Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]([NH:26][C:27](=[O:53])[CH:28]([NH:32][CH2:33][CH:34]([NH:42]C(OCC1C=CC=CC=1)=O)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:29]([CH3:31])[CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[NH2:42][CH:34]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][NH:32][CH:28]([CH:29]([CH3:30])[CH3:31])[C:27]([NH:26][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:24])([CH3:25])[CH3:23])[CH:16]=1)[CH2:12][NH2:11])=[O:53]
Reactant: CC(C)C(NCC(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)NC(CNC(=O)OCc1ccccc1)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C(NCC(N)Cc1ccccc1)C(=O)NC(CN)Cc1ccc(O)c(C(C)(C)C)c1

Procedure:
To a solution of 132 mg (0.183 mmol) of N-[2-benzoxycarbonylamino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]-2-[[2-(benzoxycarbonylamino)-3-phenylpropyl]amino]-3-methyl butanamide in methanol (2 ml), 10% palladium carbon (80 mg) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 days. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to yield 2-[(2-amino-3-phenylpropyl)amino]-N-[2-amino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]-3-methyl butanamide in the amount of 24.2 mg (29%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][S:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:45][C:42]7([CH2:44][CH2:43]7)[CH2:41][N:40]6[C:46](=[O:56])[CH:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH3:67][O:68][CH2:69][CH2:70][CH:71]([NH:75][C:76]([O:78][CH3:79])=[O:77])[C:72]([OH:74])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C>[CH3:55][O:54][C:52](=[O:53])[NH:51][CH:47]([C:46]([N:40]1[CH:39]([C:36]2[NH:37][CH:38]=[C:34]([C:29]3[CH:28]=[CH:27][C:26]4[C:31](=[CH:32][CH:33]=[C:24]([C:21]5[CH:22]=[CH:23][C:18]([C:15]6[NH:14][C:13]([CH:9]7[N:8]([C:72](=[O:74])[CH:71]([NH:75][C:76]([O:78][CH3:79])=[O:77])[CH2:70][CH2:69][O:68][CH3:67])[CH2:12][CH2:11][S:10]7)=[N:17][CH:16]=6)=[CH:19][CH:20]=5)[CH:25]=4)[CH:30]=3)[N:35]=2)[CH2:45][C:42]2([CH2:44][CH2:43]2)[CH2:41]1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6SCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Reactant: COCCC(NC(=O)OC)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(NC(=O)OC)C(=O)N1CCSC1c1ncc(-c2ccc(-c3ccc4cc(-c5c[nH]c(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)n5)ccc4c3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39.2 %

Procedure:
2-{5-[4-(6-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-1H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-thiazolidine-3-carboxylic acid tert-butyl ester (49.9 mg, 0.064 mmol) was dissolved in DCM (0.33 mL) and HCl in dioxane (4M, 0.33 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.5 mL) and DIEA (24.6 mg, 0.191 mmol) was added. A solution of (L) 4-methoxy-2-methoxycarbonylamino-butyric acid (12.1 mg, 0.064 mmol), HATU (24.1 mg, 0.064 mmol) and DIEA (8.2 mg, 0.064 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 3 hrs all volatiles were removed in vacuo. The crude material, which was purified by RP-HPLC (eluent: water/MeCN w/0.1% TFA) to yield the product (21.3 mg) as a TFA salt.
Reaction SMILES: P([O-])(O)(O)=O.[K+].[OH-:7].[Na+].[CH3:9][CH:10]([CH:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)O)[CH:11]=[CH2:12].[Cl-].[Na+]>O>[CH3:9][CH:10]([C:13]1[C:15](=[O:16])[CH2:19][CH:18]([OH:7])[CH:17]=1)[CH:11]=[CH2:12]
Reactant: C=CC(C)C(O)c1ccco1
Reactant: [OH-]
Agent: O=P([O-])(O)O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: C=CC(C)C1=CC(O)CC1=O
Temperature: 150 °C

