Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(O)C=C.[S:7]([CH2:16][CH2:17][C:18]([O:20]CC=C)=[O:19])[CH2:8][CH2:9][C:10]([O:12]CC=C)=O>CCOCC>[S:7]1[CH2:8][CH2:9][C:10](=[O:12])[CH:17]([C:18]([OH:20])=[O:19])[CH2:16]1
Reactant: C=CCOC(=O)CCSCCC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C=CCO
Solvent: CCOCC
Product: O=C(O)C1CSCCC1=O
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a mixture of sodium hydride (60% in oil, 1.6 g, 38.7 mmol) in 10 mL of dry ether at room temperature was added allyl alcohol (2.25g, 38.7 mmol) in a dropwise manner. The resultant mixture was stirred for 15 min. A solution-of 3,3′-thiodipropionic acid, diallyl ester (5.0 g, 19.3 mmol) in 10 mL ether was slowly added and the mixture refluxed for 5 h. The reaction was cooled to room temperature and then quenched with water and the pH adjusted to 4 with IN HCl. The ether layer was separated and the aqueous layer was extracted with ether (2×100 mL). The combined etheral layer was washed with sautrated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by flash column chromatography on silica gel eluted with hexane: ether (9 :1) to give 2.57 g of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43](O)=[O:44].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([C:35]3[NH:34][C:42]4[C:37]([CH:36]=3)=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc5ccccc5[nH]4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in DMF (30 mL). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.3 g, 2.4 mmol) and indole-2-carboxylic acid (0.4 g, 2.2 mmol) were added. The reaction was initiated by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.0 mmol) and stirred at room temperature overnight. The mixture was poured into cold water (120 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc solution was washed with water (3×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid residue was slurried with hot acetone (20 mL) to give 1H-indole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 70%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.08-2.11 (m, 1H), 2.56-2.65 (m, 2H), 2.85-2.98 (m, 1H), 4.99 (d, J=5.5 Hz, 2H), 5.15-5.22 (dd, J=5.4 and 12.7 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 7.16-7.22 (m, 3H), 7.42 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.75-7.83 (m, 3H), 9.15 (t, J=5.4 Hz, 1H), 11.15 (s, 1H), 11.64 (s, 1H); 13C NMR (DMSO-d6) δ 22.00, 30.34, 37.92, 48.89, 102.95, 112.31, 119.78, 121.54, 121.92, 123.45, 127.04, 127.14, 131.18, 131.57, 133.06, 134.33, 136.54, 139.29, 161.52, 166.97, 167.55, 169.83, 172.75; Anal. calcd. for C23H18N4O5+0.24H2O: C, 63.54; H, 4.28; N, 12.89. Found: C, 63.39; H, 4.38; N, 12.80.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:19].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=3)=[CH:4][C:3]=2[OH:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1O
Reaction time: 8 h

Procedure:
To 3.0 g (2.5 mmol) of above resin-bound 2-amino-5-(4-trifluoromethyl-phenoxy)-phenol were added 1.62 g (7.5 mmol) of 4-bromophenylacetic acid, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-acetamide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[O:22][C:21](=[O:23])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[CH3:24].Br[CH2:26][CH:27]=[CH:28]C.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:28]([C@H:20]1[CH2:19][C@H:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[C:13]([CH3:24])[CH:14]=2)[O:22][C:21]1=[O:23])[CH:27]=[CH2:26]
Reactant: CC=CCBr
Reactant: Cc1cc([C@H]2CCC(=O)O2)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CC[C@H]1C[C@H](c2ccc(F)c(C)c2)OC1=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.2 mmol) in anhydrous THF (20 mL) was added (R)-5-(4-fluoro-3-methyl-phenyl)-dihydro-furan-2-one (194 mg) in 1 mL THF at −70° C. over a period of 15 minutes. After completing the addition, the mixture was stirred for an additional 20 min at −70° C. and then for 10 min at room temperature. The mixture was cooled down again to −70° C. and a pre-cooled solution of 200 mg 1-bromo-but-2-ene and 400 μL HMPA in 1 mL THF slowly added. The mixture was further stirred at −70° C. for 2 h and the temperature was slowly raised to room temperature over a period of 2 h. The reaction was quenched by pouring into saturated NH4Cl (20 mL) and followed extraction with ethyl acetate (3×30 mL). The combined organic layers were washed with 20 mL brine twice and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by flash column chromatographed eluting with 0% to 50% ethyl acetate/hexane gradient solvent to give the anti/syn products (94:6 ratios).
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.C[O-].[Na+].O[N:15]=[C:16](Cl)[C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH:1]1([C:4]2[O:10][N:15]=[C:16]([CH:17]3[CH2:19][CH:18]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: ON=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1c(C2CC2c2ccccc2)noc1C1CC1
Temperature: 25 °C

