Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[CH:11][CH:12]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(O)cc3)ccnc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 165d (43 mg, 0.085 mmol) was reacted with isopropylsulfonyl chloride (14.5 mg, 0.102 mmol), N,N-diisopropylethylamine (33 mg, 0.255 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (16 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.38 (d, J=6.99 Hz, 6 H) 2.73 (s, 3 H) 3.54-3.65 (m, 1 H) 6.69 (d, J=6.99 Hz, 1 H) 7.01 (d, J=9.19 Hz, 2 H) 7.20 (d, J=9.19 Hz, 2 H) 7.27 (d, J=8.82 Hz, 1 H) 7.60 (dd, J=8.82, 2.57 Hz, 1 H) 7.70-7.75 (m, 2 H) 8.51 (d, J=6.99 Hz, 1 H) 8.81 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 484 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10][CH:9]1[C:32](=[O:44])[NH:33][C:34]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH:35]1[CH:37]=[CH2:38])=O)(C)(C)C.C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:42]([O:41][C:39]([C:34]1([NH:33][C:32]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:15]=3)[CH2:12][NH:8]2)=[O:44])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:40])[CH3:43]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC

Procedure:
Compound 5 was kept in TFA-DCM 1:2 (3 mL) at RT for 60 min. Toluene (3 mL) was added. The sample was co-evaporated to dryness. Purity by HPLC >95%. M+H+ 502.4.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].O[N:22]=[C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)[NH2:24]>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:14][N:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]4[NH:29][CH:30]=[N:31][C:27]=4[CH:26]=3)[N:24]=2)=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: C[C@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Product: C[C@H]1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F

Procedure:
Title compound was prepared following general procedure 3 starting from Intermediate 27 (300 mg; 1.04 mmol; 1 eq.), and Intermediate 1 (183.98 mg; 1.04 mmol; 1 eq.). After evaporation of the solvents, the solid residue was triturated with ACN, filtered and dried under vacuum to give the title compound as an off-white solid. 1H NMR (DMSO-d5) δ 12.78 (br m, 1H), 8.50-8.26 (m, 2H), 8.04-7.68 (m, 3H), 3.16 (m, 1H), 3.02-2.90 (m, 1H), 2.69-2.55 (m, 1H), 1.87-1.20 (m, 6H), 0.78 (d, J=6.1 Hz, 3H). HPLC (Method A), Rt 5.04 min (Purity: 98.4%). LC/MS (Method B): 426.3 (M+H)−; 428.1 (M+1-1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH3:23])=[O:22])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Cc1ccccc1CN
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C)cc3)c2)o1

Procedure:
2′-Methyl-N-(2-methylbenzyl)-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 2-methylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.01,(1H, t), 8.01,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.56-7.51,(3H, m), 7.26,(1H, m), 7.18-7.15,(3H, m), 4.48,(2H, d), 2.56,(3H, s), 2.33,(3H, s), 2.31,(3H, s). LCMS; retention time 3.47 min, MH+ 398.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[C@H:25]12[CH2:31][C@H:28]([NH:29][CH2:30]1)[CH2:27][O:26]2.C(N(CC)CC)C>C(O)C>[C@H:25]12[CH2:31][C@H:28]([N:29]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=4)[N:5]=[C:4]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:16]=[CH:17][C:3]=34)[CH2:30]1)[CH2:27][O:26]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 150 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (56 mg, 0.15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (22 mg, 0.16 mmol) in ethanol (4 mL). The suspension was treated with triethylamine (59 μL, 0.45 mmol) and was then heated in the microwave reactor for 15 minutes at 150° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 75% acetonitrile to provide 3-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenol. MS (ES+): 386.3 (M+H)+
Reaction SMILES: CC(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]1)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[ClH:17].[CH3:14][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1)[CH3:15]
Reactant: CN(C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)[C@H]1CC[C@H](N)C1
Reaction time: 0.83 h

