Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:23](=[O:24])[CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Br:15])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1Br
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)Cc2ccccc2Br)c[nH]1
Temperature: 0 °C
Yield: 54.9 %

Procedure:
Ethylpyrrole-2-carboxylate (1.9428 g, 13.96 mmol) in a minimal amount (5 mL) of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (4.0458 g, 30.34 mmol) and 2-bromophenylacetyl chloride (6.7116 g, 28.74 mmol) in dichloroethane (44 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 2 h. 19.2977 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜100 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 80:20 to 60:40 Hexanes:EtOAc) to obtain 2.5751 g (54.9%) 63 as a white solid. Note: A small amount of CH2Cl2 was required to solubilize the crude product before placement on the silica column. 1H (CDCl3, 400 MHz): δ 10.32 (1H, broad s), 7.57-7.53 (2H, m), 7.38-7.37 (1H, m), 7.29-7.21 (2H, m), 7.13-7.07 (1H, m), 4.35 (2H, q, J=7.2 Hz), 4.25 (2H, s), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 191.78, 161.04, 134.91, 132.62, 131.66, 128.59, 127.40, 126.95, 126.25, 124.98, 124.17, 114.88, 60.92, 46.56, 14.26 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.26; CH2 carbons: 60.92, 46.56; CH carbons: 132.62, 131.66, 128.59, 127.40, 126.95, 114.88 ppm. HPLC: 10.078 min.
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([NH:23][CH:24]([C:33]([O:35]CC)=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]1=[O:38])([OH:4])=[O:3].[OH-].[Na+]>C(O)C>[C:33]([CH:24]([NH:23][CH:8]1[C:7](=[O:38])[N:6]([CH2:5][C:2]([OH:4])=[O:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([OH:35])=[O:34]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)C(c2ccccc2)Sc2ccccc21
Reaction time: 4 h
Yield: 79.2 %

Procedure:
400 mg of the compound obtained in Example 22 was dissolved in a mixture consisting of 5 ml of ethanol and 2.9 ml of a 1N aqueous solution of sodium hydroxide, and the resulting solution was stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, it was dissolved in 40 ml of water and a small amount of insoluble matter was removed. Then, the aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid. The precipitated crystals were separated by filtration and washed with water to obtain 280 mg of the desired compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O:9]=[C:10]([CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:11].CCCCCCC.C1C=CC=CC=1>[Cl-].[Zn+2].[Cl-].O>[C:1]([O:7][CH2:8][CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O:9]=[C:10]([CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:11]
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)C=C(C)C
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)=O

Procedure:
A mixture of 2.6 kg. of methyl acetoacetate, 2.75 kg. of mesityl oxide, 400 g. of zinc chloride, 2 l. of heptane, and 2 l. of benzene was refluxed for 5 days. The water formed during the reaction was azeotropically distilled off and collected in a separator. A brown oily product remained in the flask. The oily product was then washed with water, sodium bicarbonate solution, and again with water. The oil which remained after washing was dried over calcium chloride and the heptane-benzene solvent removed under vacuum. The remaining oil was distilled under high vacuum over a packed column. From the distillation there was obtained first a forecut of unreacted ethyl acetoacetate and mesityl oxide, a second fraction of isophorone by product and finally crude 3,5,5-trimethyl-2-cyclohexen-1-on-4-carboxylic acid methyl ester with a boiling range of 95°-104° at 0.4-0.6 mm.Hg. This crude material was utilized for all experiments without further purification. Pure 3,5,5-trimethyl-2-cyclohexen-1-on-4-carboxylic acid methyl ester was obtained by chromatographic separation on silica gel G (finely divided powdered Silica containing trace amounts of calcium sulfate), using petroleum ether and ethyl ether in a volume ratio of 7 to 3.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8](=[CH:10][CH2:11][CH2:12][C@H:13]([CH2:15][CH:16]=[O:17])[CH3:14])[CH3:9]>C1COCC1>[CH3:7][C:8](=[CH:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][OH:17])[CH3:14])[CH3:9]
Reactant: CC(C)=CCC[C@@H](C)CC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)CCO
Temperature: 0 °C
Yield: 114.6 %

