Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[Br:13]Br>CC(O)=O>[Br:13][C:11]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.5 %

Procedure:
To a solution of 5-nitroindoline (from Aldrich, 2.0 g, 12.2 mmol) in 15 mL of AcOH was added Br2 (1.0 mL, 19.4 mmol) in a portion and the resulting solution was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid (3.9 g, >95%) of the desired product as a HBr salt, which was subjected to the following reaction without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9]
Reactant: [I-]
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Yield: 96.7 %

Procedure:
A mixture of 0.86 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile, 3.2 g of sodium iodide, and 10 mL of acetone is heated to reflux overnight, protected from light. The volatiles are removed in vacuo and 30 mL of diethyl ether is added to the residue. The insolubles are collected and the volatiles removed in vacuo. The residue is purified via column chromatography using hexane/ethyl acetate (2:1) to afford 1.02 g of the desired product as a clear oil.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:7]1[CH2:12][CH2:11][N:10]([C:13](OC(C)(C)C)=O)[CH2:9][CH2:8]1.O1CCOCC1.[CH2:32]([N:34](CC)CC)C.ClCC#N>Cl.C1COCC1>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:32]#[N:34])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2nnco2)CC1
Reactant: CCN(CC)CC
Agent: Cl
Agent: N#CCCl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#CCN1CCC(=C(c2ccccc2)c2nnco2)CC1
Reaction time: 1 h
Yield: 51.7 %

Procedure:
tert-Butyl 4-((1,3,4-oxadiazol-2-yl)(phenyl)methylene)piperidine-1-carboxylate (100 mg, 0.29 mmol) was diluted with 4 M HCl in 1,4-dioxane (1.2 mL, 4.8 mmol) and stirred 1 h. The reaction was concentrated and the residue diluted with THF (1.5 mL), triethylamine (0.5 mL, 3.8 mmol) and chloroacetonitrile (0.25 mL, 3.9 mmol). The reaction was stirred 3 d, concentrated, diluted with MeOH, filtered and purified by preparative HPLC to yield 45 (43 mg, 0.15 mmol, 53%) as a white solid. 1H NMR: (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.41-7.31 (m, 3H), 7.20-7.16 (m, 2H), 3.55 (s, 2H), 3.02 (t, J=5.8 Hz, 2H), 2.75 (t, J=5.8 Hz, 2H), 2.61 (t, J=5.8 Hz, 2H), 2.39 (t, J=5.8 Hz, 2H); LC/MS: (ES+) m/z (M+H)=281; HPLC Rt=0.97 min., column G, conditions B.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH2:38])[C:19]3=[O:39])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([C:46]([NH:59][C:60]2[S:61][CH:62]=[C:63](/[C:65](=[N:69]/[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])/[C:66](O)=[O:67])[N:64]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:66](=[O:67])/[C:65](/[C:63]2[N:64]=[C:60]([NH:59][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:61][CH:62]=2)=[N:69]\[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])[C:19]3=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The product obtained in Step 2 (3.25 g) and 2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]acetic acid (5.64 g) were dissolved in dichloromethane (93 ml) and tetrahydrofurnan (93 ml) under a nitrogen stream, and the solution was cooled to 0° C. Dicyclohexylcarbodiimide (2.32 g) was added to this solution by small portions, and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.5 g of the objective compound as yellow crystals.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Zr+4:5].[C:6]1([B:12]([C:19]2[CH:23]=[CH:22][CH2:21][C:20]=2[Si](C)(C)C)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[Cl-:1].[C:6]1([B:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2([Zr+3:5])[CH:23]=[CH:22][CH:21]=[CH:20]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Zr+4]
Reactant: C[Si](C)(C)C1=C(B(c2ccccc2)c2ccccc2)C=CC1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: [Zr+3]C1(B(c2ccccc2)c2ccccc2)C=CC=C1
Temperature: -20 °C
Reaction time: 24 h

