Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[OH:2][C@@H:3]([C@H:5]1[C:34](=[O:35])[N:7]2[C:8]([C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])=[C:9]([C:12]3[S:16][C:15]4=[CH:17][N:18]([CH3:20])[CH:19]=[N+:14]4[CH:13]=3)[C@H:10]([CH3:11])[C@H:6]12)[CH3:4]>C1COCC1.P([O-])([O-])([O-])=O.[Pd]>[OH:2][C@@H:3]([C@H:5]1[C:34](=[O:35])[N:7]2[C:8]([C:21]([O-:23])=[O:22])=[C:9]([C:12]3[S:16][C:15]4=[CH:17][N:18]([CH3:20])[CH:19]=[N+:14]4[CH:13]=3)[C@H:10]([CH3:11])[C@H:6]12)[CH3:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3c[n+]4cn(C)cc4s3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3c[n+]4cn(C)cc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The total volume of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-2-yl)-1-carbapen-2-em-3-carboxylate iodide was dissolved in a mixture of 2 ml of THF and 2 ml of {fraction (1/15)} M phosphate buffer (pH 6.8), 77 mg of 10% Pd-C was added. The reactor was purged with hydrogen, and the reaction mixture was stirred at room temperature for 5 hours. The catalyst was collected by filtration with Celite and washed with water. The filtrate was washed with 20 ml of ethyl acetate, and purified by column chromatography on DIAION HP-20 to give 14.1 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=[C:4]([NH2:15])[CH:3]=1.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C(#N)C>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([NH:21][C:22]([NH:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([CH3:14])[N:5]=1)=[O:23])=[O:20]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Cc1cc(N)nc(C)c1-c1ccccc1
Solvent: CC#N
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)nc(C)c1-c1ccccc1
Reaction time: 2 h

Procedure:
4,6-Dimethyl-5-phenyl-2-pyridylamine (0.5 gram) was dissolved in 25 ml acetonitrile and reacted with 2-chlorobenzoyl isocyanate (0.6 gram) under nitrogen at room temperature. A precipitate formed immediately and the reaction was stirred for approximately 2 hours. The solid product was collected, washed with a small amount of acetonitrile, and identified by NMR as the desired product, m.p. 176°-189° C.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:15].[Al+3].[Br-].[Br-]>C1C=CC=CC=1>[Br-:15].[C:1]1([S+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Br-]
Solvent: c1ccccc1
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 128.2 %

Procedure:
In 200 ml of benzene were dissolved 21.1 g (0.1 mol) of diphenylsulfoxide, and 160.0 g (0.6 mol) of aluminum bromide at room temperature were added thereto, followed by allowing to react at 80° C. for 2 hours with stirring. The reaction solution was poured into 1000 ml of ice and extracted 3 times with methylene chloride. Thus obtained organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to give 22.0 g (yield: 64%) of triphenylsulfonium bromide as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:10]1([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([NH:13][C:14](=[O:16])[CH3:15])=[CH:3][C:2]=3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)Nc1ccc(NCC2CC2)c(N)c1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(NC(C)=O)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Following procedure 13B, N-{3-amino-4-[(cyclopropylmethyl)amino]phenyl}acetamide (5.50 g, 25.11 mmol), DIPEA (6.50 ml, 37.5 mmol), 4-ethoxyphenylacetic acid (5.40 g, 30.0 mmol) and HATU (11.40 g, 30.0 mmol) in DMF (100 ml) were stirred at room temperature overnight. Isolated the desired product (4.5 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCc1ccc(OCCCCl)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-hydroxyphenyl)ethanol (13.82 g, 100.0 mmol) and potassium carbonate (34.0 g, 250.0 mmol) in 125.0 mL of acetone was stirred as 1-bromo-3-chloropropane (24.0 g, 150.0 mmol) was added dropwise. The reaction was stirred at 60° C. overnight, and then filtered through celite, washed with acetone and concentrated. The residue was dissolved in EtOAc (250 mL) and washed with 2N Na2CO3, water, and saturated NaCl solution. After drying over Na2SO4 the solution was concentrated to give 21 g (98%): Mp 49-50° C.; MS m/z 197 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[N:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38](=[O:39])[C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccncc6)cn5n4)c3)c2)CC1
Yield: 59 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), pyridine-4-carboxylic acid (54 mg, 0.438 mmol), oxalyl chloride (63 μL, 0.734 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N-methylpyrrolidone (3 mL) as starting materials and in the same manner as in Example 412, the title compound (111 mg, 59%) was obtained as a pale-green powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](OCC)(OCC)(OCC)[CH3:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:27]([CH3:28])=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (150 mg) was heated in a sealed vessel with triethyl orthoacetate at 90° C. for 3 h. The mixture was cooled to room temperature and concentrated to give a crude residue that was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 272. 1H NMR (dmso-d6, 400 MHz) δ 7.86 (m, 2H), 7.48 (m, 1H), 7.69 (m, 1H), 7.44 (m, 1H), 7.28-7.23 (m, 2H), 6.57 (s, 1H), 4.22 (t, 2H), 3.00 (t, 2H), 2.18 (s, 3H). MS (ESI) 474.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[C:23](Br)=[CH:22][N:21]=[CH:20][N:19]=1)([OH:17])[CH2:13]2>CO.CCOC(C)=O.N.CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][N:19]=1)([OH:17])[CH2:13]2
Reactant: OC1(c2ncncc2Br)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Product: OC1(c2ccncn2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl

Procedure:
Hydrogenate the product of Step 1 (22 mg) in CH3OH-EtOAc (1:1, 10 ml) and NH3/CH3OH (7N, 1 ml) in the presence of Lindlar catalyst at 1 atm for 2 h, filter and concentrate to produce the title compound. 1H NMR (CDCl3) δ9.15 (s, 1H), 8.70 (d, 1H), 8.00 (m, 2H), 7.80 (d, 1H), 7.25 (m, 4H), 7.19 (t, 2H), 5.61 (s, 1H), 3.15 (br s, 2H), 2.50 (dd, 2H), 2.25 (m, 4H), 1.65 (d, 2H).
