Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[N:4][CH:3]=1.[Na].[NH2:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12>CO.C(Cl)Cl>[NH2:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][S:1][C:2]3[S:6][N:5]=[N:4][CH:3]=3)[CH2:14][S:15][C@H:10]12
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: Sc1cnns1
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(CSc3cnns3)CS[C@@H]3C(N)C(=O)N23)cc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Sodium 5-mercapto-1,2,3-thiadiazole (2.45 g) was suspended in methanol (20 ml), and a solution of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (5.60 g) in methylene chloride (20 ml) was added dropwise. The mixture was stirred for 30 min. under ice-cooling, an insoluble material was filtered off, and the solvent was evaporated to obtain a crude material (6.38 g). The crude material was subjected to silica gel chromatography eluting with chloroform-ethyl acetate to obtain p-methoxybenzyl 7-amino-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (4.90 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:28]=2)[CH:23]=[CH:22]1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:25]=[C:24]4[CH:23]=[CH:22][NH:21][C:29]4=[N:28][CH:27]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: COc1cccc(Nc2nc(-c3cnc4[nH]ccc4c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 7-azaindole-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 121. NMR: (CDCl3): 3.91 (s, 3H, CH3), 4.15 (s, 3H, CH3), 6.66 (m, H, ArH), 6.89 (m, H, ArH), 7.17 (m, H, ArH), 7.24 (s, H, ArH), 7.38-7.42 (m, 3H, 3×ArH), 7.51 (s, H, ArH), 9.04 (sbr, H, NH), 9.13 (m, H, ArH), 9.56 (m, H, ArH). MS: (ESI+) MH+=372.25
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Cl)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[O:6].[CH2:14]([N:16]([CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH3:15]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[O:6])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:23][CH3:24])[CH2:14][CH3:15]
Reactant: CCN(CC)CCCCCN
Reactant: CC1(C)CN1P(=O)(Cl)N1CC1(C)C
Solvent: C1CCOC1
Product: CCN(CC)CCCCCNP(=O)(N1CC1(C)C)N1CC1(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)phosphinoyl chloride in about 170 mL of THF are treated by dropwise addition with 0.026 moles of 5-diethylaminopentylamine in 25 mL of THF, stirred for several hours at ambient temperature, filtered, concentrated by rotary evaporation and vacuum distilled to yield about 90% pure P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(5-diethylamino-1-pentyl)-phosphinic amide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](O)=O)=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.ON1C2C=CC=CC=2N=N1.CN(C)[CH:35]=[O:36]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:35]([CH2:8][C:7]2[C:2]([NH2:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=2)=[O:36])=[CH:17][CH:16]=1
Reactant: CSc1ncc(C(=O)O)c(N)n1
Reactant: CN(C)C=O
Reactant: COc1ccc(CN)cc1
Agent: On1nnc2ccccc21
Product: COc1ccc(CNC(=O)Cc2cnc(SC)nc2N)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-amino-2-methylmercaptopyrimidine-5-carboxylic acid (185 mg, 1 mmol) and p-methoxybenzyl amine (164 mg, 1.2 mmol) in N,N-dimethylformamide was added 1-hydroxybenzotriazole (92 mg, 92 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (229 mg, 1.2 mmol). The reaction mixture was stirred at room temperature over night. The solvent was removed under reduce pressure. The residue was dissolved in ethyl acetate (30 mL) and washed by water (30 mL) and brine (30 mL), dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexanes:ethyl acetate=1:1) to give the desired product as a white powder (245 mg, 81%).