Procedure:
(1-S-trans)-[3-(N,N-Dimethylamino)cyclopentyl]carbamic acid 1,1-dimethylethyl ester (0.537 g, 2.35 mmol) in 1,4-dioxan (4 ml) was treated with a saturated solution of hydrogen chloride in 1,4-dioxan (15 ml) and additional 1,4-dioxan (8 ml). After 50 minutes at 21° C., another portion of a saturated solution of hydrogen chloride in 1,4-dioxan (5 ml) was added, and after a further 2.5 h, the opaque solution was concentrated by evaporation to give the title compound as a beige solid, which was used without characterisation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH2:20]([O:22]/[CH:23]=[CH:24]/B1OC(C)(C)C(C)(C)O1)[CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22]/[CH:20]=[CH:21]/[C:2]1[CH:3]=[C:4]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:24]
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: NS(=O)(=O)c1cnc(NCC2CCOCC2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: CCO/C=C/c1cc(S(N)(=O)=O)cnc1NCC1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 388A (0.65 g), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.735 g), palladium acetate (0.013 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.057 g), and potassium phosphate (0.788 g) in CH3CN (9 ml) and water (6 mL) was heated at reflux overnight. After it cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to give the title compound.
Reaction SMILES: CO.O.[CH3:4][C:5](O)=O.C[C:9]1[C:14]([F:15])=[N:13][C:12]([CH3:16])=[CH:11][N:10]=1.[F:17][B-:18]([F:21])([F:20])[F:19].C[O+](C)C>C(Cl)Cl>[F:17][B-:18]([F:21])([F:20])[F:19].[F:15][C:14]1[C:5]([CH3:4])=[N+:10]([CH3:9])[CH:11]=[C:12]([CH3:16])[N:13]=1
Reactant: Cc1cnc(C)c(F)n1
Reactant: CC(=O)O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1c[n+](C)c(C)c(F)n1