Procedure:
Powdered LiAlH4 (12.5 g, 329 mmol) was introduced into a 5 L round bottom flask along with 2 L of THF (dried over 3 Å molecular sieve). The slurry was stirred mechanically under N2 and the temperature was lowered to 0° C. (R)-citronellal (5, Takasago, Rockleigh, N.J.) (100 g, 648 mmol) was added neat over about 15 min and the residue was rinsed into the flask with an additional 500 mL of THF. Notwithstanding the fact that TLC indicated complete consumption of citronellal, the mixture was warmed to a gentle reflux and subsequently cooled to 0° C. The reaction was worked up by sequential dropwise addition of the following to the vigorously stirring mixture: 12.5 mL water, 12.5 mL 3 M NaOH, and a solution of 37.5 mL water in 37.5 mL THF. After filtration through celite and thorough washing of the solids with MTBE, the solvent was evaporated to yield 116 g of crude citronellol. This oil was distilled (bulb-to-bulb, 120-140° C., 0.8 mm Hg) to give 6 (93.4 g, 92%) as a clear oil, TLC Rf (10% MTBE/petroleum ether) =0.09. 1H NMR (CDCl3) (δ): 5.10 (m, 1H), 3.66 (m, 2H), 2.1-1.8 (m, 3H), 1.68 (s, 3H), 1.7-1.5 (m, 2H), 1.60 (s, 3H), 1.4-1.3 (m, 2H), 1.17 (m, 1H), 0.90 (d, J=6.66 Hz, 3H); 13C NMR (CDCl3) (δ): u: 131.2, 61.0, 39.8, 37.1, 25.4; d: 124.6, 29.1, 25.6, 19.4, 17.6; IR (cm−1): 3331 (b), 2927, 1454, 1377, 1058; MS (m/z, %): 55 (64), 69 (100), 82 (44), 95 (33), 109 (14), 123 (18), 138 (6), 156 (6); HRMS calcd for C10H20O: 156.1514. Found: 156.1514; [α]D17=+3.74 (c 1.02, EtOH).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH2:12]>O.[Cl-].C([N+](CC)(CC)CC)C.C(#N)C.[Pd].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>[O:12]1[CH:4]=[CH:3][CH:2]=[C:10]1[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Product: O=C1Cc2ccc(-c3ccco3)cc2N1
Temperature: 85 °C

Procedure:
6-Bromo-oxindole (0.40 g, 1.88 mmol), 2-tributyltinfuran (0.71 mL, 2.26 mmol), and tetraethylammonium chloride hydrate (0.31 g, 1.88 mmol) were combined and dissolved in acetonitrile (15 mL). The palladium catalyst, bistriphenylphosphinedichloropalladium (II) (0.66g, 0.09 mmol) was added and the reaction was warmed to 85° C. under nitrogen for 20 h. The reaction was cooled to room temperature and diluted with water (15 mL) before passing the mixture through celite. The pad of celite was washed with EtOAc and the filtrates were combined and separated. The aqueous layer was washed with EtOAc (2×20 mL each). The combined organic phases were washed with brine and dried over sodium sulfate. The volatiles ere removed in vacuo. The resulting residue was triturated with diethyl ether and the solid was collected by filtration (0.13 g, 34%). 1H NMR 300 MHz (DMSO-d6) δ 10.5 (s, 1H); 7.75 (s, 1H); 7.30 (m, 2H); 7.11 (s, 1H); 6.91 (m, 1H); 6.60 (m, 1H); 3.52 (s, 2H).
Reaction SMILES: [C:1]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[NH:17][C:18]([NH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[CH2:25][CH2:24]1)=[O:19])([O:3]CC)=O.CC(C)([O-])C.[K+].C1COCC1.CS(O)(=O)=O>C(O)C>[CH3:36][O:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][N:20]2[C:1](=[O:3])[C:6]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:8][C:7]=3[NH:17][C:18]2=[O:19])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1NC(=O)NCCN1CCN(c2ccccc2OC)CC1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3sc(-c4ccccc4)cc3c2=O)CC1
Yield: 51.1 %

Procedure:
A solution of Example 5B (387 mg, 0.762 mmol) in ethanol (5 mL) was treated with 1M potassium t-butoxide/THF (0.84 mL), heated to reflux for 90 minutes, cooled, quenched with 1N HCl(0.84 mL), and partitioned between water and ethyl acetate. The insoluble solid was collected, washed with ethyl acetate, slurried in methanol, treated with methanesulfonic acid (2 equiv), and concentrated. The product was crystallized from ethanol to provide 180 mg the title compound as the bis methanesulfonate salt.
Reaction SMILES: [Br:1][C:2]1[C:14](F)=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2.BrC1C([Cl:38])=CC(C(O)=O)=C2C=1C1CCC(C(OCC)=O)CC=1N2>>[Br:1][C:2]1[C:14]([Cl:38])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Cl)c(Br)c23)C1
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(F)c(Br)c23)C1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)cc(Cl)c(Br)c23)C1
Yield: 78 %