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]12[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][C:50]([CH2:58][OH:59])([CH2:51]3)[CH2:49]1)[CH2:55]2>>[Cl:17][C:18]1[C:19]([O:59][CH2:58][C:50]23[CH2:51][CH:52]4[CH2:53][CH:54]([CH2:55][C:48]([F:47])([CH2:57]4)[CH2:49]2)[CH2:56]3)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CC3CC(CC(F)(C3)C1)C2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 3-fluoroadamantan-1-yl methanol, the title compound was obtained as a colorless solid (0.16 g, 35%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 3.84 (s, 2H), 2.87 (s, 6H), 2.30 (br s, 2H), 1.87-1.76 (m, 6H), 1.61-1.52 (m, 6H); MS (ES−) m/z 461.1, 463.1 (M−1).
Reaction SMILES: [C:1]1([C:18]([OH:20])=O)[C:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O.S(Cl)(Cl)=O>[C:18]([C:1]1[C:14]2[CH2:13][C:12]3[C:7](=[C:8]([C:15](=[O:17])[C:1]4[CH:14]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc2c1Cc1cccc(C(=O)O)c1C2
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cccc2c1Cc1cccc(C(=O)c3ccccc3)c1C2
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 9,10-dihydro anthracene-1,5-dicarboxylic acid (52, 1 g, 3.73 mmol) in 200 μl of dimethyl formamide and 20 ml of thionyl chloride was refluxed for 3 hours. The resulting solution was evaporated to dryness under vacuum, 60 ml of benzene added, and warmed to 60° C. to obtain a solution. This solution was slowly added to a 250 ml round bottom flask containing a mixture of AlCl3 and 20 ml of benzene. The resulting mixture was stirred for 18 hours at room temperature and poured into 100 ml of an ice/water mixture containing 10 ml of conc. HCl. The organic layer was separated and the aqueous layer was washed twice with 100 ml portions of benzene. After drying over Na2SO4, the combined organic extracts were dried under vacuum to yield a brown colored crude product. This was further purified by flash column chromatography to obtain a dark yellow, oily product (0.39 g, 27%) (According to NMR studies the product is 80+% pure). 1H NMR (300 MHz, CDCl3): δ 4.04 (s, 4H), 7.20-7.86 (m, 16H), 7.51 (d, 2H, J=6 Hz), 7.70 (d, 2H, J=6 Hz), 13.00 (broad s, 2H). 13C NMR (300 MHz, CDCl3): δ 33.95, 125.48, 126.98, 128.51, 128.55, 129.94, 130.30, 133.24, 135.74, 137.88, 197.15.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:19][CH2:18][C:17]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])([CH3:20])[CH:16]([OH:27])[CH:15]=[CH:14][CH:13]([CH3:28])[CH:12](/[C:29](/[CH3:56])=[CH:30]/[CH:31]=[CH:32]/[C:33]([O:50][CH:51]([O:53][CH2:54][CH3:55])[CH3:52])([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([O:41][CH:42]([O:44][CH2:45][CH3:46])[CH3:43])[CH2:39][CH3:40])[O:11][C:9](=[O:10])[CH2:8]1)[CH3:5])[CH3:2].[CH2:57](Cl)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1.C(OCC)(=[O:67])C>N1C=CC=CC=1>[C:57]([O:27][CH:16]1[C:17]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])([CH3:20])[CH2:18][CH2:19][CH:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:8][C:9]([O:11][CH:12](/[C:29](/[CH3:56])=[CH:30]/[CH:31]=[CH:32]/[C:33]([O:50][CH:51]([O:53][CH2:54][CH3:55])[CH3:52])([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([O:41][CH:42]([O:44][CH2:45][CH3:46])[CH3:43])[CH2:39][CH3:40])[CH:13]([CH3:28])[CH:14]=[CH:15]1)=[O:10])(=[O:67])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Reactant: ClCc1ccccc1
Reactant: CCOC(C)=O
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)c2ccccc2)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Solvent: c1ccncc1
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=O)c2ccccc2)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Reaction time: 12 h