Procedure:
Water (500 ml) and potassium dihydrogenphosphate (2.0 g) were placed in an autoclave, and the mixture was adjusted to pH 5.1 with an aqueous 1N NaOH solution at 30° C. α-Methylallyl-2-furylcarbinol (15 g) was then added, and the mixture was heated at 150° C. for 5.5 hours while stirring. After cooling, the reaction mixture was adjusted to pH 7.1 with an aqueous 1N NaOH solution at 30° C. and re-heated at 150° C. for 5 hours while stirring. After completion of the reaction, the mixture was admixed with sodium chloride (10 g) and extracted with methyl isobutyl ketone. The solvent was removed from the reaction mixture, and distillation of the resulting residue gave 2-(α-methylallyl)-4-hydroxy-2-cyclopentenone with the yield of 12 g (80%). B.P., 88°-90° C./0.12 mmHg.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30]>CS(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30])[C:3]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Nc2ccc(F)c([N+](=O)[O-])c2)c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(Nc2cccc([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a suspension of 60% of NaH in mineral oil (300 mg, 7.41 mmol) in DMSO (2.5 mL) is added dimethyl malonate (851 μL, 7.41 mmol). The mixture is heated to 60° C. for 10 minutes and then cooled to ambient temperature before (4-fluoro-3-nitro-phenyl)-(3-nitro-phenyl)-amine (686 mg, 2.47 mmol) is added. The resulting mixture is heated to 60° C. for 3 hours and quenched with saturated aqueous NH4Cl solution. The mixture is extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The crude product is purified by column chromatography (EtOAc/Hexane, gradient) to give the desired product: 1H NMR (400 MHz, CDCl3) δ. 7.94 (s, 1 H), 7.88 (d, 1 H), 7.70 (d, 1 H), 7.51-7.47 (m, 1 H), 7.44-7.40 (m, 2 H); 7.32-7.28 (m, 1H), 5.27 (s, 1H), 3.83 (s, 6H); LC-MS: 390.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[Na+].[I-].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:6]([Cl:11])[CH:5]=1
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCC2CC2)c(Cl)c1
Yield: 67.7 %

Procedure:
3-Chloro-4-hydroxy-benzoic acid methyl ester (1.1 g, 6.0 mmol, 1.0 eq) was dissolved in acetone (14 mL), NaI (0.45 g, 3.0 mmol, 0.5 eq) and K2CO3 (1.66 g, 12.0 mmol, 2.0 eq) were added ad the mixture was stirred at room temperature for 20 min. (Bromomethyl)cyclopropane (0.53 mL, 5.4 mmol, 0.9 eq) was added, and the mixture was refluxed for 2 days. The solvent was concentrated under reduced pressure, NaOH 10% was added, and the crude was extracted with DCM and dried. The title product (0.88 g, yield 32%) was recovered and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:31][CH:30]([CH2:32]Br)[CH2:29][C:28]=2[CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:6][CH2:7][N:8]([CH2:32][CH:30]2[CH2:29][C:28]3[CH:34]=[C:24]([O:23][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:25]=[CH:26][C:27]=3[O:31]2)[CH2:9][CH2:10]1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: Cc1ccccc1CC1(O)CCNCC1
Product: Cc1ccccc1CC1(O)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=444.6 (M+H+) was prepared from 4-(2-methyl-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[Br:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[NH:28][N:27]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH:8]([C:6]3[C:5]([O:11][CH3:12])=[C:4]([CH:13]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]4)[C:3]([CH3:24])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:27]=[C:26]([Br:25])[C:34]=12
Reactant: Nc1ncnc2[nH]nc(Br)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)n2nc(Br)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a mixture of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.0 g, 2.7 mmol) (from Example 1, Step 5, racemic intermediate) and 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.629 g, 2.94 mmol) in N,N-dimethylformamide (8 mL) was added potassium iodide (44 mg, 0.27 mmol) and cesium carbonate (1.30 g, 4.01 mmol). The resulting mixture was heated to 120° C. and stirred for 4 h. After cooling, water was added and stirred briefly before the solids were filtered. The resulting solids were washed with water, purified on silica gel (eluted with 0-10% MeOH in dichloromethane) to give 1.11 g (75%) of the desired product as a yellow gum. LCMS calculated for C23H29BrClN6O3 (M+H)+: m/z=551.1; Found: 551.1.
Reaction SMILES: [N:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][N:12]=3)[C:7](=[O:15])[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S1C=C[CH-]OS1>C(O)C>[OH:15][C:7]1[C:6]([OH:16])=[C:5]2[C:14]([N:1]=[CH:2][CH:3]=[CH:4]2)=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: O=C1C(=O)c2cccnc2-c2ncccc21
Agent: c1csso[cH-]1
Solvent: CCO
Product: Oc1c(O)c2cccnc2c2ncccc12
Temperature: 25 °C
Yield: 75.2 %

