Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)#[N:22].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:1][C@@H:2]([CH3:20])[CH2:3][C@H:4]([CH3:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(OC(=O)c3ccc(C#N)cc3)cc2)cc1
Yield: 46.2 %

Procedure:
0.30 g of (S,S)-4-[4-(3"-chloro-1"-methylbutoxy)phenyl]phenol, 0.16 g of 4-cyanobenzoic acid, 0.22 g of dicyclohexylcarbodiimide, 0.04 g of 4-pyrrolidinopyridine and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (7:3) as a developing solvent to thereby give 0.2 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])OC[C:6]=2[CH:13]=1.C([Li])CCC.CN(OC)[C:21](=[O:23])[CH3:22].C1C[O:29][CH2:28]C1>C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:28][O:29][C:6]=2[CH:13]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Reactant: C1CCOC1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)OCC(C)(C)O2
Reaction time: 0.5 h

Procedure:
To the product of step (a) (110 g, 0.46 mol) in 1.0 L of THF at −78° C. was added 236 mL (0.51 mol) of 2.14 M n-butyllithium in hexanes via a dropping funnel. After 30 minutes, N-methyl-N-methoxy acetamide (71 g, 0.69 mol, available from TCI) was added. After 2 hours, the reaction mixture was quenched with water, diluted with 2.0 L of 1.0 M aqueous phosphate buffer (pH=7.0) and extracted once with diethyl ether. The diethyl ether phase was washed once with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a light orange oil. The oil was dissolved in a minimum volume of ethyl acetate, diluted with hexanes, and to give the title compound as a crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10][C:11]3[C:17](C=O)=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CSS(C)(C)=O.[O:26]1[CH2:30]C[CH2:28][CH2:27]1.C(=O)(O)[O-:32].[Na+]>Cl.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][C:27]([O:26][CH3:30])=[O:32])[CH2:13][CH:12]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:11]3[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: COc1cccc(-c2cc3cccc(C=O)c3o2)c1
Reactant: C1CCOC1
Agent: CS[SH](C)(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC1(c2cccc(OC)c2)CC=C2C=CC=C2O1
Reaction time: 24 h

Procedure:
A mixture of 7.4 g of the product of Step A, 4.4 g of methyl methylsulfinyl methyl sulfide, 75 ml of tetrahydrofuran and 7 ml of Triton B was refluxed for one hour and then was poured into water and extracted with dichloromethane. The extracts were dried and concentrated to obtain 10 ml of produce which was dissolved in a 2N hydrochloric acid solution in methanol. The solution was stirred for 24 hours, treated with sodium bicarbonate, and stirred for one hour. After separating, extraction was carried out with ether and the extracts were washed and concentrated to obtain 9 g of product which was chromatographed on silica to obtain (eluant: hexane-ethyl acetate (9-1)) 4.3 g of the desired product which was used as is.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1ccccc1F
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccc1F

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(2-fluorophenyl)acetate hydrochloride (prepared from 2-fluorophenylglycine (Fluka) and ethanol using General Procedure H), the title compound was prepared as a solid (mp=153-170° C.). The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>C(#N)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[CH:37]=1)[C:32]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:33])([O-:28])=[O:27]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)cc23)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3,5-dinitrobenzoyl chloride (0.158 g, 0.684 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from acetonitrile to yield 0.17 g (63%) of the title compound: mp 254°-256° C. Analysis calculated for C22H21N5O5 : C, 60.68; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.73; N, 15.88.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]2[C:15]([CH:16]=1)=[N:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][C:12]=1[O:17]C)[N:7]=2.[Cl-].[Cl-].[Cl-].[Al+3].C1C=CC=CC=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:19][C:5]1[CH:4]=[C:3]([OH:2])[CH:16]=[C:15]2[C:6]=1[N:7]=[C:8]1[C:13](=[N:14]2)[C:12]([OH:17])=[CH:11][CH:10]=[CH:9]1
Reactant: COc1cc(C)c2nc3cccc(OC)c3nc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(O)cc2nc3c(O)cccc3nc12
Temperature: 25 °C
Yield: 84 %