Procedure:
Following the procedure used to prepare Intermediate 24D, 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid was converted into ethyl 5-bromo-8-carbamoyl-6-chloro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate as a light brown solid (8.54 g, 78% yield). Mass spectrum m/z 399, 401 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C1(C=CC(O)=CC=1)O.[OH-].[K+]>>[C:10]([CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#CCc1cccc(F)c1F
Agent: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)CCC(C#N)c1cccc(F)c1F
Temperature: 160 °C

Procedure:
To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M−OEt).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH:12]=2)[CH:7]=[N:6]1.Cl>CC(C)=O.C(OCC)(=O)C>[O:2]=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:19][CH:18]=3)[CH:12]=2)[CH:7]=[N:6]1
Reactant: COC(Cn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21)OC
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=CCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21

Procedure:
A mixture of N-[1-(2,2-dimethoxyethyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide (2.0 g, 4.64 mmol) and 2N aqueous HCl (6.0 mL)in acetone (40 mL) was heated to reflux for 3 hours, cooled and diluted with ethyl acetate (300 mL). The layers were separated, and the organic was dried (Na2SO4), filtered, and concentrated under reduced pressure to provide N-[1-(2-oxoethyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.55 (s, 2 H), 3.7 (m, 2 H), 7.0 (m, 4 H), 7.1 (m, 2 H), 7.3 (m, 1 H), 7.4 (m, 4 H), 8.0 (s, 1 H), 8.15 (s, 1 H), 10.4 (s, 1 H), and 12.8 (s, 1 H); MS (ESI) 384.1 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:19])=[C:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>C1COCC1>[OH:1][C:2]1[C:7]2[C:8]([CH3:19])=[C:9]([CH2:14][CH2:15][C:16](=[O:18])[O:17][N:38]3[C:42](=[O:43])[CH2:41][CH2:40][C:39]3=[O:44])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)=C2C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)ON1C(=O)CCC1=O)=C2C
Temperature: 25 °C
Yield: 34.1 %

Procedure:
Alternate Synthesis To a solution of 100 mg (0.30 mmol) of the acid 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in 15 mL of anhy. THF under argon and cooled in an ice-water bath was added 150 mg (3 eq) of carbonyldiimidazole (CDI) (Fluka Chem. Co.) as a solid in one lot. The reaction was stirred at ~0° C. for ~1 hr. The ice bath was removed and the stirred reaction allowed to warm up to RT over 1.5 hr. To the reaction was then added 345 mg (10 eq) of N-hydroxysuccinimide (NHS) (Aldrich) as a solid in one lot and the reaction stirred at RT under argon for 18 hrs. The reaction mixture was then evaporated under reduced pressure and the residue partitioned between 100 mL of EtOAc and 30 mL of 0.1N aq. HCl. The phases were separated and the organic layer washed with 0.1N HCl (2×30 mL), water (1×30 mL), 50 mM phosphate buffer pH 8 (3×30 mL), sat. aq. NaCi (1×30 mL), dried (Na2SO4), evaporated under reduced pressure and the residue dried under high vacuum. The residue was then subjected to PLC, eluting with 50% EtOAc-CH2Cl2. The upper product band was isolated and the silica washed with EtOAc. The washings were evaporated under reduced pressure and dried under high vacuum to give 44 mg of the desired product 1-[3-(5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-yl)-1-oxopropoxy]-2,5-pyrrolidinedione as a glass/amorphous solid.
Reaction SMILES: C1(C([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:56]/[O:57][CH3:58])/[C:27]([NH:29][CH:30]3[C:37](=[O:38])[N:36]4[CH:31]3[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][S:49][C:50]3[N:54]([CH3:55])[N:53]=[N:52][N:51]=3)=[C:35]4[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:56]/[O:57][CH3:58])/[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][S:49][C:50]2[N:54]([CH3:55])[N:53]=[N:52][N:51]=2)=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(/C=C/CSc3nnnn3C)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(/C=C/CSc3nnnn3C)SCC12)c1csc(N)n1