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A:- 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H). 12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v. 13. n.m.r. in solvent B: 3.46 (d,1H), 3.72 (d,1H); 3.97 (s,3H); 4.25 (s,3H); 4.11 (d,1H); 4.63 (d,1H); 5.13 (d,1H); 5.73 (d,1H); 6.97 (s,1H); 7.57 (d,1H); 7.98 (dd,1H); 8.93 (d,1H). 14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v. 15. n.m.r. in solvent B: 3.43 (d,1H); 3.69 (d,1H); 3.97 (s,3H); 4.19 (s,3H); 4.23 (d,1H); 4.66 (d,1H); 5.12 (d,1H); 5.69 (d,1H); 7.0 (s,1H); 7.98 (d,1H); 8.2 (s,1H); 8.6 (d,1H). 16. The starting material was prepared by reaction of 3,6-difluoropyridazine and trimethyloxonium tetrafluoroborate in CH2C 12 for 15 hours at ambient temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate. This compound in acetonitrile was treated with a solution of ammonia in chloroform in the presence of 1 equivalent of NaHCO3 for 0.5 hours at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium tetrafluoroborate. 17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v. 18. n.m.r. in solvent B: 1.53 (s,6H); 3.5 (m,2H); 3.7 (s,3H); 3.95 (d,1H); 4.5 (d,1H); 5.15 (d,1H); 5.8 (d,1H); 7.0 (s,1H); 7.3 (s,2H). 19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluoropyrazine and trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium tetrafluoroborate. 20. n.m.r. in solvent B: 1.53 (s,6H); 2.38 (s,3H); 2.53 (s,3H); 3.5 (m,2H); 4.1 (s,3H); 4.2 (d,1H); 4.85 (d,1H); 5.1 (d,1H); 5.85 (d,1H); 7.05 (s,1H); 7.9 (s,1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.Cl.[CH3:28][N:29]([CH2:31][C:32](Cl)=[O:33])[CH3:30].C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:28][N:29]([CH2:31][C:32]([N:14]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[S:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)(=[O:13])=[O:12])=[O:33])[CH3:30]
Reactant: CN(C)CC(=O)Cl
Reactant: COc1cc(NS(=O)(=O)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N(C(=O)CN(C)C)S(=O)(=O)c2ccc3c(ccn3C)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of Example 4 (20.0 g, 53.2 mmol) in THF (250 mL) at room temperature was treated with dimethylaminoacetyl chloride hydrochloride (12.3 g, 77.8 mmol), DMAP (650 mg, 5.3 mmol), and diisopropylethylamine (25.2 g, 195.0 mmol), stirred for 8 hours, and concentrated to ⅓ its original volume. The mixture was diluted with ethyl acetate (400 mL), washed with 5% NaHCO3 (2×200 mL) and water (200 mL), dried (Na2SO4), filtered, concentrated to a volume of 120 mL, diluted with methyl tert-butyl ether (120 mL), stirred for 18 hours, cooled to 0° C., stirred for 2 hours, and filtered. The resulting solid was washed with 1:1 ethyl acetate/methyl tert-butyl ether (100 mL) and dried under vacuum to provide 22.5 g (92%) of the desired product.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].C1N([CH2:10][CH2:11][OH:12])CCN(CCS(O)(=O)=O)C1.[Na+].[Cl-].[Cl-].[K+].[OH2:23]>>[O:23]=[CH:10][C@@H:11]([C@H:10]([C@@H:11]([C@@H:10]([CH2:11][OH:12])[OH:23])[OH:12])[OH:23])[OH:12]
Reactant: O
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Ten to twenty μg of plasmid pL133 DNA were added to 62.5 μl of 2M CaCl2 and 437.5 μl of H2O. The 0.5 ml of DNA were then added dropwise to 0.5 ml of 2× HeBS (10 g/L Hepes, pH =7.5; 16 g/L NaCl; 0.74 g/L KCl; 0.25 g/L Na2PO4 ; and 2 g/L dextrose), forming a milky precipitate. The mixture was allowed to stand for 10-20 minutes at room temperature before it was added to the cells. A longer incubation time may result in a coarser precipitate that does not transform well, but sometimes a longer incubation time may be necessary to form a precipitate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[C:20]1([CH3:29])[C:21]([C:26](Cl)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:26](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:29]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1C
Yield: 44.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and o-toloyl chloride (Aldrich, 0.22 g, 1.4 mmol) in 15 mL THF were processed using the method described in Example 129 to afford the title compound (0.15 g, 0.49 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.23 (d, J=0.7 Hz, 3H), 2.26 (s, 3H), 2.70 (s, 3H), 3.31 (s, 3H), 3.77 (t, J=5.3 Hz, 2H), 4.35 (t, J=5.3 Hz, 2H), 7.23 (t, J=7.5 Hz, 2H), 7.27-7.35 (m, 1H), 8.08-8.14 (m, 1H); MS (DCI/NH3) m/z 305 (M+H)+; Anal. calculated for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C, 63.43; H, 6.53; N, 9.14.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Br:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[OH-].[Li+]>CO>[CH2:41]([O:40][C:38]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Br:29])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Methyl (2S)-2-amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-propanoate trifluoroacetate (83.8 mg, 0.166 mmol) in methanol (2.0 mL) was treated with triethylamine (92.5 μL, 0.663 mmol) and chilled to 0° C. Benzyl chloroformate (20.8 μL, 0.146 mmol) was added and the solution stirred 2 h at 0° C. Aqueous lithium hydroxide solution (4.0 M, 0.21 mL) was added and the solution stirred 2 h. Purification by preparative LCMS afford product as a white solid (69 mg, 81%). 1H NMR (400 MHz, CDCl3): δ 7.48 (brs, 1H), 7.46–7.43 (m, 1H), 7.31–7.26 (m, 6H), 5.65 (t, J=8.2 Hz, 1H), 5.03 (s, 2H), 4.45–4.41 (m, 1H), 3.45 (dd, J=17.5, 8.5 Hz, 1H), 3.36–3.19 (m, 2H), (2.94 dd, J=14.2, 9.7 Hz, 1H); LCMS found for C20H20BrN2O7S (M+H)+: m/z=511.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O>N1C2C(=CC=CC=2)C=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2cc3c(cc2c1O)OCO3
Solvent: c1ccc2ncccc2c1
Product: Oc1ccnc2cc3c(cc12)OCO3
Yield: 65.9 %