Procedure:
24.8 g (106.5 mmol) of zirconium tetrachloride and 150 ml of toluene were placed under argon in a 0.5 l two-neck flask. The white suspension was cooled to −20° C. and a solution of 30.68 g (101.4 mmol) of diphenylboranyltrimethylsilylcyclopentadiene in 150 ml of toluene was added. The brown suspension was stirred at room temperature for 24 hours and filtered through a D3 frit. The filtrate was evaporated to dryness under reduced pressure. The brown residue was stirred a number of times with n-hexane, giving a brown powder. This was dried to constant weight under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([OH:8])[CH:7]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26](=[O:27])[O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][C:6]=2[OH:8])=[CH:15][CH:14]=1)[CH3:17]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCc1ccc(Cc2ccc(N)cc2O)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2O)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-(4-ethylbenzyl)phenol (0.25 g) in tetrahydrofuran (10 mL) was added N-benzyloxycarbonyloxysuccinimide (0.41 g), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give benzyl N-[4-(4-ethylbenzyl)-3-hydroxyphenyl]carbamate (0.40 g).
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]/[C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](/C=C/C(=O)OC(C)(C)C)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](CCC(=O)OC(C)(C)C)CC2)cc1

Procedure:
0.150 g of ethyl trans-4-[4-((E)-2-tert-butoxycarbonylvinyl)cyclohexyl]benzoate (0.42 mmol, 1 eq.) is dissolved in 15 mL of ethanol in a Parr bottle. 0.044 g of 10% palladium-on-charcoal (0.04 mmol, 0.1 eq.) is added and the medium is subjected to 50 psi of hydrogen for 5 hours. The medium is filtered through Whatman paper, washed with ethanol and evaporated to give 0.19 g of ethyl trans-4-[4-(2-tert-butoxycarbonylethyl)cyclohexyl]benzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.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>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Reaction time: 20 h
Yield: 42.1 %

Procedure:
To a mixture of 4-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 4-(4-nitrophenyl)pyridine as a solid (342 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]([CH3:17])[CH2:14][N:13](CC(C4C=CC(OC)=CC=4)(O)C)[CH:12]([CH3:30])[C:11]=3[N:10]=[N:9]2)=[CH:4][CH:3]=1>Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH:15]([CH3:17])[CH2:14][NH:13][CH:12]([CH3:30])[C:11]=3[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)(O)CN2CC(C)c3c(nnn3-c3ccc(F)cc3)C2C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CNC(C)c2nnn(-c3ccc(F)cc3)c21
Temperature: 90 °C
Yield: 92.3 %

Procedure:
The product of Example 238, Step 3 (90 mg, 0.22 mmol) was dissolved in a solution of HCl in dioxane (4M, 2 mL). The reaction was heated at 90° C. for 16 h. The solvent was removed in vacuo to afford the title compound (50 mg, 92%). MS (ESI) mass calcd. C13H15FN4, 246.10; m/z found, 247.16 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:36]2\[C:37](=[O:51])[N:38](C(=O)C)[C:39]3[C:44]\2=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:36]2\[C:37](=[O:51])[NH:38][C:39]3[C:44]\2=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)/[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccc(CN)cc2)cc1

