Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH3:5][O:6][C:7]([CH:9]([N:11]([C:20](=[O:23])[CH2:21]Cl)[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])[CH3:10])=[O:8].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([CH:9]([N:11]([C:20](=[O:23])[CH2:21][NH:3][N:2]([CH3:4])[CH3:1])[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])[CH3:10])=[O:8]
Reactant: CN(C)N
Reactant: COC(=O)C(C)N(C(=O)CCl)c1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)C(C)N(C(=O)CNN(C)C)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 25 %

Procedure:
18 g (0.3 mol) of N,N-dimethylhydrazine is added at room temperature to 28.4 g (0.1 mol) of N-(1'-methoxycarbonyl-ethyl)-N-chloroacetyl-2,6-dimethylaniline in 150 ml of toluene. The reaction mixture is then stirred at 50°-60° C. for 96 hours. After cooling to room temperature, there is added about 100 ml of 1 N sodium hydroxide solution, and the organic phase is separated. The aqueous solution is extracted with toluene, the toluene solutions are combined, and washed once with water. After being dried with sodium sulfate, the toluene solution is concentrated in a water-jet vacuum. The brown oil remaining is taken up in petroleum ether, whereupon the product crystallises and is filtered off. The petroleum ether solution is concentrated by evaporation to leave 7.7 g of product in the form of brown oil; nD21 =1.5272.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)=[CH:3]1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([Cl:27])=[O:23])=[CH:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-oxoandrost-4-ene-17β-carboxylic acid (30 g) in methylene chloride (300 mL) and dimethylformamide (1.82 mL) a solution of oxalyl chloride (9.28 mL) in methylene chloride (30 mL) was added dropwise at 0° C. under nitrogen atmosphere. After stirring at 0° C. for 1 hour the reaction was completed. The volatile compounds were removed under vacuum, the solid was taken up with cyclohexane (200 mL) and evaporated to dryness (twice). The 3-oxo-androst-4-ene-17β-carbonyl chloride (30.33 g) so obtained was dissolved in chloroform (1.5 L), cooled to 0° C. and treated with 1,1,1,3,3,3-hexafluorophenylpropyl amine (46.078 g) and pyridine (38.3 mL). The reaction mixture was heated at reflux for 7 hours. After staying overnight at room temperature the reaction mixture was washed with 1N HCl (2×100 mL), with brine, with water until neutral and dried over sodium sulfate. The solvent was evaporated under vacuum and the brownish solid purified by flash chromatography on silica gel (eluant: n-hexane/ethyl acetate 70/30) to yield 9.2 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)[CH:43]=1)OC1C=CC=CC=1)#[N:27]>>[C:26]([NH:28][C:29]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:23])=[N:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]2[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]2)[CH:43]=1)#[N:27]
Reactant: CN(CCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Product: CN(CCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.54 g (1.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,5-pentanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. %]) =643 ([M+H]+, 7), 229 (54), 154 ([m-NO2 -benzylOH] 100); IR (KBr): 2165 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the tartaric acid salt which forms a dry foam under reduced pressure.
Reaction SMILES: [Cl-:1].[CH:2]1([C:8]2([CH2:14][N:15]3[C:19]([CH3:21])([CH3:20])[CH2:18][O:17][C:16]3=[O:22])[CH2:13][CH2:12][NH2+:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(OC([N:59]1[CH2:63][C@@H:62]([C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=2)[C@@H:61]([C:71](O)=[O:72])[CH2:60]1)=O)(C)(C)C.N1CCCC1>C(Cl)Cl>[Cl-:1].[CH:2]1([C:8]2([CH2:14][N:15]3[C:19]([CH3:20])([CH3:21])[CH2:18][O:17][C:16]3=[O:22])[CH2:9][CH2:10][N:11]([C:71]([C@@H:61]3[C@H:62]([C:64]4[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=4)[CH2:63][NH2+:59][CH2:60]3)=[O:72])[CH2:12][CH2:13]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CC[NH2+]CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)[C@H](c2ccc(F)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCNC1
Product: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@H]2C[NH2+]C[C@H]2c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a suspension of 4-cyclohexyl-4-[(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)methyl]piperidinium chloride (150 mg; 0.4532 mmol) in methylene chloride (4.0 mL) was added N-methylmorpholine (183 mg; 0.2 mL). After 20 min, the following reagents were added sequentially: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg; 0.6798 mmol), 1-hydroxybenzotriazole (92 mg; 0.6798 mmol) and the product of step D (154 mg; 0.4985 mmol). The final reaction mixture was maintained at ambient temperature for 48 h. The reaction mixture was diluted with methylene chloride (100 mL) followed by washing the organic solution with saturated sodium bicarbonate and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to provide the crude N-BOC protected pyrrolidine that was purified on silica gel (50% ethyl acetate/hexane as the elution solvent). The crude N-BOC protected pyrrolidine was then dissolved in ethyl acetate (2 mL) followed by the addition of a saturated solution of hydrogen chloride in ethyl acetate (2 mL). The reaction mixture was maintained at ambient temperature for 2 h at which time the volatiles were removed in vacuo. The crude product was triturated to high purity with diethyl ether which furnished 204 mg of the title compound as a hydrochloride salt.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:8])([CH3:9])[CH3:7]
Reactant: [H][H]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 90.6 %