Procedure:
A mixture of 17 g (73 mmoles) of 4-hydroxy-6,7-methylenedioxyquinoline-3-carboxylic acid, ref. 3 g, of Cu powder and 100 ml of quinoline was heated at reflux for one-half hour at an internal temperature of 235°-240°. The mixture was filtered, cooled and diluted with 250 ml of Skelly C. Filtration of the resultant precipitate yielded a light brown solid, mp 276°-279° dec. Recrystallizations from EtOH gave 9.1 g of the quinoline, mp 280°-281° C dec. ref. D. Kaminsky and R. I. Meltzer, U.S. Pat. No. 3,287,458. (Nov. 22, 1966) [Chem. abstr. 66, 65399 u (1967)].
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]#[CH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.Br[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]#[C:12][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[N:4][CH:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: C#Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Brc1cnc(N2CCOCC2)c2nc(C#Cc3ccc4ccccc4n3)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 80a (200 mg, 0.7 mmol) and 2-bromoquinoline (0.800 mg, 4 mmol) in dry DMF (5 mL) and DIEA (0.7 mL, 4 mmol) under an Argon gas atmosphere, CuI (12 mg, 0.06 mmol) and (Ph3P)2PdCl2 (46 mg, 0.06 mmol) were added. The reaction was stirred at rt overnight, poured into water (50 mL) and extracted with DCM (3×30 mL). The combined organic extracts were washed with water (20 mL), brine (2×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-50% EtOAc/heptanes) to give compound 80b as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H16BrN5O: 434.0 (M+H). found: 434.2.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.O[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[CH:1]1([O:6][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of cyclopent-3-enol (840 mg, 10.0 mmol) in CH2Cl2 (25.0 mL) was added 2-hydroxyisoindoline-1,3-dione (1.96 g, 12.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (740 mg, 32%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57-2.87 (m, 4H) 5.12 (t, J=6.19 Hz, 1H) 5.75 (s, 2H) 7.74 (dd, J=5.68, 3.16 Hz, 2H) 7.79-7.87 (m, 2H). MS (ES) [M+H] calculated for C13H12NO3, 230.07; found 230.20.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH3:18][Si:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][SH:22].C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CN1CCCC1=O>[CH3:18][Si:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][S:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccoc2)c2ccc(Br)cc2o1
Reactant: C[Si](C)(C)CCS
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCSc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Temperature: 105 °C
Yield: 54.3 %

Procedure:
A mixture of 7-bromo-4-(furan-3-yl)coumarin (Coumarin 4) (1.5 g, 5.15 mmol), 2-(trimethylsilyl)ethanethiol (830 mg, 6.18 mmol), and K2CO3 (1.77 g, 12.9 mmol) in 1-methyl-2-pyrrolidinone (12 mL) was heated at 105° C. for 4 h. After cooling, them was added saturated aqueous NH4Cl (10 mL), then H2O (50 mL) and the mixture was extracted twice with EtOAc. The organic extracts were washed 4 times with H2O, dried over MgSO4 and evaporated to a residue which was chromatographed on silica gel eluting with a 1:3 mixture of EtOAc and hexane, to afford the title compound (963 mg) as a tan solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)[CH3:2].C([Li])CCC.[CH:13]12[O:19][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2>C1COCC1>[CH2:1]([N:3]1[C:7]([C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:19])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: C1CCC2OC2C1
Reactant: CCn1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nccc1[C@H]1CCCC[C@@H]1O
Yield: 56.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 4a by using 1-ethylpyrazole (2.50 g, 26.0 mmol), butyl lithium (1.63 M solution in hexane; 18.1 mL, 29.5 mmol), cyclohexene oxide (2.97 g, 30.3 mmol) and THF (60 mL), to yield the title compound (2.86 g, 57%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:5][C:4]=1[O:19][C:20]([F:23])([F:22])[F:21])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:9][CH2:8][CH2:7][C:6]1[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[C:4]([O:19][C:20]([F:21])([F:22])[F:23])[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)c(OC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCN)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.8 %

Procedure:
To a solution of tert-butyl 4-cyano-3-(trifluoromethoxy)phenethylcarbamate (150 mg, 0.45 mmol) in DCM (3 mL) was added TFA (1.5 mL). The resulting reaction mixture was stirred at room temperature for 1.5 h. The mixture was concentrated to afford the crude title product (120 mg, crude), which was used directly for next step without further purification. MS (ESI) m/z 231.1 [M+H]+.