Procedure:
Prepared analogously to Example 139b from (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl-phenylamino)-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone and hydrazine hydrate solution in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@H:13]3[CH2:14][C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15](OC)=[O:16])=[CH:4][C:3]=1[CH3:21].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:38](=[O:39])[C:37]([C:32]3[NH:31][C:30]4[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=4[S:34](=[O:36])(=[O:35])[N:33]=3)=[C:15]([OH:16])[C@H:9]3[C@@H:8]2[C@H:13]2[CH2:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:4][C:3]=1[CH3:21]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(F)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]32)ccc1F
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Methyl (1S,2R,3S,4R)-3-(4-fluoro-3-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylate (0.090 g, 0.31 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.10 g, 0.31 mmol) was added followed by N-methylmorpholine (0.071 mL, 0.65 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.062 g, 0.32 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.13 mL, 0.92 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (50 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 50 to 100% ethyl acetate in hexanes) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-3-methyl-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.12 g, 0.21 mmol, 68%), as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.43-2.85 (9H, m), 2.29 (3H, s), 3.07 (3H, s), 3.45-3.47 (1H, m), 5.17-5.21 (2H, m), 6.95-7.05 (3H, m), 7.59-7.66 (3H, m). LC-MS (ESI) calcd for C26H27FN4O6S2 574.64, found 575.3 [M+H+].
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=4[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:41])=O>C(Cl)Cl.O1CCCC1.CN(C)C=O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:17])[NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([Cl:41])=[O:31])=[CH:28][C:27]=4[N+:35]([O-:37])=[O:36])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
A suspension of the product of Example 52B (500 mg, 0.976 mmol) in anhydrous methylene chloride (10 mL) and tetrahydrofuran (5 mL) was treated with oxalyl chloride (2M in methylene chloride, 0.976 mL, 1.951 mmol) and N,N-dimethylformamide (3 drops), and the resulting solution was stirred under a nitrogen atmosphere for 2 hours at room temperature. The solvent was removed by rotary evaporation in vacuo and the residue dried on hi-vacuum to give the title compound as a yellow solid (0.571 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([N:9]1[C:15](=[O:16])[CH:14]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:13][CH2:12][C:11](=[O:28])[NH:10]1)[CH3:8])(C)(C)[CH3:2].[C:30]([O-])([O-])=O.[K+].[K+].IC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1.ClCCl>[CH2:1]([O:5][C:6](=[O:29])[CH:7]([N:9]1[C:15](=[O:16])[CH:14]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH2:13][CH2:12][C:11](=[O:28])[N:10]1[CH3:30])[CH3:8])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)OC(C)(C)C)N1NC(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C)N1C(=O)C(N2C(=O)c3ccccc3C2=O)CCC(=O)N1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 91 %

