Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:23][S:20]([O:12][CH2:11][C:8]1[S:7][C:6]([CH2:5][O:4][CH3:3])=[N:10][CH:9]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1ncc(CO)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1ncc(COS(C)(=O)=O)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-(methoxymethyl)thiazol-5-yl)methanol (319 mg, 2.00 mmol) in dry CH2Cl2 (15.0 mL) was treated at 0° C. with Et3N (0.36 mL, 2.59 mmol) followed by DMAP (25 mg, 0.20 mmol) and Ms-Cl (0.20 mL, 2.53 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (10 mL). The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give 469 mg (quant.) of crude (2-(methoxymethyl)thiazol-5-yl)methyl methanesulfonate as an yellow oil: TLC: rf (1:4 hept-EA)=0.39. A solution of this crude material (469 mg) in DMF (4.5 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (2.35 g of a 9.6% solution in DMF, 1.98 mmol) in DMF (4.5 mL) pre-treated for 30 min with DIPEA (0.68 mL, 3.96 mmol) and the reaction mixture was stirred for 4 days at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 07: tR=0.72 min, [M+H]+=255.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: CC(C)(CCCl)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Yield: 82.6 %

Procedure:
92.5 g (0.72 mol) of 4-chlorophenol and 99.4 g (0.72 mol) of potassium carbonate in 500 ml of toluene are heated under reflux for 2 hours, the water of reaction distilling off azeotropically. The mixture is cooled to 40° C., and 110 g (0.6 mol) of 1,5-dichloro-3,3-dimethyl-pentan-2-one in 300 ml of toluene are added. The reaction mixture is heated at 100° C. for 5 hours, and is then cooled and filtered off under suction from the inorganic residue. The filtrate is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and evaporated down. 136.3 g (82.6% of theory) of crude 1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one are obtained, and this product is directly reacted further. ##STR32##
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([F:25])[CH:24]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH3:3].[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[F:25][C:23]1[CH:24]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:6]=[C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:22]=1
Reactant: CN(C)Cc1cc(F)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)Cc1cc(F)cc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 4-{3-[(dimethylamino)methyl]-5-fluorophenoxy}piperidine-1-carboxylate (180 mg, 0.51 mmol) in DCM (2.4 mL) was added 4.0M hydrogen chloride in dioxane (1.0 mL, 4.1 mmol). The reaction solution was stirred at room temperature for 6 hours. The solvent was removed to give the desired product as white solid (145 mg, 87%). LCMS (M+H)+: 253.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1)[CH3:11]
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CCN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(C=O)cn2)CC1
Yield: 89 %

Procedure:
6-chloropyridine-3-carbaldehyde (5.0 g, 35.32 mmol) and 1-ethylpiperazine (20.16 g, 176.60 mmol, 22.42 mL) were heated overnight in a mixture of DMF/water (1:1, 40 mL) at 100° C. The reaction mixture was extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to provide 6-(4-ethylpiperazin-1-yl)pyridine-3-carbaldehyde, which was used in the next reaction without any further purification (6.91 g, 89% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.31 (q, 2H), 2.39 (m, 4H), 3.66 (m, 4H), 6.91 (d, J=9.2 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 8.55 (s, 1H), 9.7 (s, 1H); LRMS (ES+) m/z 219.8.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](B1OC(C)(C)C(C)(C)O1)[CH:27]=[CH2:28]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[S:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:27]=[CH2:26]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1sc2c(c1Br)c(=O)n(C)c(=O)n2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCc1c(C(=O)OCC)sc2c1c(=O)n(C)c(=O)n2C

Procedure:
To a stirred solution of Step 5 intermediate (24.5 g, 70.60 mmol) in dry THF (350 ml) was added cesium carbonate (46.0 g, 141.20 mmol) and allyl boronic acid pinacol ester (23.8 ml, 127.08 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (8.1 g, 7.06 mmol) was added and the reaction was refluxed for 24 h under nitrogen atmosphere. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were concentrated and the residue obtained was purified by silica gel column chromatography using 5% ethyl acetate in pet ether to give 4.62 g of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3H), 3.41 (s, 3H), 3.56 (s, 3H), 4.18-4.24 (m, 2H), 4.31-4.40 (m, 2H), 4.99-5.15 (m, 2H), 5.95-6.03 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7].FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O.N1C(C)=CC=CC=1C>ClCCl>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][C@H:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CON(C)C(=O)[C@H](CCCO)CCC(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CON(C)C(=O)[C@H](CCCO[Si](C)(C)C(C)(C)C)CCC(C)C