Procedure:
A solution of methyl 3-cyclopropyl-3-oxopropanoate (0.36 mL, 2.9 mmol) in methanol (8 mL) was cooled to 0°C. and treated with sodium methoxide (0.76 mL of a 25% wt. solution in MeOH). After stirring fo(20 minutes, trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride rac-I-6D (0.57 g, 2.9 mmol) in methanol (0.5 mL) was added dropwise. The reaction mixture was warmed to rt and stirred fo(1 h. The reaction was concentrated in vacuo, diluted with water and extracted with dichloromethane. The aqueous was acidified with 6N HCl to pH=5 and extracted again with dichloromethane. The organics were washed with brine dried over Na2SO4, filtered, concentrated to yield 5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazole-4-carboxylic acid as clear oil which was directly used in the next step without further purification. MS m/z 270.1 (M+1).
Reaction SMILES: N(CC(O)=O)C.[C:7]1([S:13]([NH2:16])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:17][C:18]1[CH:48]=[CH:47][C:21]([CH2:22][N:23]2[C@@H:31]3[C@@H:27]([CH2:28][CH2:29][CH2:30]3)[C:26]([OH:32])=[C:25]([C:33]3[NH:38][C:37]4[CH:39]=[CH:40][C:41](I)=[CH:42][C:36]=4[S:35](=[O:45])(=[O:44])[N:34]=3)[C:24]2=[O:46])=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I>[F:17][C:18]1[CH:48]=[CH:47][C:21]([CH2:22][N:23]2[C@@H:31]3[C@@H:27]([CH2:28][CH2:29][CH2:30]3)[C:26]([OH:32])=[C:25]([C:33]3[NH:38][C:37]4[CH:39]=[CH:40][C:41]([NH:16][S:13]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)(=[O:15])=[O:14])=[CH:42][C:36]=4[S:35](=[O:45])(=[O:44])[N:34]=3)[C:24]2=[O:46])=[CH:20][CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Agent: I[Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C1C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A reaction flask was charged with copper iodide (50.4 mg, 0.265 mmol), sarcosine (N-methyl glycine) (37.7 mg, 0.42 mmol), benzenesulfonamide (251 mg, 1.59 mmol), (4aR,7aS)-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 39c, 300 mg, 0.53 mmol) and potassium phosphate (338 mg, 1.59 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (8 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 16 h, and then allowed to cool to 25° C. The mixture was passed through a plug of Celite and washed with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 40%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-N-[3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-benzenesulfonamide (110 mg, 0.19 mmol, 35%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.60 (2H, m), 1.94 (1H, m), 2.05 (1H, m), 3.29 (1H, bs), 3.84 (1H, bs), 4.46 (1H, bs), 4.86 (1H, d, J=14.4 Hz), 7.14 (2H, t, J=9.6 Hz), 7.35-7.43 (4H, m), 7.47-7.62 (4H, m), 7.74 (2H, m), 10.75 (1H, s). LC-MS (ESI) calcd for C28H25FN4O6S2 596.12, found 597.2 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:19]1[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=2)[N:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:19]2[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=3)[N:20]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cn1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 6-(tert-butoxycarbonylamino)pyridin-3-ylboronic acid (316.0 mg, 1.33 mmol) in dioxane (5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (130.0 mg, 0.44 mmol), K3PO4 (280.0 mg, 1.33 mmol) and Pd(PPh3)4 (25.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(6-(tert-butoxycarbonylamino)pyridin-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (160 mg, 80%).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@@H:13]([O:27][CH3:28])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:29][C:30]1[C:39]([F:40])=[C:38](F)[C:37](C)=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:29][C:30]1[C:39]([F:40])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@@H:13]([O:27][CH3:28])[CH2:12]2)[C:37]([CH3:38])=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@@H]1C1(N)CC1
Reaction time: 4 h
Yield: 15.9 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(R)-methoxypyrrolidine (550 mg, 1.41 mmol) was dissolved in ethanol (40 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 550 mg) and stirred for 4 hours under a pressured hydrogen atmosphere (4.5 kg/cm2). The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (5 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (249.8 mg, 0.80 mmol) and triethylamine (3 ml) and stirred for 2 days in an oil bath of 120° C. under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved in chloroform (100 ml) and washed with a 10% citric acid aqueous solution (50 ml×2) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After adding water (20 ml) to the reaction solution, the aqueous solution was washed with dichloromethane (50 ml×3), adjusted to pH 11 with sodium hydroxide aqueous solution and then washed with dichloromethane (50 ml×2). This was adjusted to pH 7.4 with concentrated hydrochloric acid and extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative silica gel thin layer chromatography (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1), and the resulting crude product was purified by recrystallizing from ethanol-diisopropyl ether and then dried under a reduced pressure to obtain 57 mg (16%) of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[C:10]2[CH:19]([C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[O:16][CH3:15])[N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccc2ccc(O)c(C(c3ccccc3OC)N3CCOCC3)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-methoxy-2-naphthol and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 28.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].BrC1C=NNC=1.IC(C)C.C(N1C=C([B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)C=N1)C>CCOC(C)=O.CN(C=O)C>[CH:7]([N:5]1[CH:6]=[C:2]([B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)[CH:3]=[N:4]1)([CH3:9])[CH3:8]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1cc(Br)cn1
Agent: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)I
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C

