Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: OCC#Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3,4-dichloroiodobenzene (5.00 g), copper(I) iodide (69.8 mg), triphenylphosphine (240 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (378 mg), propargyl alcohol (1.19 ml), diisopropylethylamine (12.8 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 5 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-80:20) to give the object product (3.21 g) as a pale-brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:39][C:33]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=1[CH2:31][C@H:18]([NH:17][C:13]([C:9]1[S:10][C:11]([CH3:12])=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[CH3:16])[CH:8]=1)=[O:15])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (208 mg, 0.88 mmol) [prepared according to the procedure of Example 164], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (288 mg, 0.82 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (503 mg, 1.07 mmol) in Chloroform (8.5 mL). DIEA (770 μL, 4.41 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (292 mg, 0.55 mmol, 62%): LC-MS (ES) m/z=535 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8](=O)[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1.C(O)(=O)C>O>[C:26]([C:25]1[CH:29]=[C:21]([N:20]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:9]=[C:8]2[C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1CCCCC1=O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc([N+](=O)[O-])cc3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 40 g. (0.15 mole) of 2-(p-nitrophenacyl)cyclohexanone, 23 g. (0.15 mole) of 5-aminosalicylic acid and 187 ml. of glacial acetic acid was heated under reflux under nitrogen for 3 3/4 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and concentrated to a red solid which was chromatographed on silica gel. The material eluted with 3% methanol in chloroform was recrystallied from acetonitrile to provide 3.8 g. (7%) of orange crystals, m.p. 241°-242°.
Reaction SMILES: [S:1]1[C:7]2[C:8](=[C:11](C(OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][S:10][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C[O-].[Na+]>C(O)C>[S:1]1[C:7]2[C:8](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][S:10][C:6]=2[CH2:5][N:4]=[CH:3][CH2:2]1
Reactant: CCOC(=O)C(C(=O)OCC)=C1CSC2=C1SCCNC2
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C=C1CSC2=C1SCC=NC2

Procedure:
(cb) 2.56 g of diethyl [3,4-dihydrothieno[2,3-f][1,4]thiazepin-8(5H)-ylidene]malonate was suspended in 15.6 ml of ethanol and, after the addition of 4.3 ml of 2N ethanolic sodium methylate solution, the mixture was heated to reflux until the reaction was completed. The solvent was removed in vacuo and the residue was taken up in 60 ml of water and extracted several times with methylene chloride. After washing the organic phases with water and drying with sodium sulfate, they were chromatographed on silica gel. After recrystallization, there was obtained ethyl [6,7-dihydrothieno[2,3-f][1,4]thiazepine-8-(5H)-ylidene]acetate in the form of yellowish crystals, m.p. 86°-87° (ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([S:19][CH3:20])[C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27][NH2:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([S:19][CH3:20])[C@H:14]([C:16](=[O:18])[NH:28][CH2:27][CH2:26][C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([OH:22])[CH:24]=1)[CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: NCCc1cccc(O)c1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS[C@H]([C@@H](C)C(=O)NCCc1cccc(O)c1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a stirred solution of (2S)-2-[(1R,2S)-2-carboxy-1-methylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.7 g, 5.6 mmol) in CH2Cl2 (20 mL) were added 3-hydroxyphenethylamine hydrobromide (2.44 g, 11.2 mmol), BOP(3.72 g, 8.4 mmol), HOBT (1.29 g, 8.4 mmol), and diisopropylethylamine (4.88 mL, 28.0 mmol) at room temperature. After being stirred at room temperature for 2 hr, the mixture was quenched with 1N HCl (80 mL×3), extracted with AcOEt, dried (MgSO4) and concentrated in vacuo to give a crude oil, which was purified by flash column chromatography (hexane:AcOEt=1:1) to give (2S)-2-{(1R,2S)-2-[2-(3-hydroxy-phenyl)-ethylcarbamoyl]-1-methylsulfanyl-propyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a gum (2.07 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:23](O)[CH3:24]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:23][CH3:24])=[O:7]
Reactant: CCO
Reactant: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(C2=CC(=O)CCC2CC)c(Cl)c1Cl

Procedure:
A stirred solution of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (3.43 g, 0.01 mole) in ethanol (50 ml) containing sulfuric acid (4 drops) was heated at reflux for 4 hours. The ethanol was evaporated at reduced pressure, the residue dissolved in ether, washed with dilute sodium hydroxide, water, dried over magnesium sulfate and evaporated in vacuo to give 3.31 g of ethyl [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)-phenoxy]acetate which melted at 110°-112° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=4[CH3:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:36](/B(O)O)=[CH:37]/[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](/[CH:36]=[CH:37]\[CH3:38])=[CH:29][C:28]=4[CH3:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C/C=C\B(O)O
Reactant: Cc1cc(Br)ccc1OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)c(C)c1
Temperature: 100 °C
Yield: 71.9 %

