Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8](=S)[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:22]O>O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[Cl:17])[O:11][N:22]=2)=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)OCc1ccc(Cl)cc1)c1sccc1Cl
Reactant: NO
Agent: Cl
Solvent: O
Product: Clc1ccc(COc2noc(-c3sccc3Cl)n2)cc1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A stirred solution of (3-chlorothiophene-2-carbonyl)-thiocarbamic acid O-(4-chloro-benzyl) ester (52.3 mg, 0.151 mg), hydroxylamine hydrochloride (20.7 mg, 0.298 mmol) was refluxed under argon for 1 h. The solution was cooled to room temperature, then water (6 mL) was added to precipitate the product, and the mixture was filtered. The filter cake was dissolved in dichloromethane, filtered through glass wool, and rotary evaporated to dryness. The product was recrystallized from dichloromethane/methanol to yield 3.1 mg (6.2%) of the title compound as a white solid. 1H NMR (CDCl3): 7.58 (d, J=5.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.1 Hz, 1H), 5.36 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12](=[S:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1C=CC=CC=1.C(O)C>[C:5]1([C:3]2[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:18][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (1.790 g, 8.99 mmol) and ethyl 2-amino-2-thioxoacetate (Example 4A, 1.20 g, 9.01 mmol) in benzene (80 mL) and ethanol (10 mL) was stirred at room temperature for 18 h. The mixture was heated at 80° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate (100 mL). The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual clear oil was chromatographed on silica gel (4×10 cm, elution toluene-ethyl acetate 0-2-4%) and gave a yellow oil (1.588 g). This was distilled in vacuo (bp: 105-115° C./0.1 torr, bulb to bulb distillation, air bath temperature) to provide the title material (1.409 g, 67%) as a pale yellow syrup which solidified to an almost colorless solid upon standing. LC (Method C): 2.009 min. HRMS (ESI) calcd for C12H12NO2S [M+H]+ m/z 234.0583. found 234.0597. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.48 (t, J=7.2 Hz, 3H), 4.52 (q, J=7.2 Hz, 2H), 7.35-7.49 (m, 3H), 7.75 (s, 1H), 7.93-8.00 (m, 2H).
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([C:23]1[CH:27]=[CH:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH:24]=1)[C:12]([NH:14][C@H:15]1[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]1=[O:22])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH:26]=[CH:27][C:23]([C@@H:11]([C:12]([NH:14][C@H:15]4[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]4=[O:22])=[O:13])[CH2:10][C:9]([OH:42])=[O:8])=[CH:24]3)=[CH:33][CH:32]=2)=[CH:35][CH:36]=1)#[N:41]
Reactant: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 81 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4, 4-dimethyl-2-oxo-tetrahydrofuran-3 (S)-yl)succinamic acid benzyl ester was hydrogenolyzed in EtOH/EtOAc for 3h to give a 81% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4, 4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48]CC(C)=CC=C)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCO.[Pd]>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[OH:48])(=[O:40])=[O:41])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC=C(C)COc1ccccc1S(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 104.9 %

Procedure:
4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-penta-2,4-dienyloxy)-benzenesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoic acid (0.55 g, 0.70 mmole), (Step 1, Example 183) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixture was filtered through Celite and concentrated. The residue was chromatographed with 35-40% EtOAC/hexane to give the desired product (0.50 g, 95%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]#[N:30])=[C:24](B(O)O)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:29]#[N:30])=[C:22]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:18])[CH:3]=2)[CH:21]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: CCCCC(C(=O)OCC)n1ccc(I)cc1=O
Product: CCCCC(C(=O)OCC)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