Procedure:
1.9 g of Z-Asp(OtBu)-Ser(tBu)-OtBu are hydrogenated in 100 ml of methanol in the presence of 0.1 g of Pd/C 10%. After the theoretical amount of hydrogen has been taken up the mixture is filtered and the filtrate is evaporated to dryness. Chromatography on silica gel with methylene chloride/MeOH (98:2) gives 1.28 g (91%) of H-Asp(OtBu)-Ser(tBu)-OtBu, MS: 389 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of m-bromoiodobenzene (25.0 g. 881.1 mmol) in diisopropylamine (500 ml), there were added bis(triphenylphosphine)palladium dichloride (1.24 g. 1.80 mmol) and copper (I) iodide (1.24 g, 2.03 mmol). The solution was degassed via a rapid stream of argon, and trimethylsilylacetylene (9.51 g, 97.0 mmol) was added over a period of 15 min. The reaction mixture was stirred at room temperature until G.C. analysis indicated the disappearance of starting material (2 h). The reaction mixture was cooled to room temperature and filtered to remove salts. The filtrate was concentrated in vacuo, and the oily residue was taken up in dichloromethane. The solution was washed with an aqueous 5% HCl solution (2×200 ml), water (2×200 ml) and brine (1×200 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo yielding the crude product as a yellow oil. The liquid chromatographed from silica gel in pentane. Elution with pentane gave the product (1b) (20.59 g, 91%) as a clear liquid: bp 81°-82° C., 1H NMR (200 MHz, CDCl3) c 0.30 (s), 7.23(m).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([O:23][CH3:24])=[CH:14][C:15]([NH2:22])=[C:16]([CH:21]=2)[C:17]([O:19]C)=O)[CH2:4][CH2:3]1.O.N.[C:27](#[N:29])[CH3:28]>>[O:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:16]3[C:15](=[CH:14][C:13]=2[O:23][CH3:24])[N:22]=[C:27]([CH3:28])[NH:29][C:17]3=[O:19])[CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)c1cc(OCCCN2CCOCC2)c(OC)cc1N
Agent: Cl
Agent: N
Solvent: O
Product: COc1cc2nc(C)[nH]c(=O)c2cc1OCCCN1CCOCC1
Yield: 98 %

Procedure:
Dry HCl gas was passed (until the clear solution observed) to a solution of methyl 5-(3-morpholinopropoxy)-2-amino-4-methoxy-benzoate (1.0 g, 3.0 mmol) in acetonitrile (16 mL) for 30 min at rt. The reaction mixture was refluxed for 3 h and attained to rt. The solution was poured into ice cooled water and basified with ammonia solution. The solution was extracted with EtOAc (3×100 mL) and the combined EtOAc layer was washed water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an off-white color solid (1.0 g, 98%), mp 236-238° C. 1H NMR (400 MHz, CDCl3): δ 11.60 (1H, br s), 7.59 (1H, s), 7.08 (1H, s), 4.23 (2H, t, J=6.6 Hz), 3.97 (3H, s), 3.73 (4H, t, J=4.6 Hz), 2.56 (2H, t, J=7.0 Hz), 2.56 (3H, s), 2.48 (4H, t, J=4.4 Hz), 2.09 (2H, pentet, J=6.8 Hz); LC-MS (positive ion mode): m/z 334 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Fc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(F)c1
Yield: 39.2 %