Procedure:
To a solution of (8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (10 mg, 12.5 μmol) obtained in Example 3-2 in pyridine (0.5 mL) were added N,N-dimethylaminopyridine (8 mg, 62.5 μmol) and benzyl chloride (17.6 mg, 125 μmol) at room temperature, and the reaction mixture was stirred at the same temperature under nitrogen atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=25:75) to give the title compound (6 mg, 55%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Product: CCC(CC)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Temperature: 100 °C

Procedure:
191 mg of the product obtained in Stage 1 above, 2.5 ml of butanol and 0.115 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 90 to 110° C. for 5 hours. The reaction medium is then left to return to ambient temperature and left to crystallize, followed by separating, washing with 10 ml of isopropanol and drying under vacuum at approximately 50° C. In this way 148 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:21])=[O:20])[CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)=[O:4].Br[C:32]1[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([Cl:39])[CH:33]=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:19]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])(=[O:20])=[O:21])[CH:7]=[C:8]([C:32]2[C:37]([CH3:38])=[CH:36][N:35]=[C:34]([Cl:39])[CH:33]=2)[CH:9]=1)=[O:4]
Reactant: Cc1cnc(Cl)cc1Br
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
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: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(-c2cc(Cl)ncc2C)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 43.1 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2,4,6-trimethylbenzensulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (125 mg, 0.29 mmol, 0.6 equiv.) and 4-bromo-2-chloro-5-methylpyridine (96 mg, 0.47 mmol, 1.0 equiv.) were dissolved in benzene (4 mL). After adding methanol (0.94 mL) and aqueous Na2CO3, Pd(PPh3)4 (108 mg, 0.094 mol, 0.2 equiv.) was then added and the resulting mixture was heated at reflux for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. After drying the organic layer over Na2SO4, the solvent was removed under reduced pressure. The crude material was purified by reversed phase HPLC (acetonitrile/water/TFA), yielding the title compound as a colorless solid (54 mg, 0.125 mmol, HPLC Rt 9.087 min, ES+433.0, ES−431.0).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[CH:12][CH:13]=[C:14]3[C:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)=[C:17]([C:33]([O:35]CC)=[O:34])[NH:16][C:15]=23)[CH:7]=[CH:8][CH:9]=1)[CH3:2].CCO.O.[Li+].[OH-]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[CH:12][CH:13]=[C:14]3[C:18]([CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=4)=[C:17]([C:33]([OH:35])=[O:34])[NH:16][C:15]=23)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1[nH]c2c(-c3cccc(OCC)c3)nccc2c1CCOc1ccc(OC(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cccc(-c2nccc3c(CCOc4ccc(OC(F)(F)F)cc4)c(C(=O)O)[nH]c23)c1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 7-(3-ethoxyphenyl)-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (80 mg, 0.15 mmol) in THF (2 mL) was added EtOH (0.4 mL)m and water (0.4 mL). Solid LiOH (75 mg, 3.1 mmol) was then added in a single portion. After 2 h at r.t. and 2 h at 50 C, the reaction was quenched with 5% potassium bisulfate until acidic (˜pH 3) which caused a white precipitate to form. This was filtered and washed with water to yield the title compound (65 mg). HRMS (ESI) calc (M+H)+=487.1475. found 487.1478.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][C:14]=1[CH3:20].CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:3][CH2:4]2)=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cc(O)ccc1Br
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1cc(OCC2CCCCC2)ccc1Br

Procedure:
The title compound was prepared by substituting cyclohexylmethanol for (3-(dimethylamino)phenyl)methanol and 4-bromo-3-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][O-:11].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5](=[NH:6])[O:11][CH3:10]
Reactant: C[O-]
Reactant: N#Cc1cccc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 471.7 %

Procedure:
To a solution of 3-chlorobenzonitrile (4.0 g, 29.1 mmol) in methanol (30 mL) was added sodium methoxide (0.16 g, 2.9 mmol). The mixture stirred at rt for 2 d, diluted with water, and extracted with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (2.32 g, 47%) as a clear oil. MW=169.61. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.46-7.42 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 3.94 (s, 3H); APCI MS m/z 170 [M+H]+.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:35]=[CH:34][C:10]([CH2:11][CH:12]([NH:24][S:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:13]3[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[N:3]1.N1C=C[CH:39]=[CH:38][C:37]=1S(C(NCC1C=CC(C2SC=CN=2)=CC=1)C1N=C(NCC(O)=O)C=CC=1)(=O)=O>C(O)(C)C>[CH:38]([O:22][C:21](=[O:23])[CH2:20][NH:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[CH:5][CH:4]=[N:3]3)=[CH:35][CH:34]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:18]=1)([CH3:39])[CH3:37]
Reactant: O=C(O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Reactant: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OC(=O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 90 %

Procedure:
Reaction was carried out in the same manner as in Example 29 except for using (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)-acetic acid hydrochloride (25.8 mg, 0.0439 mmol) obtained in Example 7-(b) in place of (6-{(pyridin-2-ylsulfonyl) [4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)-acetic acid, and using isopropanol (0.20 ml) in place of 1-hexanol. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (20.6 mg) as a colorless oil. (Yield: 90%)
Reaction SMILES: O1C2C=CC(C3C(=O)OC(O)(C4C=CC(OC)=CC=4)C=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]=[N+:39]=[N-:40])[CH:17]=3)=CC=2OC1.CCCCCCCCCCN.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O:82][C:83]1C(OC)=CC(C=O)=C[C:84]=1[OH:93].N(CCOCCOCCOCCOC1C=C(C=C(OC)C=1OC)C=O)=[N+]=[N-]>C1COCC1.C(O)CO.O>[N:38]([CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][C:18]1[CH:17]=[C:16]([CH:15]2[O:93][CH2:84][CH2:83][O:82]2)[CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25])=[N+:39]=[N-:40]
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OCCOCCOCCOCCN=[N+]=[N-])c2)cc1
Reactant: COc1cc(C=O)cc(O)c1OC
Agent: CCCCCCCCCCN
Agent: COc1cc(C=O)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: OCCO
Solvent: O
Product: COc1cc(C2OCCO2)cc(OCCOCCOCCOCCN=[N+]=[N-])c1OC