Reaction SMILES: CN1CCN(C)C1=O.[C:9]([NH:12][NH2:13])([NH2:11])=[NH:10].Cl.[N:15]1([CH2:22][C:23]2[S:27][C:26]([C:28](Cl)=O)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.O>CCCCCC>[NH2:10][C:9]1[NH:12][N:13]=[C:28]([C:26]2[S:27][C:23]([CH2:22][N:15]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:24][CH:25]=2)[N:11]=1
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1ccc(CN2CCCCCC2)s1
Agent: Cl
Solvent: CCCCCC
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: Nc1nc(-c2ccc(CN3CCCCCC3)s2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 ml of 1,3-dimethyl-2-imidazolidinone and 18.0 g (163.2 mM) of aminoguanidine hydrochloride were added to 24.0 g (81.6 mM) of 5-(hexahydro-1H-azepin-1-yl)methyl-2-thiophenecarbonyl chloride, and the mixture was stirred at room temperature for 1 hour. Then, 16.3 g (60% oil, 408 mM) was added and the mixture was stirred overnight at 130° C. The reaction solution was cooled to room temperature, 50 ml of water and 500 ml of n-hexane were added to effect separation of layers. To the resulting lower layer was added 1,000 ml of saturated brine, and then the mixture was extracted seven times with 500 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under a reduced pressure, and 1,000 ml of acetonitrile was added. With ice-cooling, 150 ml of 4 N hydrochloric acid/ethyl acetate was added, and the thus precipitated crystals were collected by filtration. The resulting crystals were added to 200 ml of 1 N sodium hydroxide, extracted three times with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate and then concentrated to 1/10 volume under a reduced pressure. The thus precipitated crystals were collected by filtration to give 10.4 g (51% in yield) of the title compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28].[ClH:52].C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:52].[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=3)[CH2:41][CH2:42]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccncc3)CC2)n1
Reaction time: 16 h
Yield: 72.3 %

Procedure:
0.35 g of isonicotinic acid (2.84 mmol) and 0.87 g of triethylamine (8.62 mmol) were dissolved in 30 ml of dimethylformamide. 0.45 g of hydroxybenzotriazole (HOBt, 3.33 mmol), 1.1 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.18 mmol), and 0.6 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.13 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was then partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2-10%). The oily residue was re-dissolved in isopropanol, and 1 N hydrochloric acid in diisopropyl ether was added. The mixture was slowly evaporated to yield 1.0 g of the title compound as a yellowish foam.