Procedure:
Using 0.15 g of 3-fluorobenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.11 g of 2-(3-fluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (79)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[CH:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([C:2]2[CH:3]=[C:4]([NH2:16])[CH:5]=[N:6][C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[CH2:19][CH2:18]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: COc1cccc(-c2ncc(N)cc2Br)c1
Product: COc1cccc(-c2ncc(N)cc2C2CC2)c1
Yield: 68 %

Procedure:
Obtained (0.1 g, yield 68%) following the procedure described in Intermediate 27, starting with 5-bromo-6-(3-methoxyphenyl)pyridin-3-amine (Intermediate 40) (0.61 mmol, 0.172 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.68 mmol, 0.123 ml).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH2:17]2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: ClCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CN(CCOC3CCCCO3)CCO2)cc1
Temperature: 100 °C
Yield: 71.5 %

Procedure:
A mixture of 2-(4-octyloxy-phenyl)-morpholine (1.99 g; 6.8 mmol), 2-(2-chloroethoxy)-tetrahydro-2H-pyran (1.21 ml; 8.2 mmol), K2CO3 (1.89 g; 13.7 mmol) and NaI (0.20 g; 1.4 mmol) in DMF (15 mL) was heated to 100° C. overnight. After cooling to RT the reaction mixture was partitioned between 5% aqueous NaHCO3 solution and Et2O. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc) to afford 2-(4-octyloxy-phenyl)-4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-morpholine (2.04 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>C(Cl)Cl>[Br:15][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C1OCc2cc(CCO)ccc21
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1OCc2cc(CCBr)ccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (1.2 g, 6.8 mmol) in DCM at 0° C. was added carbon tetrabromide (2.3 g, 6.8 mmol), triphenylphosphine (1.8 g, 6.8 mmol), and imidazole (0.46 g, 6.8 mmol). The mixture was allowed to stir at 0° C. for 5 minutes, and then allowed to warm to RT and stir for 1.5 hours. The crude was concentrated and purified by silica gel chromatography (43% EtOAc with Hexanes) to obtain 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 241/243 (M+1)+.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[N:15]1([CH2:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH2:28][CH:27]([NH2:32])[CH2:26][CH2:25]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[S:43]([NH:46][CH:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:48][C:49](O)=[O:50])(=[O:45])=[O:44].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[S:43]([NH:46][CH:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:48][C:49]([NH:32][CH:27]1[CH2:26][CH2:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:23]=2)[CH2:28]1)=[O:50])(=[O:45])=[O:44]
Reactant: NC1CCc2cc(CN3CCCCC3)ccc2C1
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCc2cc(CN3CCCCC3)ccc2C1
Temperature: 25 °C

Procedure:
6-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamine bis-TFA salt (Step F) (0.143 g, 0.327 mmol), 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid (0.128 g, 0.360 mmol), HOBt (0.057 g, 0.425 mmol) and EDC (0.081 g, 0.425 mmol) were dissolved in CH2Cl2 (25 mL) and stirred at RT. TEA (0.228 mL, 1.64 mmol) was added drop-wise to the mixture and the reaction was stirred at RT until HPLC analysis showed complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the crude material. The crude was purified by flash column chromatography to furnish the title compound. MS (APCI pos) 582 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([OH:19])=O)[CH:9]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)=[O:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
To a stirred solution of 2′,6-dichloro-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid (500 mg, 1.68 mmol) in DMF (10 mL) at room temperature, tert-butyl piperazine-1-carboxylate (345 mg, 1.85 mmol), BOP (892 mg, 2.02 mmol) and DIEA (542 mg, 4.2 mmol) were added and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (550 mg, 70% yield). ESI-MS m/z: 465.4[M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH2:15]>CC(O)=O.CC(C)=O>[CH:11]1[C:12]2[C:7]([S:6][C:5]3[C:14]([N:13]=2)=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:8][C:9](=[O:15])[CH:10]=1
Reactant: O
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3sc-2c1
Reaction time: 0.33 h

