Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: Oc1ccc(OCCCCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CCCCCOc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 62.1 %

Procedure:
Compound 13a (0.15 g, 0.58 mmol) and compound N-methylaniline (0.07 mL, 0.64 mmol) were stirred in acetonitrile (5 mL) for 30 mins and then diisopropylethylamine (0.24 mL, 1.74 mmol) was added dropwise. The reaction was then stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 13 as a colorless oil (0.05 g, 0.36 mmol, 30% yield). MS (ESI, positive) m/z calcd. for C18H24NO2 [M+H]+: 286.18, found: 285.95. 1H NMR (CDCl3, 400 MHz) δ 7.25 (t, J=8.8 Hz, 2H), 6.70-6.85 (m, 7H), 4.72 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.36 (t, J=7.6 Hz, 2H), 2.95 (s, 3H), 1.85-1.78 (m, 2H), 1.63-1.71 (m, 2H), 1.47-1.55 (m, 2H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.Cl[C:33]([O:35][CH2:36][CH2:37]Cl)=[O:34].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([N:6]5[CH2:37][CH2:36][O:35][C:33]5=[O:34])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N2CCOC2=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.5 %

Procedure:
To a 6 ml tetrahydrofuran solution of 150 mg (0.425 mmol) of the compound obtained in Example 44, 79 μl (0.765 mmol) of 2-chloroethyl chloroformate and triethylamine were added, and the mixture was stirred at room temperature for 20 hours. Further, 30 μl (0.29 mmol) of 2-chloroethyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. To a 2 ml ethanol solution of the residue, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. Then, the reaction mixture was neutralized with a 1M aqueous solution of hydrochloric acid, and extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to obtain 116 mg (65%) of the captioned compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=O)[CH3:14])=[CH:8][CH:7]=1.[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19].O>C1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:19][CH2:18][CH:17]([OH:16])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CC(=O)Cc1ccc(OCCCO)cc1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(OCCCO)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 27.4 %

Procedure:
A mixture of 1-[4-(3-hydroxypropoxy)phenyl]-propan-2-one (1.8 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (1.8 g) were mixed in dry benzene (80 ml) and boiled under reflux in a Dean and Stark apparatus until water evolution was complete. The solvent was evaporated, the residue dissolved in methanol, platinum oxide (50 mg) added and the imine reduced in the presence of hydrogen at atmospheric pressure. When hydrogen uptake ceased the catalyst was removed by filtration and the solvent evaporated. The residue was chromatographed on silica-gel in 4% methanol-dichloromethane to give the title compound (0.94 g) as a colourless oil. Crystallisation from etherhexane gave a white solid, mp 97°-103°, as a 74:26 mixture of diastereoisomers.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[S:25])[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCc1nn(C)c2c(=S)[nH]c(-c3ccccc3OCC)nc12
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75 ml) and ethanol 300 ml were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=3)[N:8]=[N:7][C:6]=2[C:21](O)=[O:22])[CH2:3][CH2:2]1.C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:6]2[N:7]=[N:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=3)[C:5]=2[CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:22])[CH2:29][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC2CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 183.8 %

Procedure:
5-(Cyclopropylmethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylic acid (503 mg, 1.60 mmol) obtained in Example 96b), HOBt (109 mg, 0.800 mmol, 0.5 eq.) and cyclopropylamine (0.149 ml, 2.08 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8 ml), WSC (376 mg, 1.92 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (50 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (3:1, 40 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (518 mg, 1.47 mmol, 91.6%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10])#[CH:2].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:13]=1[CH3:19]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:12]1[C:13]([CH3:19])=[C:14]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][OH:10])[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1ccccc1CO
Reactant: Cc1c(Br)cccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C#Cc1ccccc1CO
Temperature: 60 °C
Yield: 57 %