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C:12]=12)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([CH3:17])=[C:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][CH:12]12)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc[n+](Cc2ccccc2)c2c1-c1ccccc1C2
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CC1=C2c3ccccc3CC2N(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.15 g) is added to a suspension of 1-benzyl-4-methyl-9H-indeno[2,1-b]pyridinium bromide (0.92 g) in ethanol (10 mL) chilled in an ice bath. The cooling bath is removed and the mixture is stirred at room temperature for 1 h and at 60° C. for 2 h. More sodium borohydride (0.18 g) is added and stirring is continued at reflux temperature for 4 h. After the addition of another portion of sodium borohydride (0.10 g), the mixture is stirred at reflux temperature overnight. After cooling to room temperature, ice-cold water is added and the precipitate is separated by filtration. The precipitate is dissolved in ether, the resulting solution is dried (Na2SO4), and the solvent is evaporated to afford the crude product that is used without further purification. Yield: 0.66 g (crude); Mass spectrum (ESI+): m/z=276 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10]([C:12]2[S:20][C:15]3=[N:16][CH:17]=[CH:18][N:19]=[C:14]3[CH:13]=2)=[O:11])[CH:8]=1.C[Al](C)C.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34](OC)=[O:35])=[CH:27]1>C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:34](=[O:35])[C:33]2[CH:38]=[CH:39][CH:40]=[C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)[CH:32]=2)=[CH:8][C:7]=1[NH:9][C:10]([C:12]1[S:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1)=[O:11]
Reactant: Cc1ccc(N)cc1NC(=O)c1cc2nccnc2s1
Reactant: COC(=O)c1cccc(-c2ccsc2)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(-c3ccsc3)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a suspension of N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride 29 (73.5 mg, 0.229 mmol) in toluene (1.5 mL) was added trimethylaluminum (0.458 mL, 0.916 mmol) and was stirred for 15 min. methyl 3-(thiophen-3-yl)benzoate 82 (50 mg, 0.229 mmol) in toluene (1.5 mL) was added. The reaction mixture was stirred overnight at 60° C. Quenched with a saturated solution of NaHCO3 and extracted twice with EtOAc. Organic layer was washed with brine, dried, and evaporated. Purification by HPLC gave the title compound N-(2-methyl-5-(3-(thiophen-3-yl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 83 (6 mg, 5%). NMR (400 MHz, DMSO-d6) 2.27 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.64-7.72 (m, 3H), 7.87 (d, J=7.8 Hz, 1H), 7.91 (d, J=2.3 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 8.01 (dd, 2.7 Hz and 1.6 Hz, 1H), 8.27 (t, J=1.6 Hz, 1H), 8.55 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.37 (s, 1H), 10.53 (s, 1H). (m/z)=471 (M+H)+.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:49])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41][CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:43])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25]CC[Si](C)(C)C)=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:47]([O:46][C:44]([CH:42]([O:41][P:37]([CH2:36][CH:35]=[CH:34][CH2:33][CH:7]([CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([OH:25])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24])[C:6]([OH:49])=[O:5])([O:39][CH3:40])=[O:38])[CH3:43])=[O:45])[CH3:48]
Reactant: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)C(=O)OCC[Si](C)(C)C)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O)OC
Yield: 78.2 %

Procedure:
A solution of 2-{4-[(1-ethoxycarbonyl-ethoxy)-methoxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (14 mg, 0.018 mmol) in THF (1 mL) was stirred with a 1M solution of TBAF in THF (55 μL, 0.055 mmol) for 1 hour. The reaction mixture was concentrated, acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine and dried. The product was purified by silica gel column chromatography EtOH-EtOAc (0-10%). Further purification was performed by dissolving the product in CH2Cl2 and passing the compound through a 13 mm Acrodisc syringe filter with a 0.45 μm Nylon membrane to provide 8 mg (77%) of the product. 1H NMR (300 MHz, CDCl3) δ 0.92 (t, 3H, J=7 Hz), 1.30 (d, 3H, J=8 Hz), 1.79 (s, 3H), 2.10-2.39 (m, 4H), 2.15 (s, 3H), 2.53 (d, 1H, J=8 Hz), 2.65 (d, 1H, J=22 Hz), 2.68 (d, 1H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.70 and 3.74 (d, 3H, J=11 Hz), 3.76 (s, 3H), 4.07 (m, 2H), 4.96 (dq, 1H, J=7 Hz), 5.20 (s, 2H), 5.27 (br t, 1H, J=7 Hz), 5.33-5.55 (m, 2H), 7.51-7.56 (m, 1H), 7.68-7.74 (m, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 29.0, 30.1 ppm; MS (m/z) 569.2 [M+H]+, 591.3 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[OH:25][CH:26]([CH2:29][OH:30])[CH2:27][NH2:28].CO>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:28][CH2:27][CH:26]([OH:25])[CH2:29][OH:30])=[O:8]
Reactant: NCC(O)CO