Procedure:
A mixture of 4-bromo-2-methylphenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (32.5 mg, 0.058 mmol, Example 143), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.76 mg, 5.79 μmol, Combiphos Catalysts, Inc.), (Z)-prop-1-enylboronic acid (14.92 mg, 0.174 mmol, Aldrich) and cesium carbonate (94 mg, 0.289 mmol, Aldrich) in DMF (0.6 mL) and water (0.12 mL) was heated under microwave conditions (100° C., 20 min). The reaction mixture was purified by preparative HPLC (C18 column; 40-100% methanol in water containing 0.05% trifluoroacetic acid) to give the title compound (21.8 mg, yellow solid, 72%) upon lyophilization. MS (ESI) 523 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][CH:4]=[N:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:1][N:2]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cc1ccc(Br)cc1
Reactant: Cn1nccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccnn2C)cc1
Temperature: 80 °C

Procedure:
(1-Methyl-1H-pyrazol-5-yl)boronic acid (2.0 g, 16 mmol), 1-bromo-4-methylbenzene (1.96 mL, 15.9 mmol), sodium carbonate (5.05 g, 47.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (557 mg, 0.794 mmol) were combined in a mixture of water (20 mL) and 1,2-dimethoxyethane (100 mL), and heated at 80° C. for 18 hours. After the reaction mixture had cooled, it was filtered through Celite, and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 0% to 50% ethyl acetate in heptane) provided the product as a yellow oil. Yield: 1.15 g, 6.68 mmol, 42%. LCMS m/z 173.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 3.89 (s, 3H), 6.29 (d, J=2.0 Hz, 1H), 7.30 (br AB quartet, JAB=8 Hz, ΔvAB=18 Hz, 4H), 7.51 (d, J=1.9 Hz, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]=2)=[O:5])C.[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>CN(C=O)C.O>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([OH:32])=[O:31])=[O:5])[N:7]=[C:8]2[C:25]#[N:26])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Reactant: CC(C)(N)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 92 %