150 mg (0.41 mmol) of ethyl 2-(4-iodo-2-oxopyridin-1(2H)-yl)hexanoate (racemate) and 97 mg (0.53 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 114 mg (purity 95%, 70% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.O>CN(C)C=O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([O:1][CH2:2][CH2:3][C@@H:4]2[CH2:6][C@@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:9][CH2:8]2)=[N:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 860 mg (2.83 mmol) benzyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate in 14.5 ml anhydrous N,N-dimethylformamide at ambient temperature was added 147 mg (3.68 mmol) sodium hydride. The solution was stirred for 20 minutes. 669 mg (2.83 mmol) 2-bromo-5-(methylsulfonyl)pyridine was added into the solution. It was heated to 50° C., and stirred for 3 hours. 100 ml water was added into the mixture, and it was extracted with 50 ml ethyl acetate three times. The crude product was dried and purified using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) to give the title compound as colorless oil. 1H NMR (CDCl3): δ 8.71 (d, J=2.4 Hz, 1H), δ 8.03 (dd, J=8.8 Hz, 2.5 Hz, 1H), δ 7.30-7.37 (m, 5H), δ 6.84 (d, J=8.7 Hz, 1H), δ 5.13 (s, 2H), δ 4.49 (t, J=7.1 Hz, 2H), δ 4.10-4.16 (m, 2H), δ 3.07 (s, 2H), δ 2.75-2.76 (m, 2H), δ 2.08-2.12 (m, 1H), δ 1.74-1.75 (m, 2H), δ 1.50-1.56 (m, 2H), δ 1.29-1.40 (m, 2H), δ 0.88-0.99 (m, 2H), δ 0.56-0.70 (m, 2H). LC/MS 459.2 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].OO.S(S([O-])=O)([O-])(=O)=[O:18].[Na+].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
4-methylthio-3-nitrobenzoic acid (4.36 g, 20 mM) was dissolved in acetic acid (200 ml), and treated at ambient temperature with H2O2 (2.5 ml, 30%, 22 mM). After stirring at ambient temperature for 4 days, excess peroxide was decomposed with sodium metabisulfite, and solvent evaporated. The residue was purified by chromatography on silica, eluting with methanol, to give 4-methanesulphinyl-3-nitrobenzoic acid (4.1 g, 89%), mp 238-239°. Nmr (DMSO-d6): δ 2.90 (s, 3H); 8.29 (d, 1H); 8.56 (dd, 1H); 8.68 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: ClCCCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCCCl)ccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
Compound b2 may be prepared according to reported methods (see, e.g., Gumbley, P.; Koylu, D.; Thomas, S. W. Macromolecules 2011, 44, 7956). 1-Bromo-3-chloropropane (0.650 mL, 0.00658 moles) was added to a solution of 5-hydroxy-2-nitrobenzaldehyde (1.0 g, 0.00598 moles), and potassium carbonate (1.66 g, 0.0120 moles) in anhydrous DMF (6 mL). The solution was stirred at 40° C. for 24 hours. The reaction was diluted with ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution (75 mL), water (75 mL), and brine (75 mL). The organic layer was dried with anhydrous magnesium sulfate, which was removed by filtration. The filtrate was concentrated, and the resulting residue was subject to silica gel chromatography using a gradient of 100% hexanes to 50% ethyl acetate in hexanes. The fractions containing the product were collected, and volatiles were removed by rotary evaporation. The resulting residue was dried overnight to yield 5-(3-chloropropoxy)-2-nitrobenzaldehyde as a bright-green yellow solid (yield 87%*). 1H NMR (400 MHz, CD2Cl2) δ 10.42 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 7.32 (d, J=2.9 Hz, 1H), 7.18 (dd, J=9.0, 2.9 Hz, 1H), 4.27 (t, J=5.9 Hz, 2H), 3.76 (t, J=6.3 Hz, 2H), 2.35-2.24 (m, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 189.05, 163.84, 135.04, 127.84, 119.16, 114.57, 66.28, 41.74, 32.35 HRMS m/z: calculated for C10H10ClNO4 [M+H]+, 244.0371. found, 244.0366.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].P(Br)(Br)[Br:14].[OH-].[Na+]>CCOC(C)=O>[Br:14][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(C)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bromination. To a solution of 1.65 g of 2,5-dimethyl-4-nitro-pyridine 1-oxide in 50 mL dry EtOAc was added 11.1 mL PBr3 at rt. The mixture was heated to reflux over 0.5 h. Reflux continued for 3 h, then cooled to rt and poured into ice and EtOAc. The resulting mixture was brought to pH 10 with addition of NaOH pellets and layers were separated. An additional EtOAc extraction was combined with the first and the organic layers were washed with brine, dried whith Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes-EtOAc) to provide 4-bromo-2,5-dimethyl-pyridine (248 mg). LCMS (m/z) 186.
