Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].O>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in sulfuric acid (40.8 mL) with stirring at 0° C. was added a solution of nitric acid (2.72 g, 0.0389 mol) and sulfuric acid (3.89 g, 0.0389 mol). The mixture was stirred (1 hr) then poured into 200 g ice and 100 ml water. The solid was filtered and collected. The solution was neutralized with 28% NH3 in water to pH ˜5. The solution was extracted with EtOAc (3×300 ml). The solid also was dissolved in EtOAc and neutralized with 28% NH3 in H2O. The organic layers were combined, concentrated with 30 g silica gel, and purified by flash chromatography (20 to 60% EtOAc/hexanes) to afford the title compound (2.40 g, 36%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](COCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.51 g of sodium hydride (55% content), and a solution of 5.0 g of trans-1,4-dihydroxymethylcyclohexane dissolved in 20 ml of tetrahydrofuran was added dropwise thereto with stirring under ice-cooling, and the reaction mixture was stirred at room temperature for 50 minutes. To the reaction mixture was added 3.79 ml of benzyl bromide with stirring under ice-cooling and the mixture was stirred under ice-cooling for 1 hour and further at room temperature overnight. The insolubles were separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with an aqueous sodium chloride solution, 10% aqueous hydrochloric acid solution, an aqueous sodium chloride solution and an aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=20/1-5/1) to obtain 1.75 g of the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:6].C(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1F
Agent: O=C=O
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1F

Procedure:
The title compound was prepared by a method analogous to that described for Example 109, using Isomer 2 of methyl 3-(3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate in Step C. 1H NMR (400 MHz, CD3OD, δ): 8.57 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.43-7.46 (m, 2H), 7.34-7.38 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.66 (t, J=7.2 Hz, 1H), 3.48 (t, J=7.2 Hz, 2H), 2.50 (t J=6.8 Hz, 2H), 1.67-1.82 (m, 2H), 1.29-1.48 (m, 2H), 0.89 (t, J=7.6 Hz, 3H). MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6×50 mm, 3 μm. Modifier: 0.05% DEA. Gradient: 95% CO2/5% ethanol linear to 60% CO2/40% ethanol over 3.0 minutes. Flow: 4 mL/min. Retention time: 1.42 minutes, 99% ee (Isomer 2).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[C:15]([F:23])=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:11][CH3:12])[C:15]=2[F:23])[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: CCOc1cccc(B(O)O)c1F
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: CCOc1cccc(-c2cc(F)c(N)c(Cl)c2)c1F
Yield: 43.2 %

Procedure:
The title compound (65 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (120 mg, 0.53 mmol) and 3-ethoxy-2-fluorophenylboronic acid (120 mg, 0.69 mmol) as a colourless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:38]([CH2:43][CH:44]1[CH2:46][O:45]1)[S:39]([CH3:42])(=[O:41])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(O)C>[CH2:31]([N:38]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:43][CH:44]([OH:45])[CH2:46][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Reactant: CS(=O)(=O)N(Cc1ccccc1)CC1CO1
Solvent: CCO
Product: CCOC(=O)CN1CCN(CC(=O)OCC)CCN(CC(O)CN(Cc2ccccc2)S(C)(=O)=O)CCN(CC(=O)OCC)CC1

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 4.83 g (20 mmol) of N-benzyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2e), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)[OH:22]>Cl.C1COCC1.O>[CH3:20][O:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]3[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:2][O:22][CH:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[CH:27][CH:28]=4)[C:10]3=2)[CH:15]=1
Reactant: COc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3CO)ccc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c3c(ccc2c1)-c1ccccc1COC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
Add several drops of HCl (5M) to a stirred solution of crude [2-(2-hydroxymethyl-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanol in THF (5 mL) and water (0.5 mL). Stir at r.t. for 24 h. Quench with aq. NaHCO3 and dilute with CH2Cl2. Wash the organic phase with water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3/MeOH) in CH2Cl2) to yield 1-{2-[4-(8-methoxy-11,13-dihydro-12-oxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-11-yl)-phenoxy]-ethyl}-piperidine (105 mg, 64%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:10][C:6]([CH3:11])([CH2:5][S:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(CCl)C(=O)O
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC(C)(C)C(=O)O
Temperature: 23 °C
Reaction time: 24 h

