Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH:12]([CH3:14])[CH3:13])[CH2:5]2.[CH3:15][N:16]1[C:20](=[O:21])[CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[C:17]1=[O:38].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)(Cl)Cl.[Pd].[Pd].C(Cl)Cl>[CH:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([CH2:22][N:18]4[CH2:19][C:20](=[O:21])[N:16]([CH3:15])[C:17]4=[O:38])=[CH:24][CH:25]=3)[CH:3]=2)[C:7]1=[O:11])([CH3:14])[CH3:13]
Reactant: CN1C(=O)CN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1=O
Reactant: CC(C)N1Cc2cc(Br)ccc2C1=O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)N1Cc2cc(-c3ccc(CN4CC(=O)N(C)C4=O)cc3)ccc2C1=O
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
5-bromo-2-isopropylisoindolin-1-one (4A4) (0.418 mmol, 106 mg) was mixed with 3-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione (4E1) (0.418 mmol, 138 mg), tricyclohexylphosphine (0.050 mmol, 14 mg), tris(dibenzylidineacetone) dipalladium chloroform adduct (0.021 mmol, 22 mg) and potassium phosphate (0.710 mmol, 151 mg) in dioxane (2 ml) and water (1 ml). The mixture was heated to 130° C. for 15 minutes in the microwave before addition of DCM (2 ml) and water (2 ml). The reaction was stirred vigorously for 30 minutes before collection of the organic layer using a hydrophobic fritted tube followed by concentration. Purification was achieved using basic HPLC and the desired fractions concentrated to give 1-(4-(2-isopropyl-1-oxoisoindolin-5-yl)benzyl)-3-methylimidazolidine-2,4-dione (Example 4a) 49.2 mg (31.2%); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, 1H) 7.67-7.59 (m, 4H) 7.37 (d, 2H) 4.7 (sept, 1H) 4.62 (s, 2H) 4.4 (s, 2H) 3.79 (s, 2H) 3.07 (s, 3H) 1.31 (d, 6H) LCMS m/z (M+H) 378.2.
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH2:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:34]([OH:36])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:37][N:38]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>O.CN(C)C=O>[OH:37][NH:38][C:34]([CH:11]1[CH2:10][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH2:33])=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:36]
Reactant: On1nnc2ccccc21
Reactant: C=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: C=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)NO)cc1
Yield: 40.1 %

Procedure:
The procedure of Example 45 was followed using the product from Example 43 (230 mg, 0.456 mmol), 1-hydroxybenzotriazol (111 mg, 0.821 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (157 mg, 0.821 mmol), hydroxylamine in water 50% solution (0.251 ml, 4.1 mmol) in dimethylformamide (3 ml) to give 95 mg (40%) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:19])[N:3]=1.O.[Li+].[OH-]>O1CCOCC1>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:19])[N:3]=1
Reactant: CCOC(=O)COc1cc(C)c2c(Cl)nn(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCC(=O)O)nc2c1c(Cl)nn2C
Reaction time: 2 h