Procedure:
To a stirring solution of 1.1 kg of ceric ammonium nitrate in 12.5 liters of H2O and 1.25 liters of HOAc at 10° C. was added dropwise a solution of 100 g of phenothiazine in 500 ml acetone over a period of 20 minutes. The resulting mixture was stirred for another 20 minutes and the product 3H-phenothiazin-3-one was then filtered off. The filtered 3H-phenothiazin-3-one was washed with water thoroughly and dried to give 92 g of crude 3H-phenothiazin-3-one. The crude 3H-phenothiazin-3-one was extracted with minimum volume of CH2Cl2. Upon dilution of the CH2Cl2 solution with 10 times the volume of cyclohexane, a precipitate was formed which was filtered and dried to afford 35 g of 3H-phenothiazin-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:11]([Cl:12])=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[Cl:13].[Br:19]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:19][C:10]1[C:11]([Cl:12])=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Br:1])[C:6]([Cl:13])=[CH:7][C:8]=1[NH2:9]
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Br)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: Nc1cc(Cl)c(Oc2ccc(Cl)cc2Br)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
Into a magnetically stirred solution of 4-(2-bromo-4-chlorophenoxy)-3,5-dichloroaniline (6.38 grams, 17.36 mmol) in benzene (35 milliliters) was added N-bromosuccinimide (3.71 grams, 20.83 mmol). The reaction mixture was stirred for two hours at room temperature, transferred to a separatory funnel and washed with saturated Na2SO3 solution (2x), water (2x) and brine (1x). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product which when subjected to flash column chromatography on 760 grams of silica gel (4:1 hexane:ethyl acetate) afforded pure 2-bromo-4-(2-bromo-4-chlorophenoxy)-3,5-dichloroaniline (5.15 grams, 11.53 mmol, 66%). Elemental analysis of the product indicated the following:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10](C(OC(C)(C)C)=O)[C@H:11]([C:17]([O:19]C(C)(C)C)=[O:18])[CH2:12][CH2:13][C:14](=[O:16])O.Cl.[NH2:32][C:33]1[CH:34]=[C:35]([S:41]([OH:44])(=[O:43])=[O:42])[CH:36]=[C:37]([Cl:40])[C:38]=1[CH3:39].C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.C(#N)C.FC(F)(F)C(O)=O.CN(C=O)C>[Cl:40][C:37]1[C:38]([CH3:39])=[C:33]([NH:32][C:14](=[O:16])[CH2:13][CH2:12][C@@H:11]([C:17]([OH:19])=[O:18])[NH2:10])[CH:34]=[C:35]([S:41]([OH:44])(=[O:43])=[O:42])[CH:36]=1
Reactant: Cc1c(N)cc(S(=O)(=O)O)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(S(=O)(=O)O)cc1NC(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After 2 ml of DMF and 0.52 ml (3 mmol) of DIEA were added to 303 mg (1 mmol) of Boc-Glu-OtBu hydrochloride, 221 mg (1 mmol) of 3-amino-5-chloro-4-methylbenzenesulfonic acid, 160 mg (1.3 mmol) of HOAt and 410 mg (1.3 mmol) of HATU, the mixture was stirred at room temperature overnight. The reaction solution was diluted in water-acetonitrile and purified in accordance with the purification step A to give the protected product. The protected product obtained was dissolved in 5 ml of trifluoroacetic acid and stirred for 2 hours. After the solvent was removed by distillation, the mixture was purified in accordance with the purification step A to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C(OCC)C.CCCCCC>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([B:17]([OH:20])[OH:18])=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(I)c(F)cc1Cl
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(B(O)O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at −78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below −69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-296° C.).