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (12.0 g, 0.020 mol) was dissolved in 10 ml of dioxane and sodium carbonate (2.1 g, 0.020 mol) was added. To this solution was added a solution of 2,3-dihydroxypropylamine (1.8 g, 0.020 mol) dissolved in 15 ml of dioxane. The mixture was heated to reflux for 10 h. After cooling to room temperature, methanol (25 ml), strongly acidic ion exchange resin (Amberlyst 15, 50 g) and water (25 ml) were added to bring the pH to 3 to 4. After stirring at room temperature for 20 min, the resin was filtered off and the filtrate was evaporated to dryness. The semisolid dark crude product (12.6 g) was acetylated directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([NH:24][CH2:25][CH2:26][CH:27](OCC)[O:28]CC)=[O:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22](=[O:23])[NH:24][CH2:25][CH2:26][CH:27]=[O:28])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Yield: 90.7 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, tert-butyl (4S)-4-{[(benzyloxy)carbonyl]amino}-5-[(3,3-diethoxypropyl)amino]-5-oxopentanoate (2.75 g, 5.9 mmol, obtained from Reference Example 25) in tetrahydrofuran (12 ml) was reacted with 0.5 N hydrochloric acid (12 ml) for 1 hour at room temperature, to provide tert-butyl (4S)-4-{[(benzyloxy)carbonyl]amino}-5-oxo-5-[(3-oxopropyl)amino]pentanoate (2.1 g, 91%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH3:18][O:19][CH2:20][C:21]#[CH:22]>>[CH3:9][O:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:2]=1[C:22]#[C:21][CH2:20][O:19][CH3:18]
Reactant: C#CCOC
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1Cl
Product: COCC#Cc1nc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 22 %

Procedure:
2-Chloro-N-methoxy-N-methyl-6-trifluoromethyl-nicotinamide (1000 mg, 3.72 mmol) was reacted with 3-methoxy-propyne (0.345 ml, 4.09 mmol) to give N-methoxy-2-(3-methoxy-prop-1-ynyl)-N-methyl-6-trifluoromethyl-nicotinamide (247 mg, 22%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[SH:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CC(C)=O>[OH:12][C:10]([CH2:9][CH2:8][S:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:11]
Reactant: COC(=O)c1ccc(Cl)cc1S
Reactant: O=C(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cl)cc1SCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
179.5 g (1.3 mol) of potassium carbonate and, a little at a time, 94.5 g (0.62 mol) of 3-bromopropionic acid were added to a solution of 125.4 g (0.62 mol) of methyl 2-mercapto-4-chlorobenzoate in 1.5 l of acetone, and the reaction mixture was stirred at room temperature for 12 hours. The solvent was distilled off, the residue was taken up in water and the mixture was extracted with diethyl ether. The aqueous phase was then made acidic using concentrated hydrochloric acid, and the resulting precipitate was filtered off with suction and dried. This gave 150 g (88%) of methyl 2-(2-hydroxycarbonyleth-1-yl)thio-4-chlorobenzoate.
Reaction SMILES: [Cl-].[NH4+].[C:3]([O:7][C:8](=[O:46])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:19]2[CH:20]=[CH:21][C:22]([I:24])=[CH:23][C:18]=2[C:17](=[O:25])[N:16]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[N+:35]([O-])=O)[CH3:27])[CH:15]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C:14]1=[O:45])([CH3:6])([CH3:5])[CH3:4]>O.C(O)C.[Fe]>[C:3]([O:7][C:8](=[O:46])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:19]2[CH:20]=[CH:21][C:22]([I:24])=[CH:23][C:18]=2[C:17](=[O:25])[N:16]([CH:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[NH2:35])[CH3:27])[CH:15]([C:38]2[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=2)[C:14]1=[O:45])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(c1ccc(Cl)cc1[N+](=O)[O-])N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)C1c1ccc(Cl)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(c1ccc(Cl)cc1N)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)C1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of ammonium chloride (220 mg, 4.3 mmol) in water (2.5 mL) was added to a solution of 5-[3-(4-chlorophenyl)-4-[1-(4-chloro-2-nitrophenyl)ethyl]-7-iodo-2,5-dioxo-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester (230 mg, 0.306 mmol) in ethanol (5 mL). The resulting solution was heated to 80° C. and iron (200 mg, 3.58 mmol) was added. After 2 h at 80° C., the reaction mixture was cooled at room temperature, filtered through celite and evaporated. The residue was partitioned between ethyl acetat and water, dried (Na2SO4), and evaporated. Chromatography on silica (EtOAc/hexanes, 1:1) afforded the title compound (210 mg, 95%) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H, 3 CH2)), 1.57–1.63 (m, 4H, 2 CH2), 1.74 (d, J=7.2 Hz, 3H, CH3), 2.24 (t, J=7.2 Hz, 2H, CH2), 3.63–3.70 (m, 1H, CH), 4.28–4.35 (m, 1H, CH), 4.75 (br s, 2H, NH2), 5.28 (s, 1H, CH), 6.27 (q, J=7.2 Hz, 1H, CH), 6.60–6.69 (m, 5H, ArH), 6.90 (d, J=9.2 Hz, 2H, ArH), 7.20 (d, J=8.4 Hz, 1H, ArH), 7.49 (dd, J=8.8 Hz, J=2.4 Hz, 1H, ArH), 7.93 (d, J=2.0 Hz, 1H, ArH). Mass spectrum (LCMS, ESI pos.): Calcd for C32H34Cl2IN3O4: 721.0; found: 722.0 (M+H)+.