Procedure:
To a solution of Ethyl 2-((3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)acetate in dioxane (5 ml) were added H2O (2.5 ml) and LiOH (111 mg, 4.65 mmol). After 2 h, more water was added and the mixture extracted with CH2Cl2. Then, the aqueous phase was acidified by drop wise addition of conc. HCl until the product precipitated. The title compound (580 mg, 98%) was filtered off and dried under reduced pressure. [1H-NMR (DMSO-d6, 400 MHz) δ 6.62 (s, 1H), 4.98 (s, 2H) 3.84 (s, 3H), 2.61 (s, 3H); HPLC-MS RtJ=0.81 min; [M+H]+=255.9, 258.0]
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1.[CH:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:34](OC)=[O:35].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[OH:35][CH2:34][C:21]1[CH:20]=[C:29]2[C:24](=[CH:23][CH:22]=1)[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28]2
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(CO)ccc2c1
Temperature: -50 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
Red-Al (0.61 ml of a 65% toluene solution, a product of Aldrich, 2.1 mmol) was added dropwise to a solution of commercially available dimethyl 2,6-naphthalenedicarboxylate (500 mg, 2.1 mmol) in anhydrous tetrahydrofuran (120 ml) cooled to −50° C. The resulting mixture was stirred at −50° C. for 1 hour and then at room temperature for 1.5 hours. To the reaction mixture were added sequentially ethyl acetate, water, 0.5N aqueous sodium potassium (+)-tartrate solution and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel column using ethyl acetate-hexane (2:1) as the eluant to obtain methyl 6-hydroxymethyl-2-naphthalenecarboxylate (288 mg, yield 65%) as a white solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(Cn2ccc3ncc(Br)cc32)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (400 mg, 2.030 mmol) and sodium hydride (60% in mineral oil) (89 mg, 2.233 mmol) in 4 mL N,N-dimethylformamide was stirred at ambient temperature for 10 minutes and 1-(bromomethyl)-3-fluorobenzene (384 mg, 2.030 mmol) was added. The mixture was heated at 100° C. for 3 hours. The mixture was cooled to ambient temperature, diluted with 100 mL of ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on Analogix IntelliFlash280 eluting with 10 to 70% ethyl acetate/hexanes to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11]([S:14][CH2:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])(=[O:13])[CH3:12]>>[C:11]([S:14][CH2:15][CH:16]([CH3:20])[C:17]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:18])(=[O:13])[CH3:12]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CC(=O)SCC(C)C(=O)Cl
Product: CC(=O)SCC(C)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Following the procedure of Example 16, L-glutamic acid is reacted with 3-acetylthio-2-methylpropanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl -1-oxopropyl]-L-glutamic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:13]=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9]C)=[O:8]>CCCCCC>[Br:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:13]=[C:14]([CH3:17])[C:15]=1[CH3:16])[O:5][C:6]([CH3:12])([CH3:11])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(C)(C)Oc1cc(C)c(C)c(Br)c1C
Solvent: CCCCCC
Product: Cc1cc(OC(C)(C)C(=O)O)c(C)c(Br)c1C
Yield: 97 %

Procedure:
Using methyl 2-(3-bromo-2,4,5-trimethylphenoxy)isobutyrate obtained in Reference Example 22, the title compound was synthesized in the same manner as in Reference Example 15. Yield 97%. mp. 151–153° C. (hexane). 1H-NMR (CDCl3) δ: 1.59 (6H, s), 2.26 (3H, s), 2.33 (6H, s), 6.67 (1H, s), 9.60 (1H, br s).
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([O:10][CH2:11][C:12]([NH:17][S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])([CH2:15]C)[C:13]#[N:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[OH-:30].[K+].Cl>[O-]O.O>[CH3:15][C:12]([NH:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])([CH2:11][O:10][C:9]1[CH:28]=[CH:29][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)[C:13]([NH2:14])=[O:30]
Reactant: [OH-]
Reactant: CCC(C#N)(COc1ccc(-n2cncn2)cc1)NS(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [O-]O
Solvent: O
Product: CC(COc1ccc(-n2cncn2)cc1)(NS(=O)(=O)Cc1ccccc1)C(N)=O
Yield: 8 %

Procedure:
1.98 g 2-[(4-[1,2,4]Triazol-1-yl-phenoxy)-methyl]-2-benzylsulfonylamino-butyronitrile, 1.3 g potassium hydroxide, 4 drops of hydro-peroxide (30%) in 10 ml water are stirred for 18 hours at room temperature. After addition of 60 ml water the solution is acidified to pH 2 by addition of a 2 N hydrogen chloride solution and extracted with ethyl acetate. After evaporation of the solvent the residue is subjected to flash chromatography (eluant: ethyl acetate) to give 0.160 g of the product as white crystals. M.p. 195-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[S:17])=[CH:11][C:10]=2[F:29])[CH:5]=[CH:4][N:3]=1.[C:30]([N:37]1[CH2:45][CH2:44][CH:40]([C:41](O)=[O:42])[CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.CCCCCC.O1CCCC1>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16]([NH:18][C:19](=[O:28])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[S:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:41]([CH:40]2[CH2:44][CH2:45][N:37]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:38][CH2:39]2)=[O:42])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1cc(Oc2ccc(NC(=S)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 88 h
Yield: 429.3 %