Reaction SMILES: [CH2:1]([N:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=O)[O:8]C1=O)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:18][N:19]([CH3:21])[NH2:20]>C1(C)C=CC=CC=1>[CH3:18][N:19]([CH3:21])[NH:20][C:9](=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1c(=O)oc(=O)c2ccccc21
Reactant: CN(C)N
Solvent: Cc1ccccc1
Product: CCCCCNc1ccccc1C(=O)NN(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
The obtained 1-pentyl-3,1-benzoxazin-2,4-(1H)-dione (0.301 g, 1.29 mmol) was dissolved in toluene (4 ml), N,N-dimethylhydrazine (0.10 ml, 1.32 mmol) was added, and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give N′,N′-dimethyl-2-pentylaminobenzohydrazide (0.218 g, 0.87 mmol, yield 67%). This was dissolved in methanol (3 ml), 36% formalin (0.35 ml, 4.31 mmol), sodium cyanoborohydride (0.174 g, 2.62 mmol) and acetic acid (0.1 ml) were added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added. The mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give an acylhydrazine compound N′,N′-dimethyl-2-(N-methyl-N-pentylamino)benzohydrazide (0.103 g, 0.39 mmol, yield 45%).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=3)[NH2:19])[C:10]=2[CH:9]=[CH:8]1.CCN(C(C)C)C(C)C.[CH3:34][C:35](=[CH2:39])[C:36](Cl)=[O:37]>ClCCl>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:19][C:36](=[O:37])[C:35]([CH3:39])=[CH2:34])[CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc(N)c3)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (10.0 g, 29.4 mmol) in dichloromethane (200 mL), was added DIPEA (12.0 g, 92.9 mmol) followed by dropwise addition of a solution of 2-methylprop-2-enoyl chloride (4.60 g, 44.0 mmol) in dichloromethane (50 mL) at −5 to 0° C. The reaction was stirred overnight at room temperature, quenched by addition of water (150 mL), and extracted with dichloromethane (×3). The organic layers were combined, washed with water and HCl solution (0.5 M in water), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C22H29N4O2Si [M+H]+: 409, found 409.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:46]([Si:48]([CH2:70][CH3:71])([CH2:68][CH3:69])[O:49][CH2:50][CH2:51][C:52]1[C:53]2[C:62]3[C:61](=[CH:63][CH:64]=1)[S:60](=[O:66])(=[O:65])[NH:59][C:58](=[O:67])[C:57]=3[CH:56]=[CH:55][CH:54]=2)[CH3:47].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:59]3[C:58](=[O:67])[C:57]4[CH:56]=[CH:55][CH:54]=[C:53]5[C:52]([CH2:51][CH2:50][O:49][Si:48]([CH2:68][CH3:69])([CH2:70][CH3:71])[CH2:46][CH3:47])=[CH:64][CH:63]=[C:61]([C:62]=45)[S:60]3(=[O:66])=[O:65])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: CC[Si](CC)(CC)OCCc1ccc2c3c(cccc13)C(=O)NS2(=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3C(=O)c4cccc5c(CCO[Si](CC)(CC)CC)ccc(c45)S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 7-(2-triethylsilanyloxy-ethyl)-1,1-dioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-3-one (431 mg, 1.1 mmol) in anhydrous tetrahydrofuiran (7 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography, eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-[1,1,3-trioxo-7-(2-triethylsilanyloxy-ethyl)-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-ylmethyl]-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To a solution of 5-cyanoindole (3.0 g, 21 mmol) in dry DMF (50 ml) was added N-chlorosuccinimide (2.94 g, 22 mmol) and the solution stirred at room temperature for 1 hour. The solution was left standing over the weekend. LC/MS showed a single product. Added ethyl acetate (150 ml) and diethyl ether (50 ml) and washed with water (3×300 ml). Dried over MgSO4 and evaporated off the solvent to yield 3.9 g of the title compound as a pale yellow solid. δH (400 MHz, d6-DMSO) 7.54 (1H, dd), 7.61 (1H, dd), 7.78 (1H, d), 8.01-8.02 (1H, m), 12.2 (1H, broad s). MS (from LCMS of reaction mixture) (ES):C9H5ClN2 requires 176; found 177 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.[Li+].[OH-].O.Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][N:4]([CH2:16][CH2:17][Cl:18])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(N(CCCl)CCCl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added methyl 2-(4-(bis(2-chloroethyl)amino)phenyl)acetate (B-4) (3.4 g, 11.68 mmol), LiOH (1.7 g, 70.83 mmol), H2O (100 mL) and THF (50 mL). The reaction mixture was stirred at 50° C. for 2 h. After cooled down to r.t., the reaction mixture was adjusted with HCl (1 N) to pH7 and extracted with EtOAc (100 ml*2), the mixture was dried over Na2SO4 and concentrated under reduced pressure. The crude product (2.8 g) was used next step without further purification. LC-MS: (M+H)+=277;
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[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[N:29][C:30]=2[Cl:32])[N:25]([CH3:33])[N:24]=1>>[Cl:32][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:25]([CH3:33])[N:24]=[C:23]([CH2:22][O:14][C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])[C:31]=12
Reactant: Cc1nnc(-c2ccc(C)c(O)c2)o1
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nnc(-c2ccc(C)c(OCc3nn(C)c4ncnc(Cl)c34)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol (73.3 mg, 0.385 mmol) and potassium carbonate (60.9 mg, 0.432 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (89.6 mg, 0.343 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 4-chloro-1-methyl-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 34.9 mg).
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](B(O)O)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:1]1([C:7]2[C:20]3[C:15]([C:14]([C:28]4[CH:29]=[CH:30][C:25]([Br:24])=[CH:26][CH:27]=4)=[C:13]4[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(Br)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Yield: 43.8 %

Procedure:
An amount of 2.46 g (8.26 mmol) of 10-phenylanthracene-9-boronic acid synthesized in the same manner as in Exemplary Synthesis 2, 9.75 g (41.3 mmol) of p-dibromobenzene, and 250 mg of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 60 ml of toluene and 15 ml of ethanol. Then, 30 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 1.48 g (3.62 mmol) of 9-phenyl-10-(4-bromophenyl)anthracene. The yield was 43.8%.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10]\NC(OC(C)(C)C)=O)=[C:4]([F:25])[CH:3]=1.Cl.NO.C([O-])(=[O:31])C.[Na+]>C(O)C.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10][OH:31])=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N/N=C(/c1ccncc1)c1cc(F)c(Br)cc1F
Reactant: CC(=O)[O-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccncc1)c1cc(F)c(Br)cc1F
Yield: 114.1 %

Procedure:
A solution of Z/E 1-(4-bromo-2,5-difluorophenyl)-1-(4-pyridinyl)methanimine (Intermediate 1, 150 mg) in ethanol (2 ml) was treated with a solution of hydroxylamine hydrochloride (44 mg) and sodium acetate (50 mg) in water (0.4 ml) then stirred at reflux for 2 h. The ethanol was removed under vacuum and the residue was partitioned between water and ethyl acetate. The aqueous layer was re-extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under vacuum. The residue was purified on an SPE cartridge (silica, 2 g) eluting with cyclohexane/ethyl acetate (4:1 to 1:1) to give the title compound as a white foam (130 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].Cl[C:13]([C:15]1([CH3:30])[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=O>>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][C:15]1([C:30]1[O:11][C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:13])=[O:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Product: CC1(c2nc3cccc(C(=O)O)c3o2)CCCN1C(=O)OCc1ccccc1

Procedure:
2-(1-(Benzyloxycarbonyl)-2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxylic acid is prepared from 3-aminosalicylic acid and benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate using identical conditions described in Example 3A. MS (ESI) m/e 381 [M+H]+.