowed to cool and was vented. A portion of the autoclave contents, containing 40 parts by weight of ethyl cyclo-oct-4-ene-1-carboxylate, was mixed with water (100 parts by volume) and sodium hydroxide (21 parts by weight). The mixture was heated under reflux for 2 hours, when metallic palladium precipitated out. This was removed by filtration, and the filtrate was poured into water (350 parts by volume) and acidified with excess concentrated hydrochloric acid to give cyclo-oct-4-ene-1-carboxylic acid as a yellow oil, which was extracted with diethyl ether (3 × 200 parts by volume). The ethereal solution was dried over sodium sulphate and the ether was evaporated off to give 32.5 parts by weight of the cyclo-octene acid. This acid was mixed with water (400 parts by volume) and sodium hydroxide (20 parts by weight) and heated in an autoclave at 320°C for 1.5 hours. The autoclave was cooled and the contents filtered, after addition of a small amount of charcoal, in order to remove inorganic materials. The filtrate was acidified with concentrated hydrochloric acid and allowed to stand overnight, to give an aqueous suspension of azelaic acid. The azelaic acid was recovered by filtration and the aqueous mother liquor was extracted with diethyl ether. The ethereal solution was dried over sodium sulphate and the ether was evaporated off. The solid residue was combined with the azelaic acid recovered by filtration, and the product was dried in a vacuum oven to give 38.6 parts by weight of crude azelaic acid.
Reaction SMILES: CC(=C)C.[CH3:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:29]3[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:36])[F:35])=[CH:33][C:28]=3[CH2:27][CH2:26][C@@H:25]([NH:38][C:39](=[O:45])[CH2:40][C:41]([NH2:44])([CH3:43])[CH3:42])[C:24]2=[O:46])=[CH:18][CH:17]=1)=[O:8].[CH2:47]([O:49][CH2:50]C)[CH3:48]>>[O:49]1[CH2:47][CH2:48][N:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[C:29]4[CH:30]=[CH:31][C:32]([C:34]([F:36])([F:37])[F:35])=[CH:33][C:28]=4[CH2:27][CH2:26][C@@H:25]([NH:38][C:39](=[O:45])[CH2:40][C:41]([NH2:44])([CH3:43])[CH3:42])[C:24]3=[O:46])=[CH:20][CH:21]=2)=[O:8])[CH2:5][CH2:50]1
Reactant: CCOCC
Reactant: CNC(=O)Nc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)N)CCc3cc(C(F)(F)F)ccc32)cc1
Agent: C=C(C)C
Product: CC(C)(N)CC(=O)N[C@@H]1CCc2cc(C(F)(F)F)ccc2N(Cc2ccc(-c3ccccc3NC(=O)N3CCOCC3)cc2)C1=O

Procedure:
Reaction of isobutylene with N-chlorosulfonylisocyanate 37 in diethyl ether gives the azetidinone derivative 38. Removal of the chlorosulfonyl group with aqueous sodium sulfite followed by reaction with di-t-butyl-dicarbonate gives the BOC-protected intermediate 40. Alkaline hydrolysis gives the protected amino acid derivative 41 in good overall yield.