Procedure:
A magnetically stirred mixture of 0.509 g (2 mmol) of 3.6-dimethoxy-1-methylphenazine, 1.0 g of aluminum trichloride (7.5 mmol), and 20 ml of benzene was heated at reflux for 18 hours. The mixture was cooled to room temperature and the solvent was removed on a rotary evaporator. The residue was treated with crushed ice and the resulting mixture was taken up in 1N sodium hydroxide and washed with dichloromethane. The combined dichloromethane layers were back-extracted with 1N sodium hydroxide and the combined aqueous layers were acidified to pH 4-5. The solution was extracted with dichloromethane containing a trace of methanol. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was was stripped to yield 1.06 g of a brown and yellow solid mixture. Flash chromatography in 6:1 toluene-acetone yielded 0.38 g of a yellow solid. This was recrystallized from toluene to yield 298 mg of orange crystals; decomposition at >256° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[CH2:22][C:21]=2[CH:37]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CCOCC>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[CH2:22][C:21]=2[CH:37]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2Cc2ccccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Trifluoromethanesulfonic anhydride (0.45 mL, 2.68 mmol) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate (611.7 mg, 2.06 mmol) and 2,6-lutidine (0.48 mL, 4.12 mmol) in anhydrous CH2Cl2 (10.3 mL) at -78° C. under argon. After 0.5 h, the reaction was warmed to RT and stirred for 1 h. The yellow solution was diluted with Et2O (50 mL) and washed sequentially with 1.0 N HCl (5 mL), 5% NaHCO3 (5 mL), and brine (5 mL). Drying (MgSO4), concentration, and silica gel chromatography (20% EtOAc/hexanes) gave the title compound as a colorless oil (808.9 mg, 92%): TLC Rf (20% EtOAc/hexanes) 0.58; 1H NMR (250 MHz, CDCl3) δ 6.98-7.30 (m, 7H), 4.35 (d, J=15.2 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.91 (d, J=15.2 Hz, 1H), 3.78-3.95 (m, 1H), 3.37 (dd, J=15.2, 4.1 Hz, 1H), 3.02 (dd, J=15.2, 9.6 Hz, 1H), 2.70 (dd, J=15.8, 4.8 Hz, 1H), 2.53 (dd, J=15.8, 9.6 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H); FTIR (CCl4) 1735, 1493, 1427, 1250, 1215, 1144,961, 856 cm-1 ; MS (ES) m/e 451.1 (M+Na)+, 446.2 (M+NH4)+, 429.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CO.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NCc1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(methanesulfonamido)methyl]benzyl alcohol (1.0 g, 4.6 mmol) in CH2Cl2 (25 mL) was added pyridinium chlorochromate (1.5 g, 7.0 mmol). The reaction mixture was stirred for 1 h at rt and poured through a pad of silica gel eluting with 2% MeOH(CHCl3. The title compound was isolated as a tan solid (1.0 g, 100%): 1H NMR (CDCl3): d 10.03 (s,1H); 7.88 (d, 2H); 7.57 (d, 2H); 4.79 (br s, 1H); 4.43 (d, 2H); 2.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C([Cl:40])=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([Cl:40])=[O:27])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)O)c3)n2)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (600 mg, 1.13 mmol) was suspended in methylene chloride (6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (567 μL, 1.13 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (264 μL, 2.27 mmol) was added dropwise. The reaction continued to stir at 0° C. for 10 min to afford the crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride as a 0.166 M solution in methylene chloride which was used in the following step with no further purification.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].Cl.[C:21]([O:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:21]([O:24][CH2:25][CH2:26][NH:27][C:16]([C@@H:9]1[NH:8][C:7](=[O:19])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:18])(=[O:23])[CH3:22]
Reactant: CC(=O)OCCN
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OCCNC(=O)[C@H]1CCCCCC[C@H](CSC(C)=O)C(=O)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.15 g, 0.52 mmol), 1-acetoxy-2-aminoethane hydrochloride (0.073 g, 0.52 mmol), 1-hydroxybenzotriazole (0.12 g, 0.52 mmol), and 4-methylmorpholine (0.17 mL, 1.56 mmol) are dissolved in methylene chloride (3.0 mL), and the reaction is cooled to 0° C. To this solution is added N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.20 g, 1.04 mmol), and the reaction is allowed to warm up to room temperature and then stirred overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (75% ethyl acetate/hexane) to give 2-acetoxy-N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-ethylamine, MS: M+1=373.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)[N:4]2[N:3]=1.[CH3:21][N:22]([CH3:32])[CH2:23][CH2:24][N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1>>[CH3:21][N:22]([CH3:32])[CH2:23][CH2:24][N:25]1[C:29]([CH2:30][O:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[O:19][N:18]=[C:17]([CH3:20])[N:16]=4)[N:4]3[N:3]=2)=[N:28][CH:27]=[N:26]1
Reactant: Cc1noc(-c2nnc3c4ccccc4c(Cl)nn23)n1
Reactant: CN(C)CCn1ncnc1CO
Product: Cc1noc(-c2nnc3c4ccccc4c(OCc4ncnn4CCN(C)C)nn23)n1