Procedure:
A mixture of 2-[6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3,7-dioxo-[1,2]diazepan-1-yl]-propionic acid tert-butyl ester (14) (314 mg, 0.84 mmol), benzyltriethylammonium chloride (30 mg, 0.13 mmol), K2CO3 (406 mg, 2.94 mmol) and iodomethane (360 mg, 2.53 mmol) in THF (8 mL) was stirred at room temperature for five days. The mixture was diluted with dichloromethane (70 mL), washed with water three times, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to dryness to afford 296 mg (91% yield) of the title compound as a mixture of diastereomers. 1H-NMR (500 MHZ, CDCl3) δ 1.25-1.35 (m, 2.5H), 1.47-1.52 (m, 0.5H), 1.60-1.75 (m, 3H), 2.37-2.52 (m, 2H), 3.05-3.14 (m, 0.5H), 3.30-3.45 (m, 3.5H), 3.45-3.58 (m, 1H), 4.14-4.28 (m, 2H), 4.52-4.58 (m, 0.5H), 4.80-4.87 (m, 0.5H), 5.13-5.28 (m, 1H), 7.70-7.90 (m, 4H). Analytical HPLC: 6.00 and 6.11 min. LC-MS (ES+): m/e=388 (M+H+).
Reaction SMILES: [OH-].[Na+].C([O-])(=O)C.Cl.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:20]/[O:21][C@H:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])/[C:15]([O:17]CC)=[O:16])[N:13]=1>CO.O>[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:20]/[O:21][C@H:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])/[C:15]([OH:17])=[O:16])[N:13]=1
Reactant: CCOC(=O)/C(=N\O[C@H]1CCNC1=O)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1nc(/C(=N/O[C@H]2CCNC2=O)C(=O)O)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.27 g of sodium hydroxide is dissolved in a mixture of 3 ml of methanol and one ml of water, and one g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3yl)oxyimino]acetate is added thereto. The mixture is stirred at 20° C. for one hour to dissolve said acetate therein. The solution is adjusted to pH 5 with 10% hydrochloric acid, and the aqueous mixture is concentrated under reduced pressure to remove methanol. The residue is adjusted to pH 3 with 10% hydrochloric acid, and the aqueous mixture is ice-cooled. Crystalline precipitates are collected by filtration, and the crystals are washed with methanol and then dried. 730 mg of (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1.[ClH:26]>O>[Cl:26][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(N)cc3)ccc2o1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(Cl)cc3)ccc2o1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 6.9 g of sodium nitrite in 40 ml of water was added drop-by-drop to a stirred mixture of 30 g of 12C and 160 ml of 6 N hydrochloric acid, the rate of addition being adjusted to maintain the temperature of the reaction mixture at 0°-5° C. The mixture was stirred for 1 hour at 0°-5° C., then added with vigorous stirring, to 50 ml of 20% aqueous cuprous chloride heated to 70° C. The resulting mixture was heated to 70° C., then allowed to cool. The solid was collected, washed with water, dried (P2O5, reduced pressure) and dissolved in tetrahydrofuran. The solution was suspended on 75 g of silica gel and dry column chromatographed, using chloroform as eluent. The product was removed from the combined appropriate fractions with tetrahydrofuran. The solvent was evaporated ad the residue was dried (drying pistol, P2O5, refluxing acetone) to give ethyl 5-(4-chlorophenyl)benzofuran-2-carboxylate (12 D), mp 108°-110° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=O)=O.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][C:23]1[O:22][N:21]=[C:20]([NH:19][C:7]2[N:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH:24]=1
Reactant: COC(=O)c1cccnc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(N)no1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccnc1Nc1cc(C)on1
Temperature: 80 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
6.7 g (24 mmol) of methyl 2-(trifluoromethylsulfonyloxy)nicotinate and 3.0 g (31 mmol) of 3-amino-5-methylisoxazole were dissolved in toluene (100 mL), and 13.1 g (40 mmol) of cesium carbonate, 1.5 g (1.6 mmol) of tris(dibenzylideneacetone)dipalladium(0), and 1.9 g (3.4 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were added to the solution. The resulting mixture was heated and stirred for one hour at 80° C. The reaction mixture was cooled, and then the solvent was distilled off. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4), and thus 4.3 g of the title compound was obtained as an orange-colored viscous product (yield: 78%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][C:8]=1[Cl:22].[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=[O:27]>C(OCC)C>[C:16]([O:15][C:13]([NH:12][CH2:11][C:10]1[CH:20]=[CH:21][C:7]([CH:26]([OH:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH3:23])=[C:8]([Cl:22])[CH:9]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)c(Cl)c1
Reactant: CC(C)(C)CC=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
Add butyllithium (8.2 mL, 13.1 mmol) to a solution of 4-bromo-3-chloro-N-(tert-butoxycarbonyl)-benzylamine (1.823 g, 5.7 mmol) in diethyl ether (46 mL) at −78° C. under nitrogen and stir for 30 min. Add 3,3-dimethylbutyraldehyde (1.427 g, 1.7 mL, 14.3 mmol), stir for 30 min at −78° C. and then warm to room temperature. Add water and extract twice the aqueous phase with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as a yellow oil (274 mg, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:10]([OH:12])=[O:11])[CH2:7][CH:6]1[CH:8]=[CH2:9])=[O:4].[CH3:13][O:14][Si:15]([CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH:25]1[O:27][CH2:26]1)([O:18][CH3:19])[O:16][CH3:17].Cl([O-])(=O)(=O)=O.[Li+]>ClCCl>[OH:27][CH:25]([CH2:24][O:23][CH2:22][CH2:21][CH2:20][Si:15]([O:14][CH3:13])([O:16][CH3:17])[O:18][CH3:19])[CH2:26][O:12][C:10]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH:6]1[CH:8]=[CH2:9])=[O:11]
Reactant: C=CC1CC1(C(=O)O)C(=O)OC
Reactant: CO[Si](CCCOCC1CO1)(OC)OC
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: C=CC1CC1(C(=O)OC)C(=O)OCC(O)COCCC[Si](OC)(OC)OC
Temperature: 25 °C
Reaction time: 360 h
Yield: 83 %

Procedure:
A mixture of 10.0 g (58 mmol) 1-methoxycarbonyl-2-vinylcyclopropane carboxylic acid, 14.0 g trimethoxysilylpropylglycidyl-ether and 100 mg lithium perchlorate in 20 ml dichloromethane were stirred at room temperature for 15 days. After removal of solvent in vacuo, 20 g (83% yield) of a clear, yellow viscous liquid remained.