Procedure:
Example 75 can be prepared as demonstrated in the literature (reference Musker, W. K.; et al. J. Org. Chem. 1996, 51, 1026-1029). Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro-2,2-dimethylpropanoic acid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at 0° C. The resulting brown suspension was allowed to warm to 23° C. and stirred for 24 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (300 mL) and washed with diethyl ether (3×75 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with diethyl ether (3×75 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated to afford a colorless oil (1.2 g, 99% crude yield). 1H NMR (300 MHz, CDCl3) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:26])[CH:23](Br)[CH3:24]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:23]([CH3:24])[C:22]([O:21][CH3:20])=[O:26])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
Using 4-hydroxy-3-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a light yellow solid (1.55 g, 61% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (d, J=6.82 Hz, 3H) 3.70 (s, 3H) 5.46 (q, J=6.65 Hz, 1H) 7.45 (d, J=8.84 Hz, 1H) 8.13 (d, J=8.84 Hz, 1H) 8.43 (s, 1H) 9.94 (s, 1 H). ESI-MS: m/z 254.1 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(pyridin-4-yl)aniline (60 mg, 0.352 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg, 0.097 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 440.3 (M+H); UV 201.7, 242.5, 278.7 nm; t 0.384 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH:5]([OH:36])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)[CH3:2].[CH3:39][N:40]=[C:41]=[O:42]>C(#N)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([O:36][C:41]([NH:40][CH3:39])=[O:42])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][C:24]3=[O:25])[CH2:21][CH2:22]2)=[O:16])=[CH:34][CH:35]=1)[CH3:38]
Reactant: CN=C=O
Reactant: CCN(CC)CC(O)CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CC#N
Product: CCN(CC)CC(CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1)OC(=O)NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(6-Diethylamino-5-hydroxyhexyloxy)benzoyl}-4-piperidinyl}-3,4-dihydrocarbostyril (0.7 g) and methyl isocyanate (0.24 ml) are dissolved in acetonitril (20 ml), and thereto is added trifuroboran ethyl ether complex (0.35 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated and purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 1-{1-[4-(6-diethylamino-5-methylaminocarbonyloxyhexyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (314 mg) as colorless oil.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 30 g (133 mmol) of benzyl 3-pyrroline-1-carboxylate in 700 mL of methylene chloride was added 57.2 g (200 mmol) of mCPBA. The reaction mixture was stirred at room temperature overnight and quenched with 250 mL of 20% NaHSO3 aqueous solution. The organic phase was separated, and the aqueous layer was extracted with methylene chloride twice (100 mL×2). The combined extracts were washed with saturated NaHCO3 aqueous solution twice (250 mL×2), brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel column with 40% EtOAc-Hexane provided the title compound (24 g, 83%). MS (M+H)+220.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[N:6][N:5]2[C:16]=1[S:17]([N:20]=[CH:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:19])=[O:18].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[N:6][N:5]2[C:16]=1[S:17]([N:20]=[CH:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:25])[CH3:26])(=[O:18])=[O:19]
Reactant: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(C#C[Si](C)(C)C)nn12)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc2nc(Cl)c(S(=O)(=O)N=CN(CC(C)C)CC(C)C)n2n1