Procedure:
A solution of Example 8F (2.58 g, 11.1 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (2.8 mL, 12 mmol), and 2,6-lutidine (1.5 mL, 13 mmol) in dichloromethane (100 mL) at 0° C. was stirred for 2 hours, diluted with dichloromethane, washed sequentially with 10% KHSO4, aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI) m/e 346 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1B(O)O)=[O:16]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:17]([CH:15]=[O:16])=[CH:22][C:21]([O:23][CH3:24])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: Brc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(Br)cc2)c(C=O)c1
Temperature: 90 °C
Yield: 56 %

Procedure:
A solution of 1,4-dibromobenzene (5.11 g, 21.67 mmol), potassium carbonate (6.91 g, 50.0 mmol) and 2-formyl-4-methoxyphenylboronic acid (3 g, 16.67 mmol) in DME (75 mL) and water (15 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(Ph3P)4 (0.578 g, 0.500 mmol) was added and then the reaction was heated to 90° C. overnight. The reaction was cooled to r.t. and evaporated on rotovap. The residue was diluted with EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-4-methoxybiphenyl-2-carbaldehyde (2.72 g, 9.34 mmol, 56% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3H) 7.18-7.26 (m, 3H) 7.34 (d, J=824 Hz, 1H) 7.52 (d, J=2.75 Hz, 1H) 7.54-7.70 (m, 2H) 9.94 (s, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[S:22]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1CCNC(=O)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCNC(=S)C1
Yield: 49.3 %

Procedure:
To a solution of ethyl 2-oxopiperidine-4-carboxylate (10.76 g, 62.85 mmol) in toluene (120 mL) was added the Lawesson's reagent (25.42 g, 62.85 mmol) under a nitrogen atmosphere. The mixture was heated to reflux for 2 h. Removed the solvent under reduced pressure and the residue was purified by silica gel column chromatography (DCM/EA=20/1) to afford ethyl 2-thioxopiperidine-4-carboxylate (5.8 g, yield 49.3%).
Reaction SMILES: Br[CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[O:37]1[CH2:38][CH2:39][N:34]([CH:2]([CH2:25][CH3:26])[CH2:3][CH2:4][CH2:5][N:6]([C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:35][CH2:36]1
Reactant: CCC(Br)CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CCCN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c1ccc(Cl)cc1)N1CCOCC1
Yield: 53.7 %

Procedure:
A solution of (2R)-2-[N-(4-bromohexyl)-N-(4-chlorobenzenesulfonyl)amino]-4-methylpentanoic acid amide (Example 24; prepared as described in Reaction Scheme 1; 0.20 g, 0.44 mmol), Et3N (0.25 mL, 1.7 mmol), and morpholine (150 mg, 1.7 mmol) in CH2Cl2 (2 mL) was stirred at rt for 18 h. The reaction was then concentrated to give a crude white wax which was purified by flash chromatography (SiO2, 85% EtOAc/5% hexanes/10% MeOH) to afford the title compound (112 mg) as a white solid in 54% yield. MS (ESI), (M+H)+ 474.4; 1H NMR (DMSO-d6) δ 7.82 (d, 2H, J=8.0), 7.64 (d, 2H, J=8.0), 7.42 (br s, 1H) 6.99 (s, 1H), 4.25 (m, 1H), 3.51-3.60 (br s, 4H), 3.18-3.41 (m, 2H), 2.25-2.35 (br s, 4H), 2.27 (m, 2H) 1.15-1.62 (m, 9H), 0.80 (d, 6H, J=6.0).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(CCCO)OCc3cc(C#N)ccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2(CCCOS(C)(=O)=O)OCc3cc(C#N)ccc32)cc1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
15.0 g (48.5 mmol) of the 1-(3-hydroxypropyl)-1-(4-methoxyphenyl)-1,3-dihydro-5-isobenzofurancarbonitrile prepared in step 5 was dissolved in 200 ml of dichloromethane, and 7.4 g (727 mmol) of triethylamine and 6.7 g (58.2 mol) of methanesulfonylchloride were added dropwise at 0° C. The solution was then stirred for 1 hr. The reaction mixture was washed with water and saturated NaCl solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to afford 18.2 g of the yellow target compound (yield: 79%). The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16]([O-:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH:26]1([NH2+]C2CCCCC2)CCCCC1.C[Si](C=[N+]=[N-])(C)C.CCCCCC>CCOCC>[CH3:26][O:17][C:16](=[O:18])[C@@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)[O-])c1ccc(Cl)cc1
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A 0.5 N potassium bisulfate aqueous solution (4.0 mL) was added to a suspension of dicyclohexylammonium (S)-t-butoxycarbonylamino-(4-chloro-phenyl)acetate (307 mg, 0.657 mmol) in ether (8.0 mL) at room temperature, and the mixture was stirred for 10 minutes. Then, the ether layer was separated, and the aqueous layer was extracted with ether (2×8 mL) and combined with the organic layer. The ether layer was washed with water (12 mL), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in benzene (1.8 mL) and methanol (0.9 mL). A solution of trimethylsilyldiazomethane in hexane (2 M, 0.36 mL, 0.72 mmol) was added dropwise under cooling with ice over five minutes, and then the mixture was stirred under cooling with ice for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (190 mg, 96%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])=[O:32])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:39]=[CH:40][CH:41]=1)=[O:32])[CH3:27]
Reactant: CN(C)CC(=O)NCc1cccc(N)c1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-dimethylaminomethylcarbonylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]([NH2:12])=[NH:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[C:16](OC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:12]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NC(=N)N)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)nc(N[C@@H](C)c2ccccc2)n1
Reaction time: 8 h
Yield: 12.9 %