Procedure:
Compound 9 is then converted to the free amine 10 by Staudinger-Reaction with triphenylphosphine and water in THF (scheme 3). Regrettably, the yields in this step were disappointing (<20%) and several byproducts made the purification rather difficult. This probably occurred due to reaction of the phosphine with one of the oxygen-containing moieties of the butenolide ring structure. To circumvent these difficulties a second reaction sequence was chosen, where the amine was generated earlier and then protected for further conversion. This second sequence (scheme 4) also starts with the reaction of 3,4-dimethoxy-5-hydroxybenzaldehyde 1 with PEG-derivative 7. The aldehyde function of azide 8 is then protected with ethylene glycol, giving dioxolane 11 in nearly quantitative yield after purification. This kind of protection allows subsequent reduction of the azide and BOC protection of the generated amine 12 without the risk of intermolecular imine formation. The dioxolane protecting group of 13 then can easily be destroyed by reaction with catalytic amounts of iodine in acetone without affecting the BOC protecting group. The product benzaldehyde 14 and ketoester 3 are then converted to the desired butenolide derivative by the same procedure as described above for the azide functionalised aldehyde 8 (scheme 3). The product of this rection is the PEG-modified, N-Boc-protected butenolide 15, which in the finishing step is deprotected by treatment with trifluoroacetic acid (TFA) in methylene chloride. The final product 16 can be isolated as the TFA salt which can be handled and stored easily at 4° C.
Reaction SMILES: [NH2:1][OH:2].Cl.[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=O)[CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1.N1C=CC=CC=1>CO>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=[N:1][OH:2])[CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=NO)c1ccc2c(c1)CCO2
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
NH2OH.HCl (7.3 g, 105 mmol) was added to a stirred solution of ketone 191 (14.2 g, 87.7 mmol) and pyridine (9.2 mL, 114 mmol) in MeOH (100 mL) and the mixture stirred at 20° C. for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1-(2,3-dihydro-1-benzofuran-5-yl)ethanone oxime (15.3 g, 99%). HCl gas was bubbled through a solution of the oxime (15.3 g, 86.5 mmol) in Ac2O (16.3 mL, 173 mmol) and HOAc (54 mL, 865 mmol), and the solution stood at 20° C. for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2×50 mL), the combined organic extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 192 (7.94 g, 52%) as a white solid: mp 92-93° C. [lit. (Blade-Font, A.; de Mas Rocabayera, T. J. Chem. Soc. P1, 1982, 814848) mp 93° C.]; 1H NMR δ 7.47 (br s, 1H, H-4), 7.21 (br s, 1H, NH), 6.99 (dd, J=8.5, 2.1 Hz, 1H, H-6), 6.69 (d, J=8.5 Hz, 1H, H-7), 4.55 (t, J=8.7 Hz, 2H, H-2), 3.18 (br t, J=8.7 Hz, 2H, H-3), 2.13 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:37])[C@@H:15]([CH2:27][CH2:28][CH2:29][NH:30][C:31]([NH2:36])=[N:32][N+]([O-])=O)[NH:16][C:17](=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)=[O:3].[C:38]([OH:41])(=[O:40])[CH3:39]>[Pd]>[NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:37])[C@@H:15]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:36])[NH:16][C:17](=[O:26])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:8][CH:7]=1)=[O:3].[C:38]([O-:41])(=[O:40])[CH3:39]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)Cc2ccc(O)cc2)cc1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(=O)[O-]
Product: N=C(N)NCCC[C@@H](NC(=O)Cc1ccc(O)cc1)C(=O)NCc1ccc(CNC(N)=O)cc1
Yield: 85 %

Procedure:
Prepared analogously to Example 4c) from (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-N2 -[(4-hydroxyphenyl)acetyl]-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 85% of theory.