Procedure:
329 mg of the compound of Step A and 9.6 ml of a 33% aqueous solution of formic acid were mixed together and heated for 25 minutes at +65° C., then cooled, diluted with water, filtered, and concentrated to dryness by distilling under reduced pressure. The residue was triturated in water and the insoluble matter formed was eliminated by filtering, and after concentrating to dryness, 142 mg of 7-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyimino-acetamido]-3-[3-(1-methyl-1H-1,2,3,4-tetrazol-5-yl)thio-propen-(E)-yl]-8-oxo-4-thia-1-azabicyclo [4,2,0]oct-2-en-2-carboxylic acid with a specific rotation of [α]D20 =-99° (c=0.8% DMSO) were obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=CC(C[C@H](NC(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)C=O)=CC=1>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Agent: O=C[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 44 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Phe Wang resin (167 mg, 0.6 mmol/g), producing 26 mg of the title compound (44% yield). MS: 594.24 (M−H+) HPLC Procedure A, retention time=14.58 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].ClCCl.O1CCOCC1>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Clc1nccc2ccccc12
Reactant: Cc1ccc(B(O)O)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2nccc3ccccc23)cc1F
Temperature: 105 °C
Reaction time: 18 h

Procedure:
500 ml of degassed dioxane were initially charged and admixed with 10.0 g (61.14 mmol) of 1-chloroisoquinoline, 18.8 g (122.0 mmol, 2.0 eq.) of 3-fluoro-4-methylbenzeneboronic acid and 24.0 g (73.66 mmol, 1.2 eq.) of Cs2CO3. The reaction mixture was degassed for 10 min and admixed with 1.25 ml (5.49 mmol, 9 mol %) of t-Bu3P and 0.412 g (1.83 mmol, 3 mol %) of Pd(OAc)2. The mixture was stirred at 105° C. for 18 h, subsequently admixed with 400 ml of dichloromethane and washed three times with 200 ml of NaHCO3 solution and water. Subsequently, the mixture was filtered through Celite, dried over MgSO4 and concentrated under reduced pressure. The viscous oil was columned on silica gel with ethyl acetate/heptane (1:5). 10.47 g were obtained, corresponding to 72.2% of theory, with a purity of 99.5%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31](=[O:34])[CH2:32]Br>CN(C)C=O>[CH3:29][O:30][C:31](=[O:34])[CH2:32][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-ol (0.99 g), N,N-dimethylformamide (40 mL), potassium carbonate (0.60 g) and bromoacetic acid methyl ester (0.32 mL) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:9 by volume) gave title compound as a white solid, 0.26 g.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4]1)[CH3:2].[C:15]([NH:22][C@H:23]([C:31](O)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(Cl)CCl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([N:3]1[C:7]([NH:8][C:31](=[O:32])[C@@H:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccncc2)cc1N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a 25 ml flask was added 1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine 20.2.0 (283 mg, 1.50 mmole), Boc-L-phenylalanine (439 mg, 1.65 mmole), EDC (375 mg, 1.95 mmole), 4-dimethylaminopyridine (202 mg, 1.65 mmole) and 5 ml of dichloromethane. The reaction was stirred at room temperature for 4 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 101.1.A (568 mg, 87% yield) as colorless amorphous. 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (brs, 1H), 8.56 (d, J=5.8 Hz, 2H), 7.64 (d, J=6.2 Hz, 2H), 7.65-7.63 (m, 5H), 6.68 (s, 1H), 5.32 (brs, 1H), 4.52 (dd, J=14.6, 7.3 Hz, 1H), 3.95 (q, J=7.2 Hz, 2H), 3.25-3.14 (m, 2H), 1.52 (s, 9H), 1.37 (t, J=7.4 Hz, 3H)
Reaction SMILES: [Br:1][CH:2]1[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][Cl:15])=[CH:11][C:4]=2[O:3]1.FC(F)(F)S(O[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][Cl:15])[CH:9]=[CH:8][C:5]=2[C:6]=1[O:7][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccc(OCCCl)cc2OC1Br
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1c(Br)oc2cc(OCCCl)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.50 g (5.15 mmol) of the hydrate of 2-bromo-6-(2-chloroethoxy)benzofuran-3-one (Example 43A) are concentrated three times with toluene under argon in order to remove water azeotropically. The residue is then dissolved under argon in 25 ml of diethyl ether and cooled to 0° C. 0.79 ml (5.66 mmol) of TEA and 1.30 ml (5.66 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate are successively slowly added dropwise, and the mixture is stirred at 0° C. for 10 min and at RT for 1 h. The diethyl ether phase is then separated off, the residue is extracted twice with diethyl ether, and the combined diethyl ether phases are concentrated. Column chromatography on silica gel 60 (mobile phase: cyclohexane) results in 2.00 g (96% of theory) of the product.