Procedure:
Step 1 A mixture of (2-ethynylphenyl)methanol (100 mg, 0.757 mmol), 1,3-dibromo-2-methylbenzene (189 mg, 0.757 mmol) and TEA (0.211 mL, 1.513 mmol) in THF (2 mL) was purged with nitrogen and treated with copper (I) iodide (2.88 mg, 0.015 mmol) and bis(triphenylphosphine)palladium(II) chloride (26.6 mg, 0.038 mmol). The mixture was heated in a sealed tube at 60° C. for 1.5 h. The mixture was filtered, the filtrate was washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide (2-((3-bromo-2-methylphenyl)ethynyl)phenyl)methanol as a white solid (130 mg, 57%). 1H NMR (400 MHz, chloroform-d) δ 7.44-7.58 (4H, m), 7.39 (1H, td, J=7.54, 1.43 Hz), 7.27-7.34 (1H, m), 7.00-7.09 (1H, m), 4.93 (2H, d, J=6.38 Hz), 2.64 (3H, s). Mass spectrum m/z 323, 325 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]2[CH:10]=[CH:9][N:8]([S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 2.160 mmol) was placed in DMF (5 mL) at 0° C. NaH (0.10 g, 2.59 mmol) was then added, and the reaction was stirred for 20 minutes. Benzenesulfonyl chloride (0.304 mL, 2.38 mmol) was then added, and the reaction was stirred for 30 minutes at 0° C. Water (50 mL) was then added. The precipitate was filtered, washed with water, washed with ether, and dried to give 5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.8 g, 99.6% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:14][O:15][C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:18].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:26])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:18][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
t-Boc-glycine (1.75 g, 1.00 ×10-2 mole), L-phenylalanine methyl ester hydrochloride (2.16 g, 1.00 ×10-2 mole), and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (2.47 g, 1.00 ×10-2 mole), and CH2Cl2 (50 ml) are stirred at room temperature for 16 hours. The reaction mixture is then washed in turn with 0.5M aqueous HCl (2 times) and saturated aqueous NaHCO3 before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate gives 6as an extremely viscous, almost colorless oil, which was shown to be homogeneous by TLC on silica gel plates and the structure corroborated by NMR. NMR (CDCl3) δ1.42 (S, 9, t-boc), 3.02 (d,2, benzylic methylene), 3.59 (S, 3, ester), 7.13 (S, 5, aromatic).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cu][C:14]#[N:15]>CN(C=O)C.C(OCC)(=O)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:14]#[N:15])[CH:11]=[CH:10]2
Reactant: N#C[Cu]
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-bromo-2-naphthol (25.0 g, 112 mmol) and copper(I) cyanide (11 g, 123 mmol) in DMF (30 mL) was heated to 135° C., stirred for 18 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), triturated with 10% sodium hydroxide, and filtered through diatomaceous earth (Celite®). The filtrate was adjusted to pH 2 and extracted with ethyl acetate. The combined extracts were concentrated, dissolved in ethanol (150 mL), triturated with water, and filtered to provide the desired product.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([O:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:19][C:18]=1[OH:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.O>ClCCl>[Si:1]([O:33][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Yield: 108.7 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (579 mg, 3.84 mmol) in dichloromethane (10 cm3) was added to a stirred solution of benzyl 4-benzyloxy-3-hydroxy-benzoate (642.3 mg, 1.92 mmol) and imidazole (327 mg, 4.80 mmol) in dichloromethane (15 cm3). A thick precipitate formed immediately. After 1 h the mixture was poured into water (50 cm3). The layers were shaken and separated and then the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined extracts were washed with brine (50 cm3) then dried (Na2SO4) and evaporated to a pale yellow oil. This was taken up in 20% ethyl acetate in petroleum ether and filtered through a plug of silica. Evaporation of the filtrate gave the title compound as a pale yellow oil (936 mg) which was used immediately for the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11][C:12]3[C:13]([N+:22]([O-:24])=[O:23])=[CH:14][C:15]4[S:19][C:18](=[O:20])[NH:17][C:16]=4[CH:21]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.S([O-])([O-])(=[O:27])=S.[Na+].[Na+]>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:12]3[C:13]([N+:22]([O-:24])=[O:23])=[CH:14][C:15]4[S:19][C:18](=[O:20])[NH:17][C:16]=4[CH:21]=3)=[O:27])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=c1[nH]c2cc(Sc3cccc4cnccc34)c([N+](=O)[O-])cc2s1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(S(=O)c3cccc4cnccc34)c([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.6 %

Procedure:
5-(5-Isoquinolylsulfanyl)-6-nitro-2,3-dihydro-benzo[d][1,3]thiazol-2-one 300 mg (0.8 mmol) was dissolved in acetic acid 20 ml, 35% hydrogen peroxide 15 ml was added, and the mixture was stirred for 15 hours at room temperature. Saturated sodium thiosulfate was added to the reaction solution, the resulting precipitates were collected and washed with water, and 5-(5-isoquinolylsulfinyl)-6-nitro-2,3-dihydro-benzo[d][1,3]thiazol-2-one 190 mg (61.6%) was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[CH2:10][N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1ccccc1Cc1ccccc1)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
Methyl 2-[N-(2-(benzyl)benzyl)-N-ethylamino]-5-pyridinecarboxylate (0.9 g, 2.5 mmol) in THF (6 ml) and methanol (6 ml) were treated with 1N aqueous sodium hydroxide (7 ml), and stirred at ambient temperature overnight. The clear solution was evaporated to low bulk, treated with water and glacial acetic acid to pH 4. The resultant white precipitate was stirred for 15 minutes, filtered, washed well with water, then sucked dry to yield the title product as a white solid (0.8 g, 92%). MS: (M+H)+347 (M·)+346
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:41](=[O:42])[C@@H:40]([NH:39][C:37]([O:36][CH3:35])=[O:38])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][CH:24]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccc(-c2ccccn2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution containing the product from Example 23Q (0.442 g, 0.95 mmol) in THF (10 mL) was treated with the product from Example 1F (0.20 g, 1.06 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.88 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-75% ethyl acetate/dichloromethane to give the title compound (0.34 g, 56% yield).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([CH:10]=[N:11]O)[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.CCN(CCOC1C=CC(CC2C=CC=CC=2)=CC=1)CC.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:11])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=[N+]([O-])c1sc(Br)cc1C=NO
Agent: CCN(CC)CCOc1ccc(Cc2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Temperature: 111 °C
Reaction time: 24 h