Procedure:
The reaction was carried out using the procedure described in Example 1, Step 4 using 6-chloro-3-(3-methyl[1,2,4]oxadiazol-5-yl)-[1,2,4]triazolo[3,4-α]phthalazine (WO-A-9850385) (125 mg, 0.44 mmol) and [2-(2-dimethylaminoethyl)-2H-[1,2,4]triazol-3-yl]methanol (Example 4, Step 2) (74 mg, 0.44 mmol). Crude residue was purified on silica, eluting product with 3% MeOH/DCM, followed by trituration with DCM and isohexane. The title compound was isolated by filtration to give a white solid (50 mg, 27%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18](OCC)=[O:19])=[C:14]([OH:23])[C:13]([CH:24]([CH3:26])[CH3:25])=[N:12]1.[H-].[Na+].BrCC1SC2C=CC=CC=2[N:35]=1.Cl.CC[O:43][C:44]([CH3:46])=[O:45]>CN(C)C=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]([NH:35][CH2:46][C:44]([OH:43])=[O:45])=[O:19])=[C:14]([OH:23])[C:13]([CH:24]([CH3:26])[CH3:25])=[N:12]1
Reactant: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2nc3ccccc3s2)c1=O
Reactant: CCOC(C)=O
Reactant: BrCc1nc2ccccc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(Cc2nc3ccccc3s2)c(=O)c(C(=O)NCC(=O)O)c1O
Reaction time: 0.67 h
Yield: 31 %

Procedure:
Ethyl 2-(1,3-benzothiazol-2-ylmethyl)-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. Sodium hydride (53 mg, 1.326 mmol) was added to a solution of the compound from example 14a) (120 mg, 0.530 mmol) in N,N-Dimethylformamide (DMF) (3 ml) at 0° C. The reaction was brought to room temperature and stirred for 40 minutes. The temperature was then reduced to 0° C. and 2-(bromomethyl)-1,3-benzothiazole (112 mg, 0.491 mmol) was added. The reaction was brought to room temperature and stirred for 3 h followed by the addition of 1N HCl. The solution was diluted with EtOAc and H2O and the layers separated. The aqueous layer was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 35-60% EtOAc/Hexanes) to give the title compound as an orange oil (61 mg, 0.163 mmol, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (s, 1H) 8.05-8.11 (m, 1H) 7.97-8.02 (m, 1H) 7.52 (ddd, J=8.21, 7.20, 1.26 Hz, 1H) 7.44 (td, J=7.58, 1.26 Hz, 1H) 5.59 (s, 2H) 4.27 (q, J=7.07 Hz, 2H) 3.20 (sept, J=6.82 Hz, 1H) 1.26 (t, J=7.20 Hz, 3H) 1.19 (d, J=6.82 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:22])=[C:4]([CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:10])=[C:6]([NH2:9])[C:7]=1[I:8].[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl.C(#N)C>[C:23]([O:26][CH2:27][C:28]([NH:9][C:6]1[C:5]([I:10])=[C:4]([CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:3]([I:22])=[C:2]([NH:1][C:12](=[O:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:7]=1[I:8])=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)OCC(Cc1c(I)c(N)c(I)c(N)c1I)OC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Yield: 64 %