Procedure:
To a solution of 1-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl) acetyl]thiourea (84.6 mg, 0.204 mmol) in N,N-dimethylformamide (2.0 ml) were added Boc-isonipecotic acid (93.5 mg, 0.408 mmol), triethylamine (0.0853 ml, 0.612 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (180 mg, 0.408 mmol), followed by stirring at room temperature for 88 hrs. Boc-isonipecotic acid (93.5 mg, 0.408 mmol), triethylamine (0.0853 ml, 0.612 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (180 mg, 0.408 mmol) were further added thereto, followed by stirring at room temperature for 32.5 hrs. To the reaction mixture were added ethyl acetate (50 ml), tetrahydrofuran (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) to partition. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide (30 ml) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then subjected to silica gel column chromatography (Fuji Silysia BW-300; hexane:ethyl acetate=1:1, then ethyl acetate) to provide a crude product of the titled compound (548 mg) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:13]=1.N1CCCCC1>C(O)C>[I:11][C:12]1[C:20]2[C:15](=[CH:16][C:17](/[CH:21]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:18][CH:19]=2)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[N:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Solvent: CCO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Oxindole (665 mg, 5 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2 g, 5 mmol) were dissolved into ethanol (25 mL). Piperidine (0.1 mL) was added and the solution was heated to 70° C. for 2 h, cooled to rt and stirred overnight. The solvent was removed in vacuo to give an orange solid which was triturated with ethanol to give the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.62-7.55 (m, 3H), 7.24 (d, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.8 Hz), 6.86 (t, 1H, J=7.6 Hz), 5.75 (s, 2H), 3.62-3.58 (m, 2H), 0.93-0.89 (m, 2H), −0.04 (s, 9H); MS ESI 518.0 [M+H]+, calcd for [C22H24IN3O2Sii+H]+ 518.4.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:24].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:24])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(NC(C)=O)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(NC(C)=O)ccc3nc21
Temperature: 0 °C

Procedure:
A mixture of N-(1-ethylpyrazole-5-yl)-5-acetamido anthranilic acid (2 g) and POCl3 (20 ml) was refluxed overnight. The reaction mixture was poured into ice-water (400 ml), neutralized with NH4OH and extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined and concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford 0.2 g of 1-ethyl-4-chloro-6-acetamido-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.ClC(Cl)C.[CH3:36][N:37]([CH3:48])[C:38](=[O:47])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH2:46])[CH:41]=1>>[CH3:36][N:37]([CH3:48])[C:38]([O:39][C:40]1[CH:41]=[C:42]([NH:46][C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:43]=[CH:44][CH:45]=1)=[O:47]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(C)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 50 %

Procedure:
1-(tert-Butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (67 mg, 0.28 mmol), EDC (64 mg, 0.33 mmol), HOBT (45 mg, 0.33 mmol) and dichloroethane (2.0 mL) were combined in a pressure rated sealed tube and stirred for 45 min. 3-Aminophenyl dimethylcarbamate (50 mg, 0.28 mmol) was added, and the mixture was heated at 85° C. for 18 hours. The mixture was concentrated and chromatographed (SiO2, 0-2% MeOH:CH2Cl2) to give the title compound in 50% yield. MS (ES+) [M+H]+=406.
Reaction SMILES: [CH3:1][NH2:2].O.CS[C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]>C(O)C>[CH3:1][NH:2][C:6]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][N:17]=1)=[CH:7][N+:8]([O-:10])=[O:9]
Reactant: COc1ccnc(CSCCNC(=C[N+](=O)[O-])SC)c1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCCSCc1cc(OC)ccn1
Reaction time: 0.33 h

Procedure:
Methylamine in ethanol (33%, 20 cc) was added to 1-methylthio-1-[2-(4-methoxy-2-pyridylmethylthio)ethylamino]2-nitroethylene monohydrate (2.01 g) and the mixture was stirred at 18° for 20 minutes and evaporated to an oil which was crystallised from propan-2-ol to give the title product (1.1 g) m.p. 107°-108.5°.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[C:4]([S:25][CH3:26])[CH2:3]1>C1COCC1.CCO.[Li+].[OH-]>[CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]=[C:4]([S:25][CH3:26])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(SC)=N3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CSC1=Nc2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C1