Procedure:
7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (US Patent Publication No. 2007/627906) (40 mg, 0.115 mmol) was dissolved in anhydrous DMF (2 mL). 3-Amino-3-methyl-butyric acid (68 mg, 0.5742 mmol) and solid sodium methoxide (25 mg, 0.459 mmol) were added sequentially and the mixture heated to 140° C. in an oil bath for 3.5 h. Upon completion, the reaction mixture was cooled and diluted with water. The solution was acidified to pH 3 with 1M hydrochloric acid inducing precipitation of the product. The free acid was isolated by filtration and dried to provide the title compound as a tan solid in 92% yield. MS ESI(−) m/e: 417.9596 (M−1), MS ESI(+) m/e: 419.9934 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OCC4C=CC=CC=4)[CH2:25]3)=[O:23])[C:17]1=[O:42])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:22](=[O:23])[C@@H:21]([N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)(=[O:14])=[O:13])[C:17]2=[O:42])[CH3:41])[CH2:25]1
Reactant: C[C@@H](C(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)N1CCC[C@H](N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
Benzyl (3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate (0.128 g) was dissolved in DCM (3.5 ml) and treated with trifluoroacetic acid (10.5 ml) and stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the residue purified by SPE (acid ion-exchange, eluting with ethyl acetate:methanol 9:1) to give the title compound (0.093 g) as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][C:23]=2[C:24]#[N:25])=[CH:19][C:18]=1[C:34]([F:37])([F:36])[F:35]>>[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]2[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:2]3[CH:14]=[C:6]4[N:7]([CH:11]5[CH2:13][CH2:12]5)[CH2:8][CH2:9][CH2:10][N:5]4[C:4](=[O:15])[N:3]=3)=[CH:26][C:23]=2[C:24]#[N:25])=[CH:19][C:18]=1[C:34]([F:35])([F:36])[F:37]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Product: N#Cc1cc(COc2cc3n(c(=O)n2)CCCN3C2CC2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and 2-(4-chloro-3-(trifluoromethyl) phenoxy)-5-(hydroxymethyl)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][N:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH2:17][CH2:18][NH:19][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCCn1c2ccc(Br)cc2c2cc(Br)ccc21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CCCNc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
N-(3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-2-nitro-N-phenylbenzenesulfonamide (0.0378 g, 0.0588 mmol, 1 equiv), cesium carbonate (0.0574 g, 0.176 mmol, 3 equiv) and benzenethiol (0.0194 g, 0.176 mmol) were mixed in 1 mL anhydrous THF. The mixture was stirred at room temperature for 3 hours. THF was removed under vacuum and the residue was purified by silica gel chromatography using Hexanes/EtOAc to afford 0.0164 g colorless oil as product, yield 60.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[B:10]([OH:12])[OH:11].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[B:10]([OH:12])[OH:11]
Reactant: C1CCNC1
Reactant: O=Cc1ccc(Cl)c(B(O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OB(O)c1cc(CN2CCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (2-chloro-5-formylphenyl)boronic acid (1.00 g, 5.42 mmol) in DCM (30 mL) were added pyrrolidine (0.45 mL, 5.42 mmol) and sodium triacetoxyborohydride (2.39 g, 11.3 mmol). The reaction mixture was allowed to stir at rt for 2.5 h and then diluted with brine. The mixture was extracted with DCM. The organic solutions were combined, dried over Na2SO4, filtered and concentrated to give [2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]boronic acid.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO.C(=O)(O)[O-].[Na+]>O.C(O)(C)C.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 12.7 g.), conc. hydrochloric acid (9.6 ml.), methanol (9.5 ml.) and tetrahydrofuran (9.5 ml.) was stirred at room temperature for 3 hours. The resultant solution was concentrated in vacuo, and the residue was suspended in water. The suspension was adjusted to pH 3.5 with sodium bicarbonate under ice cooling, and stirred at same temperature for 30 minutes. The precipitates were collected by filtration and dried over magnesium sulfate to give the powder (10 g.). The powder was suspended in water (300 ml.) and adjusted to pH 7.0 with sodium bicarbonate. The solution was adjusted to pH 6.0 with 10% hydrochloric acid and subjected to column chromatography on nonionic absorption resin (Diaion HP-20: trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (300 ml.) with 10% aqueous solution of isopropyl alcohol. The eluate was adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling, and the precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 7.2 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[S:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:21].[CH2:28]([Mg]Br)[CH2:29][CH:30]([CH3:32])[CH3:31]>C1COCC1>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[C:7](=[O:21])[CH2:8][N:9]([CH2:13][C:14]2[S:18][C:17]([CH:19]([OH:20])[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:16][CH:15]=2)[S:10]1(=[O:12])=[O:11]
Reactant: CC(C)CC[Mg]Br
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C=O)s3)S2(=O)=O)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(O)CCC(C)C)s3)S2(=O)=O)c(OC)c1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
A solution of the title B compound, 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carbaldehyde (545 mg, 1.33 mmol) in dry THF (8 mL) is added dropwise to a cold (−70° C.) solution of isopentylmagnesium bromide (2.22 mmol) in dry THF (10 mL) keeping the temperature below −65° C. The mixture is stirred at −70° C. for 45 min and the reaction is quenched with saturated aqueous NH4Cl solution. The mixture is diluted with EtOAc and the layers are separated. The organic layer is dried over anhydrous MgSO4 and the solvent is evaporated. The residue is chromatographed on silica gel using 0→100% EtOAc in hexane as the eluent to afford 2-(2,4-dimethoxy-benzyl)-5-(5-(1-hydroxy-4-methyl-pentyl)-thiophen-2-ylmethyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one a yellow oil: [M+NH4]+=500.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9]2)=[C:6]([F:17])[C:5]([F:18])=[C:4]([F:19])[CH:3]=1>[Pd].CCO>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][CH:8]([C:7]2[CH:2]=[CH:3][C:4]([F:19])=[C:5]([F:18])[C:6]=2[F:17])[NH:13][C:12]1=[O:14]
Reactant: CC1(C)CCC(c2c(Br)cc(F)c(F)c2F)NC1=O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCC(c2ccc(F)c(F)c2F)NC1=O

Procedure:
A solution of 6-(6-bromo-2,3,4-trifluorophenyl)-3,3-dimethylpiperidin-2-one (27.0 mg, 0.080 mmol, described in Intermediate 17) and 10% palladium on carbon in degassed EtOH (2 mL) was stirred under a hydrogen balloon for 3 h. The reaction mixture was filtered through a Celite pad and concentrated in vacuo to provide the title compound. MS: m/z=258 (M+1).
Reaction SMILES: [O:1]([C:8]1[C:9]([C:14]#[N:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:18])C.C(O)(C)C>C(O)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[N+:10]([O-:18])[C:9]=1[C:14]#[N:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: N#Cc1ncccc1Oc1ccccc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Temperature: 95 °C

Procedure:
A solution of 9.6 g of 3-phenoxy-2-pyridinecarbonitrile, [J. Med. Chem. 18, 1 (1975)] in 25 ml of glacial acetic acid is treated with 25 g of 40% peracetic acid in acetic acid. The mixture is heated at 95° C. for 16 hours. One hundred ml of isopropanol is added and the mixture is concentrated at reduced pressure. The residue is dissolved in 250 ml of dichloromethane and the organic layer is washed with excess dilute sodium hydroxide solution and is dried over anhydrous MgSO4.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=Cc1c(Br)ccc2c1OCO2
Product: O=Cc1c(-c2ccccc2F)ccc2c1OCO2

Procedure:
The process described in Method B was followed. 5-Bromo-1,3-benzodioxole-4-carbaldehyde (0.458 g, 2.00 mmol) and 2-fluorophenylboronic acid (0.420 g, 3.00 mmol) were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of hexane:ethyl acetate (4:1) as the eluent.