Procedure:
1 g of 1,10-phenanthroline-5,6-dione (reagent; manufactured and sold by Sigma-Aldrich Co., U.S.A.) and 0.691 g of dithioxamide (reagent; manufactured and sold by Tokyo Kasei Kogyo Co., Ltd., Japan) were added to 40 ml of ethanol, and the resultant mixture was refluxed under heating in an atmosphere of air for 13 hours. The resultant reaction mixture was allowed to cool to room temperature, and subjected to a suction filtration using a filter paper (pore diameter: 1 μm), thereby obtaining powders. For removing substances remaining unreacted in the obtained powders, the powders were washed with 100 ml of chloroform at room temperature while stirring, followed by a suction filtration using a filter paper (pore diameter: 1 μm), thereby obtaining 0.759 g of 5,6-dihydroxy-1,10-phenanthroline in the form of powders.
Reaction SMILES: [N+](C1C=C(S(O)(=O)=O)C(C)=CC=1)([O-])=O.[N+:15]([C:18]1[CH:19]=[C:20]([S:39]([OH:42])(=[O:41])=[O:40])[C:21]([CH:24]=[CH:25][C:26]2[C:27]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:28][C:29]([N+:32]([O-])=O)=[CH:30][CH:31]=2)=[CH:22][CH:23]=1)([O-])=O.O=O>>[NH2:15][C:18]1[CH:19]=[C:20]([S:39]([OH:42])(=[O:41])=[O:40])[C:21]([CH:24]=[CH:25][C:26]2[C:27]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:28][C:29]([NH2:32])=[CH:30][CH:31]=2)=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: O=O
Product: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1

Procedure:
Furthermore, 4-nitrotoluene-2-sulphonic acid can be used for the preparation of 4,4'-dinitrostilbene-2,2'-disulphonic acid, in which, for example, an approximately 30 to 50% strength aqueous solution of 4-nitrotoluene-2-sulphonic acid is reacted with oxidizing agents, for example with atmospheric oxygen. 4,4'-Dinitrostilbene-2,2'-disulphonic acid can be further processed by reduction to give 4,4'-diaminostilbene-2,2'-disulphonic acid (see Ber. 30, 3,100), and is an important intermediate product for the preparation of optical brighteners (A. Dorlars, C.-W. Schellhammer and J. Schroeder, Angew. Chem. 87, 693 (1975)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:20]([OH:22])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][N:10]([CH3:11])[C:20](=[O:22])[C:19]2[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:17]([C:16]([F:15])([F:31])[F:30])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (Bioorg. Med. Chem. Lett; 2001; 265-270; 300 mg, 1.55 mmol) was dissolved in DMF (3 mL) and to the resultant solution were added 3,5-bis(trifluoromethyl)benzoic acid (440 mg, 1.71 mmol), TBTU (548 mg, 1.71 mmol) and DIPEA (803 mg, 6.21 mmol) in the given order. The mixture was stirred for 2 h at room temperature, diluted with an aqueous solution of NaHCO3 (saturated, 25 mL) and then extracted three times with ethyl acetate. The combined organic solutions were washed three times with water and then dried over Na2SO4. The solvent was removed by evaporation and the residue was chromatographed on silica gel using a mixture of heptane and ethyl acetate as eluent (4:1). There was obtained 576 mg (85%) of N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide as an oil. 1H NMR (400 MHz, CDCl3): 2.2-2.4 (cm, 2H), 2.7 (s, 2H), 2.9-3.9 (cm, 4H), 4.9-5.1 (m, 2H), 5.4-5.8 (m, 1H), 6.8-7.1 (cm, 3H), 7.2-7.5 (3H), 7.9 (s, 1H); LCMS: m/z 434 (M+1)+.
Reaction SMILES: CS(O[C@H:6]1[C@H:11]2[CH2:12][C@H:8]([C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[N:10]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:24]([C@H:6]1[C@H:11]2[CH2:12][C@H:8]([C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[N:10]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[N+:25]=[N-:26]
Reactant: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OS(C)(=O)=O)C2)N1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](N=[N+]=[N-])C2)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-[(methylsulfonyl)oxy]-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-1 (232 mg) in dimethylformamide (2.0 mL) and water (0.4 mL), was added sodium azide (108 mg). The mixture was stirred at 80° C. for 1 hr. The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (4:1) to give the target compound (175 mg).
Reaction SMILES: C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C.[OH:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])[C@H:21]([C:37]([OH:39])=O)[CH2:20]1.Cl.Cl.[N+:42]([C:45]1[CH:63]=[CH:62][C:48]([CH2:49][O:50][C:51]([O:53][CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[O:52])=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C)C=O.C(OCC)(=O)C>[OH:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:25])[C@H:21]([C:37]([N:59]2[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][O:53][C:51]([O:50][CH2:49][C:48]3[CH:62]=[CH:63][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=3)=[O:52])[CH2:57][CH2:58]2)=[O:39])[CH2:20]1
Reactant: O=C(OCCN1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
25.7 ml of diethyl cyanophosphonate and 68.7 ml of triethylamine were added dropwise, whilst ice-cooling, to a suspension of 47.8 g of trans-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-L-proline and 64.8 g of 1-[2-(4-nitrobenzyloxycarbonyloxy)ethyl]piperazine dihydrochloride in 400 ml of dry dimethylformamide, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was diluted with 1.5 liters of ethyl acetate, and the dilute solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, to give 87.6 g of the title compound, as a powder.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][S:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH2:34])[CH3:30]>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH:34][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([S:16](=[O:17])(=[O:18])[NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)[CH3:30]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(2-benzoyl-phenylsulfamoyl)-benzoic acid and glycine ethyl ester hydrochloride (Aldrich) according to the method described in Example 1.1/d. MS (EI) 867.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([OH:15])[CH2:13][CH3:14]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:14][CH2:13][CH2:12][OH:15])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CCC(O)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CCCO)n1
Yield: 47.5 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 30 min, bromopropanol (208 μL, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 3-(3-nitro-pyrazol-1-yl)-propan-1-ol (144 mg, 48%) as an oil: H1-NMR (400 MHz, CDCl3) δ 2.09 (2H, m), 2.84 (1H, s), 3.60 (2H, t, J=5.8 Hz), 4.32 (2H, t, J=6.8 Hz), 6.82 (1H, D, J=2.4 Hz), 7.51 (1H, d, J=2.4 Hz).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:24].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35]>C1(C)C=CC=CC=1>[CH3:22][C:20]([CH3:23])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:24])=[C:4]([C:3]2[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:35])(=[O:36])[N:37]=2)[C:13]1=[O:14]
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(CCCCC(C)(C)C)C1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 852.1 %