Procedure:
A solution of 0.100 g (0.30 mmol) of ethyl 4-[(4,4-dimethyl-2-methylthio-3,4-dihydro-6-quinolinyl)ethynyl]benzoate (Compound 9) in 2 ml of THF, 1 ml of EtOH and 2 ml of 1N LiOH was stirred at room temperature for 1 h, followed by aqueous work up to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][CH:7]([C:9](=[CH2:13])[C:10]([O-:12])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>CO>[Si:5]([O:6][C@@H:7]([C@@H:9]1[CH2:13][N:23]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:10]1=[O:12])[CH3:8])([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH3:14]
Reactant: COc1ccc(CN)cc1
Reactant: C=C(C(=O)[O-])C(C)O[Si](C)(C)C(C)(C)C
Solvent: CO
Product: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
To a solution of ethyl (2-[1-(t-butyldimethyl-silyloxy)ethyl]acrylate (5 g) in methanol (100 ml) was added 4-methoxybenzylamine (2.65 g) at room temperature. After two days, the solvent was evaporated and the residual methanol was azeotropically removed using toluene. To the residual product was added tetrahydrofuran (387 ml) and the solution was stirred at room temperature. To this solution was added dropwise mesitylmagnesium bromide in tetrahydrofuran (1M, 31 ml) at room temperature. After stirring for 30 minutes, the reaction mixture was quenched with water and evaporated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated and the residue was column-chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 3:1) to give (3S*)-3-[(1R*)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (4.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[N:13]([O-])=O.[Na+].[OH-].[K+]>Cl>[F:12][C:3]1[C:2]([NH:1][NH2:13])=[CH:11][C:6]2[NH:7][C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: Nc1cc2[nH]c(=O)sc2cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: NNc1cc2[nH]c(=O)sc2cc1F
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A suspension of 5-amino-6-fluoro-2(3H)-benzothiazolone (12.98 g) in conc. hydrochloric acid (70 g) was cooled to 0° to 5° C., and a saturated aqueous solution of sodium nitrite (5.08 g) was dropwise added thereto at 0° to 5° C., followed by stirring at the same temperature for 30 minutes. The resultant mixture was cooled to -20° C., and a solution of stannous chloride (28.06 g) in conc. hydrochloric acid (30 g) was added thereto all at once, followed by stirring at 0° C. for 2 hours. The reaction mixture was neutralized with potassium hydroxide, a colloidal substance originated from stannous chloride was removed by celite and the resultant solution was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give 6-fluoro-2(3H)-benzothiazolon-5-ylhydrazine (6.60 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1.B.C(=O)([O-])[O-:23].[Na+].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:23][CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C=Cc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(CCO)cc2OC)cc1
Temperature: 60 °C

Procedure:
A solution of Example 445A (228 mg) and 1M borane in THF (1.2 mL) in THF (2 mL) at room temperature was stirred for 5 hours, and treated sequentially with 2M sodium carbonate (1 mL) and 33% hydrogen peroxide (1 mL). The mixture was heated to 60° C. for 1 hour, diluted with ethyl acetate (1100 mL), washed with water (45 mL) and brine (110 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-40% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H](CO)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of 2-(S)-(3,4-dichlorophenyl)-4-pentenoic acid (7.0 gm) (prepared as described by J. Hale et. al., Bioorganic & Medicinal Chemistry Letters 1993,3, 319-322.) in ether (50 mL) at r.t. was added portionwise over 5 min solid lithium aluminum hydride (700 mg). The reaction was heated to 40° C. for 3 hr and then stirred at r.t. for 16 hr. The reaction was poured into water containing 25 mL of 2N NaOH and extracted twice with ether. The ether layers were washed with brine, combined and dried over Na2SO4. Flash chromatograghy afforded the title compound (4.5 gm) as an oil. [α]D =+14 (EtOH, c=1.5).
Reaction SMILES: C([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15](=[O:33])[CH2:16][C@H:17]1[C:21](=[O:22])[O:20]C[N:18]1C(OCC1C=CC=CC=1)=O)(=O)C(C)(C)C.Cl.O>CC(O)=O>[NH2:18][C@@H:17]([CH2:16][C:15]([C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[NH2:7])=[O:33])[C:21]([OH:22])=[O:20]
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1C(=O)C[C@H](N)C(=O)O
Temperature: 70 °C

Procedure:
A stirred mixture of (S)-(+)-N-pivaloyl-2-[1-oxo-2-[3-(benzyloxycarbonyl)-5-oxo-oxazolidin-4-yl]ethyl]-4-chloro aniline (1.06 g, 2.24 mmol), 37% HCl (20 ml), H2O (20 ml) and CH3COOH (28 ml), was heated at 70° C. for 5.5 h. The solution was evaporated to dryness. The residue was dissolved in water (30 ml), washed with CH2Cl2 and evaporated again. The crude product was purified by flash chromatography on silica gel (chloroform: methanol:30% NH4OH=140:60:6) to yield (S)-(-)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo butyric acid as yellow crystal (0.29 g; 51.5%; m.p. 206°-208° C.; [α]20D =-12.0° (1%; CH3OOH); ee 96%.