Procedure:
4-bromo-1-isopropyl-1H-pyrazole. A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt. The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The desired compound (as determined by TLC, 12 stain) was collected as a colorless liquid. b) 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The title compound was prepared in the same manner as described for 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].CCN(CC)CC.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: COC(=O)CCN
Reactant: Clc1cc2nccnc2c(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of methyl 3-aminopropanoate hydrochloride (4.88 mmol), Et3N (6.50 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (3.25 mmol) in THF (10 mL) was stirred at room temperature overnight. Volatiles were removed under reduced pressure, and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 267 (M+H)+.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O.[S:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](=[S:36])[OH:35].P(=O)(O)(O)O>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:36][C:34]([C:30]3[S:29][CH:33]=[CH:32][N:31]=3)=[O:35])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: OC(=S)c1nccs1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSC(=O)c3nccs3)CS[C@H]12
Reaction time: 5 h
Yield: 35 %

Procedure:
to a stirred solution of 9.8 g. (0.036 moles) of 7-aminocephalosporanic acid and 6.05 g. (0.072 moles) of sodium bicarbonate in 170 ml. of aqueous phosphate buffer at pH 6.4 was added 5.35 g. (0.036 moles) of thiazole-2-thiocarboxylic acid. The mixture was stirred in a nitrogen atmosphere at 50° for 5 hours keeping the pH at 6.6 with 42% phosphoric acid. Then the mixture was cooled to 20° and the precipitated solid was removed by filtration, washed with water, acetone and ether and dried in vacuo over phosphorus pentoxide to provide 4.6 g. (35% yield) of a tan crystalline solid. Infrared and NMR spectra were consistent with the structure.
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2.C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1>[O:1]1[CH:5]([CH2:6][NH:7][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2ccc3c(c2O1)CCC3
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC1Cc2ccc3c(c2O1)CCC3)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of (±)-1-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine (0.568 g, 3.00 mmol) in tetrahydrofuran (30 mL) cooled to 0° C. was added diisopropylethylamine (0.427 g, 3.30 mmol) followed by benzyl chloroformate (0.538 g, 3.15 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (100 mL) and extracted with diethyl ether (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) afforded 0.663 g (68%) of (±)-benzyl 3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethylcarbamate as a white solid. Rf=0.30 (silica, ethyl acetate:hexanes 1:9); mp 99-101° C.; Anal. calcd. for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 73.82; H, 6.53; N, 4.25. Chiral HPLC separation of (±)-benzyl 3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethylcarbamate (Chiralcel OJ, isopropanol:hexane 7:3) provided two fractions. Fraction 1 (Rt=13.237 min, Chiralcel OJ, isopropanol:hexanes 3:7); Fraction 2 (Rt=16.526 min, Chiralcel OJ, isopropanol:hexanes 3:7).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[NH:7][C:6]=2[C:5]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]2[NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=3[C:3]=12.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][O:16][C:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[C:14]=2[C:2]([C:30]#[N:31])=[C:3]2[C:28]3[CH:27]=[C:26]([F:29])[CH:25]=[CH:24][C:23]=3[NH:22][C:4]=12
Reactant: CN(C)C=O
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(Br)c2c1[nH]c1ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(C#N)c2c1[nH]c1ccc(F)cc12
Temperature: 160 °C
Yield: 46 %

Procedure:
A mixture of 2-(12-bromo-2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (97.8 mg, 0.1991 mmol), zinc cyanide (233.7 mg, 1.9910 mmol) and tetrakis(triphenylphosphine)palladium (0) (23.0 mg, 0.01991 mmol) in anhydrous DMF was purged with high-purity Ar for five minutes, sealed with Teflon cap and heated to 160° C. for 12 hours. The reaction mixture was cooled down and filtered. The solvent was removed via vacuum pump. The residue was purified via flash chromatography to provide the title compound (37.3 mg, 46%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 2H), 8.39 (dd, J=10.2, 2.8 Hz, 2H), 7.55 (dd, 8.8, 4.4 Hz, 2H), 7.31 (td, J=8.8, 2.4 Hz, 2H), 4.33 (t, J=4.2 Hz, 2H), 2.74 (t, J=4.2 Hz, 2H), 2.35 (s, 6H); MS (ESI) m/z 403.1 (M−H)−; MS (ESI) m/z 405.0 (M+H)+