Procedure:
A solution of Example 35H (0.097 g, 0.249 mmol) and 2-amino-benzenesulfonamide (0.045 g, 0.262 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.99 g, 85%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH:13]=O)=[CH:8][CH:7]=2.[NH2:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:17]=1[C:18]([NH2:20])=[O:19].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:20][C:18](=[O:19])[C:17]3[C:16](=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=3[O:27][CH3:28])[N:15]=1)=[CH:8][CH:7]=2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc2[nH]c(CCO)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCO)cc4c3)nc2c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(2-hydroxy-ethyl)-1H-indole-5-carbaldehyde (0.300 g, 1.58 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.370 g, 1.90 mmol) in N,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt %) (0.350 g, 1.90 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.32 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen and cooled to room temperature. The solvent was evaporated under reduced pressure. Water (20 mL) was added and the solid was separated by filtration, washed with water (30 mL) and dried under vacuum. Crude compound was purified by the Simpliflash system (5:20:75 methanol/ethyl acetate/CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 0.22 g (38%). MP 237-238° C. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (br s, 1H), 11.20 (s, 1H), 8.34 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.73 (d, J=1.9 Hz, 1H), 6.48 (d, J=1.9 Hz, 1H), 6.30 (s, 1H), 4.81 (t, J=5.1 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.75 (q, J=6.63 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[N:34]=[C:33]([CH:40]=O)[CH:32]=2)=[CH:27][CH:26]=1>>[C:36]([N:35]1[C:31]([C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=2)=[CH:32][C:33]([CH2:40][NH:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][N:13]([CH:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][CH:22]=3)[CH2:18][CH2:17]2)=[N:34]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Product: CC(C)(C)n1nc(CNCCN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1-c1ccc(Cl)cc1
Yield: 57 %

Procedure:
Compound 100 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butyl pyrazole-3-carbaldehyde were used.