Procedure:
The product in Example 64e, 3,5-diamino-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene was acylated using acetoxyacetyl chloride according to the general procedure in Example 24i. After chromatography on silica gel using methylene chloride/acetonitrile (3/1) as the eluent the product was isolated in 64% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH:23]3[CH2:25][CH2:24]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:26].[CH:20]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([CH:23]3[CH2:25][CH2:24]3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of the obtained 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium(II)dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). The obtained 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the precipitate was collected by filtration to give the title compound (3.2 g).
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@:10]1([CH2:26][O:27]C(=O)C1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25])C1C=CC=CC=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CO.C1CCCCC=1.CO.ClCCl.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:26][OH:27])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@]2(COC(=O)c3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
A mixture of compound 19 (0.95 g, 2.01 mmol) and Pd(OH)2/C (20%, 1 g) was suspended in methanol/cyclohexene (1:1, 20 mL) and refluxed overnight. The reaction mixture was cooled to rt, filtered through Celite™ column, and concentrated under reduced pressure. The residue was co-evaporated with anhydrous pyridine (2×20 mL), dissolved in anhydrous pyridine, and cooled in ice-bath. Benzoyl chloride (1.15 mL, 10 mmol) was added dropwise and the mixture was stirred at RT for 20 h. Reaction was then quenched by addition of ice-cold water (40 mL), and washed with dichloromethane (2×50 mL). The organic layers were combined, concentrated under reduced pressure, re-dissolved in pyridine/methanol (1:2, 30 mL), and 2 M aqueous NaOH (5 mL) was added. After 15 min, the mixture was neutralised with acetic acid (5 mL) and solvents were removed to give an oily residue. The latter was suspended in 5% methanol/dichloromethane, applied to a silica gel column and eluted by 5 to 15% of methanol/dichloromethane as a solvent. The fractions containing compound 20 were concentrated to yield 0.54 g (70%) of glass-like solid material with the same chromatographic mobility as authentic compound.
Reaction SMILES: [I-].[C:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH:11]([N+](C)(C)C)[CH2:10][CH2:9]2)(=[O:4])[CH3:3].[C-:21]#[N:22].[K+].[CH3:24]O>O>[C:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH:11]([CH2:24][C:21]#[N:22])[CH2:10][CH2:9]2)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1ccc2c(c1)CCC([N+](C)(C)C)C2=O
Reactant: CO
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)CCC(CC#N)C2=O

Procedure:
6-Acetamido-1-oxo-1,2,3,4-tetrahydro-2-naphthyl trimethylammonium iodide (4.25 g) in methanol (30 ml )/water (40 ml ) was added to a stirred solution of potassium cyanide (1.62 g) in water (40 ml ). After 3 hours the precipitate which had formed was collected and dried to give 6-acetamido-2-cyanomethyl-1-tetralone (1.7 g; m.p. 189°-90°) ν(Nujol mull) 3350-3100, 2220, 1670, 1590cm-1 ; m+ 242.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[CH2:17][NH:18]C(OC(C)(C)C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10](=[O:27])[C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16](=[O:26])[CH2:17][NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)N1CCC[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of 4.10 g of Compound (22) obtained in the step (a) in 5 ml of methylene chloride was added 2.5 ml of trifluoroacetic acid under ice-cooling and the reaction mixture was stirred for 1 hour, then, 4 ml of trifluoroacetic acid was added to the reaction mixture and the stirring was continued for 2 hours. After reaction, the solvent was removed to give 5.82 g of glycyl-L-proline p-nitrobenzyl ester trifluoroacetic acid salt as pale brownish oil.