Procedure:
N′-(2-Chloro-6-(trimethylsilylethynyl)imidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine (2.31 g, 4.63 mmol) was dissolved in a mixed solvent of tetrahydrofuran-water (10:1), and tetrabutylammonium fluoride hydrate (1.50 g, 5.04 mmol) was added to the solution with stirring under ice-cooling. After the mixture was stirred for 20 minutes under ice-cooling, the tetrahydrofuran was distilled away under reduced pressure, and the residues were dissolved in ethyl acetate. The ethyl acetate solution was washed twice with water, dehydrated over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure to give the title compound as pale yellow crystals. The yield was 1.96 g (100%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.C(N(C(C)C)C(C)C)C.C1N=CN([C:39](N2C=NC=C2)=[O:40])C=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:39](=[O:40])[NH:14][N:13]=3)[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4n[nH]c(=O)o4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a solution of 3-iodo-1-tosyl-1H-indole-5-carbohydrazide (2.00 g, 4.39 mmol) in DMF (10 mL) at RT was added N-ethyl-N-isopropylpropan-2-amine (1.68 mL, 9.66 mmol) and CDI (0.784 g, 4.83 mmol). The reaction was stirred at RT for 30 min, followed by 65° C. in an oil bath for 15 min. It was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluted with 20-70% EtOAc in Hex) to afford 5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2(3H)-one (1.7 g, 80%) as an off white crystalline solid. MS (ESI, pos. ion) m/z: 482.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([OH:115])[CH:3]1[NH:51][C:49](=[O:50])[CH:48]([CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])[NH:47][C:45](=[O:46])[CH:44]([CH2:57][C:58]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[NH:60][CH:59]=2)[NH:43][C:41](=[O:42])[CH:40]([CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[NH:39][C:37](=[O:38])[CH:36]([CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[NH:35][C:33](=[O:34])[CH:32]([CH2:81][C:82]([NH2:84])=[O:83])[NH:31][C:29](=[O:30])[CH:28]([CH2:85][CH2:86][CH2:87][CH2:88][NH2:89])[NH:27][C:25](=[O:26])[CH:24]([NH:90][C:91]([CH2:93][NH:94][C:95]([CH:97]([NH2:99])[CH3:98])=[O:96])=[O:92])[CH2:23][S:22][S:21][CH2:20][CH:19]([C:100]([OH:102])=[O:101])[NH:18][C:16](=[O:17])[CH:15]([CH2:103][OH:104])[NH:14][C:12](=[O:13])[CH:11]([CH:105]([OH:107])[CH3:106])[NH:10][C:8](=[O:9])[CH:7]([CH2:108][C:109]2[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=2)[NH:6][C:4]1=[O:5]>[Cl-].[Na+]>[CH3:1][C@@H:2]([OH:115])[C@@H:3]1[NH:51][C:49](=[O:50])[C@H:48]([CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])[NH:47][C:45](=[O:46])[C@H:44]([CH2:57][C:58]2[C:66]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[NH:60][CH:59]=2)[NH:43][C:41](=[O:42])[C@H:40]([CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[NH:39][C:37](=[O:38])[C@H:36]([CH2:74][C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[NH:35][C:33](=[O:34])[C@H:32]([CH2:81][C:82]([NH2:84])=[O:83])[NH:31][C:29](=[O:30])[C@H:28]([CH2:85][CH2:86][CH2:87][CH2:88][NH2:89])[NH:27][C:25](=[O:26])[C@@H:24]([NH:90][C:91]([CH2:93][NH:94][C:95]([C@@H:97]([NH2:99])[CH3:98])=[O:96])=[O:92])[CH2:23][S:22][S:21][CH2:20][C@@H:19]([C:100]([OH:102])=[O:101])[NH:18][C:16](=[O:17])[C@H:15]([CH2:103][OH:104])[NH:14][C:12](=[O:13])[C@H:11]([C@H:105]([OH:107])[CH3:106])[NH:10][C:8](=[O:9])[C@H:7]([CH2:108][C:109]2[CH:110]=[CH:111][CH:112]=[CH:113][CH:114]=2)[NH:6][C:4]1=[O:5]
Reactant: CC(N)C(=O)NCC(=O)NC1CSSCC(C(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc2ccccc2)NC(=O)C(C(C)O)NC(=O)C(CCCCN)NC(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(Cc2ccccc2)NC(=O)C(Cc2ccccc2)NC(=O)C(CC(N)=O)NC(=O)C(CCCCN)NC1=O
Agent: [Cl-]
Agent: [Na+]
Product: C[C@H](N)C(=O)NCC(=O)N[C@H]1CSSC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC1=O
Reaction time: 0.25 h