Procedure:
5-Bromo-2-nitrothiophene-3-carbaldehyde oxime (45 g, 179 mmol), p-toluenesulfonic acid monohydrate (2.73 g, 14.34 mmol), dppe (1.428 g, 3.58 mmol) and Ru(PPh3)3(CO)H2 (3.29 g, 3.58 mmol) were taken up in toluene (750 mL). The flask was evacuated and back-filled with N2 (3×) before stirring at 111° C. under N2 for 24 hours. After cooling to room temperature, the reaction mixture was purified directly by flash silica gel column chromatography (0-100% EtOAc-toluene) to give the title compound as brown needles after recrystallising from EtOH-hexanes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][OH:13])[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH2:12][O:13][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)[C@@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)[C@@H]1C[C@@]2(CO)C[C@H]2N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@]2(COC3CCCCO3)C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (1R,3S,5S)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester (500 mg, 1.75 mmol), 3,4-dihydro-2H-pyran (176 μL, 1.93 mmol) and TsOH.H2O (33 mg, 0.17 mmol) in CH2Cl2 (6 mL) was stirred 3 h at RT. Then poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). Colorless oil. TLC, Rf (EtOAc)=0.85; MS (UPLC/MS): 370.4 [M+H]+, 387.4 [M+H2O]+; tR (HPLC conditions f): 2.28 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.[CH2:12]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[C:21]([N:24]3[CH:29]=[CH:28][C:27](O)=[CH:26][C:25]3=[O:31])[CH:22]=[CH:23][C:16]=2[N:15]=1)[CH3:13].N(C(OCCOC)=O)=NC(OCCOC)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:12]([C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[C:21]([N:24]3[CH:29]=[CH:28][C:27]([O:9][CH2:8][C:5]4[S:6][CH:7]=[C:3]([C:2]([F:10])([F:1])[F:11])[CH:4]=4)=[CH:26][C:25]3=[O:31])[CH:22]=[CH:23][C:16]=2[N:15]=1)[CH3:13]
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1cc(C(F)(F)F)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)cc2n1C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To a solution of (4-(trifluoromethyl)thiophen-2-yl)methanol (50 mg) in THF (3 ml) were added 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (73.9 mg), bis(2-methoxyethyl) azodicarboxylate (129 mg) and PPh3 (144 mg) at room temperature, and the mixture was stirred for 3 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 solution and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/MeOH) to give the title compound (10.2 mg) as white crystals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15]2[NH:19][N:20]=[CH:21][C:14]=12>C(Cl)(Cl)Cl>[Br:12][C:13]1[CH:18]=[N+:17]([O-:9])[CH:16]=[C:15]2[NH:19][N:20]=[CH:21][C:14]=12
Reactant: Brc1cncc2[nH]ncc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)c2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
mCPBA (270 mg) was added to a CHCl3 (5 ml) suspension containing 4-bromo-1H-pyrazolo[3,4-c]pyridine (197 mg), followed by stirring at room temperature for 10 minutes. IPE (10 ml) was added to the reaction solution and a solid precipitate was collected by filtration. A white solid of 4-bromo-1H-pyrazolo[3,4-c]pyridine 6-oxide (148 mg) was thus obtained.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]([NH:25]CC2C=CC(OC)=CC=2)=[N:6][C:7]([O:23][CH3:24])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[O:21][CH3:22])[N:9]=1)[CH3:3]>CCOCC.[Pd].CO>[CH2:2]([C:4]1[C:5]([NH2:25])=[N:6][C:7]([O:23][CH3:24])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][C:11]=2[O:21][CH3:22])[N:9]=1)[CH3:3]
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1NCc1ccc(OC)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1N
Reaction time: 18 h
Yield: 93.2 %

Procedure:
1M hydrochloric acid in ether (2 mL) and 10% palladium on carbon (40 mg) are added to {3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (115 mg, 0.25 mmol) in methanol (3 mL) under a nitrogen atmosphere. The mixture is then hydrogenated at 1 ATM for 18 hours, filtered through Celite and evaporated to give 3-ethyl-6-methoxy-5-[2-methoxy-4(trifluoromethoxy)phenyl]pyrazin-2-ylamine (80 mg).