Procedure:
To a solution of (S)-1-phenylethylguanidine (1 g, 6.13 mmol, 1 eq) [prepared by condensation of (S)-1-phenylethylamine with methylthiopseudourea sulfate in refluxing aqeous sodium bicarbonate] in methanol (5.8 mL) was added a solution of 25% NaOMe in MeOH (4.2 mL, 18.39 mmol, 3 eq). To this stirred solution was added methyl acetoacetate (0.66 mL, 6.13 mmol, 1 eq) dropwise via syringe. The mixture was allowed to stir overnight. The methanol was removed by warming under a flow of air. The residue was dissolved in 20 mL water, acidified with concentrated aqueous HCL and extracted with ether and the ether layer discarded. The aqueous layer was neutralized and extracted with ethyl acetate. The organic extracts were combined and dried over anhydrous Na2SO4, filtered and concentrated. The material was purified by flash column chromatography to give 181 mg of the title compound. Mass spectrum (NH3/CI): 230.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=C[CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.COC(C1C=NC=CN=1)=[NH:39]>>[F:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][C:5]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:39][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: COC(=N)c1cnccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2F)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 205 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-phenoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 223 and methylpyrazin-2-imidate.
Reaction SMILES: [H-].[Na+].[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C@H:12]([OH:24])[C@@H:11]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CO>CN(C=O)C>[N:3]([C@@H:6]1[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C@H:12]([O:24][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:11]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:10][C@H:7]1[S:8][CH3:9])=[N+:4]=[N-:5]
Reactant: COc1ccc(CO[C@H]2[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A suspension of sodium hydride (196 mg, 5.1 mmol) in dry DMF (10 mL) was cooled to 0° C., and a solution of methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (10) (2.53 g, 4.3 mmol) in dry DMF (20 mL) was added dropwise in 30 minutes. The resulting solution was stirred at room temperature for 30 minutes and benzyl bromide (880 mg, 5.1 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature overnight, cooled to 0° C. and dry methanol (1 mL) was added dropwise. The reaction mixture was concentrated under reduced pressure, then xylene (20 mL) was co-evaporated from the residue. The residue was taken up in CHCl3 (100 mL) washed with H2O (100 ml), saturated NaHCO2 solution (100 mL) dried over MgSO4 and evaporated to dryness. The residue was purified by chromatography using EtOAc—Hexane 1:9 as the mobile phase to give methyl 2-azido-4-O-benzyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (32) (2.0 g, 68%).
Reaction SMILES: FC(F)(F)C([N:5]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCC=CN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent is evaporated from the combined filtrate and washings. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline 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: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
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: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
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)+.