Procedure:
A pharmaceutical composition of somatostatin was prepared in 0.9% sodium chloride containing 20 mg of phosphatidyl choline and 2.7 mg of somatostatin-14 per mL. Briefly, phosphatidyl choline was slowly added under stirring to the 0.9% sodium chloride aqueous solution containing somatostatin-14. The composition was further stirred for 15 minutes until a liposome suspension was formed. Then liposomes were stepwise extruded through a polycarbonate filter with a 400 nm pore size, a 200 nm pore size filter and eventually ten times with a 100 nm pore size filter. Finally, the liposomal solution was filtered through a 0.22 μm sterilizing filter.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)=O.[CH:8]([C:10](=[N+:16]=[N-:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O>CO>[OH:2][CH2:1][CH2:3][N:4]1[CH:8]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:16]=[N:17]1
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Reactant: NCCO
Solvent: O=CO
Solvent: CO
Product: CCOC(=O)c1cn(CCO)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of ethanolamine (60 ml, 1 mole) in methanol (320 ml) at 5° was treated with formic acid until a pH of 5 was obtained. A solution of ethyl α-formyldiazoacetate (crude, approximately 0.3 mole) in methanol (320 ml) was then added and the mixture stirred at room temperature for two days. The mixture was then evaporated, chloroform (1 liter), then water (200 ml) was added and the mixture was treated with sodium bicarbonate until a pH of 7 was reached. The phases were separated and the aqueous phase saturated with sodium chloride and extracted with chloroform (6×300 ml). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was then dissolved in toluene (approximately 100 ml). The resulting crystalline solid was filtered, washed with ether and dried to provide the title compound (41.6 g) as a solid; υmax (nujol) 3320, 3140, 1725 cm-1 ; δ (CDCl3), 1.38 (3H, t, J 7.5 Hz), 4.00-4.80 (7H, m, becomes 6H, m on D2O exch), 8.40 (1H, s). This material was pure enough for further synthetic progression.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([OH:19])=[C:5]([C:7]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[O:8])[CH:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>OS(O)(=O)=O>[C:20]([O:19][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])=[O:8])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Oc1ccccc1C(=O)O)c1ccccc1O
Agent: O=S(=O)(O)O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of salsalicylic acid (salsalate) (5.0 g, 19.37 mmol) in acetic anhydride (15.0 mL, 147.0 mmol) was added 3 drops of conc. H2SO4 and the mixture was stirred at RT for 16-20 h. The mixture was diluted with ice cold water (50 mL) and precipitated solid was filtered, washed with water (2×10 mL), hexanes (20 mL) and dried to afford 2-{[2-(acetyloxy)benzoyl]oxy}benzoic acid, 11 (5.5 g, mmol) as white solid. Rf: 0.3 (50% EtOAc/hexanes).
Reaction SMILES: [CH:1](=[N:10][NH:11][C:12]([NH2:14])=[S:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])=O>>[CH3:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:14]=[C:12]([NH:11]/[N:10]=[CH:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[S:13][CH:16]=1
Reactant: Cc1cc(O)ccc1C(=O)CBr
Reactant: NC(=S)NN=CC=Cc1ccccc1
Product: Cc1cc(O)ccc1-c1csc(N/N=C/C=C/c2ccccc2)n1
Yield: 36 %

Procedure:
The compound is prepared according to the method described in example 1B from cinnamaldehyde thiosemicarbazone (0.28 mmoles) (Eur. J. Med. Chem. 25(7), 581-588, 1990) and from 2-bromo-4′-hydroxy-2′-methylacetophenone (0.28 mmoles). Yield 36%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9]O>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: Cc1cccc(Br)n1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(Br)[n+]1[O-]
Temperature: 90 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
2-Bromo-6-methylpyridine (36 g, 0.2 mol) was dissolved in acetic acid (700 ml), hydrogen peroxide (30%, 62 ml, 0.6 mol) was added and the mixture was stirred at 90° C. for 24 hours. After cooling to room temperature, the mixture was diluted with water (700 ml) and extracted with DCM (4×). The combined organic phases were washed with water, dried (sodium sulfate) and concentrated under reduced pressure to give 36 g of a red-brown liquid (0.19 mol, 94%) MS (APCI) m/z=188.0 [M+1]+.