Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1(=[O:20])(=[O:19])[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C@@H:3]([C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:2]1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[S:1]1(=[O:20])(=[O:19])[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C@@H:3]([C:9]([OH:11])=[O:10])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12

Procedure:
To a solution of 131 mg of benzyl (3S, 5R)-penam-3-carboxylate 1,1-dioxide in a mixture of 15 ml of methanol and 10 ml of ethyl acetate was added 100 mg of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen at atmospheric pressure until hydrogen uptake ceased. At this point, the reaction mixture was filtered and the solvent was removed by evaporation in vacuo. This afforded 106 mg of the title compound [alpha]D25 =203 (CH3OH; C=1). The NMR spectrum (60 MHz; D2O) showed absorptions at 4.85 (m, 1H), 4.82 (m, 1H), 3.85 (m, 2H) and 3.43 (m, 2H) ppm. The IR spectrum (film) showed absorptions at 1760 and 1730 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2cccc(Br)c21
Yield: 90.8 %

Procedure:
To 4-bromoindoline-2,3-dione (200 mg, 0.89 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.120 ml, 0.98 mmol) then add NaH (35 mg, 0.89 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 270 mg (90%) of product.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:22][CH3:23])=[C:7](B(O)O)[CH:8]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].I[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([OH:35])[CH:29]=[CH:28]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC12CC3(C)OC(C)(CC(C)(O3)O1)P2C1C=CC=CC=1>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:8]=[C:7]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([OH:35])[CH:31]=3)[CH:26]=2)[C:6]=1[O:22][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(B(O)O)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: Oc1ccc2cc(I)ccc2c1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1c(-c2ccc3cc(O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C

Procedure:
In an embodiment, 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenylboronic acid (compound (1-Y2a)) is reacted with 6-iodonaphthalen-2-ol (compound (3-LG3c)) in tetrahydrofuran in the presence of potassium phosphate tribasic, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane, and tris(dibenzylideneacetone)dipalladium(0) to provide 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a)).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7]C(=O)OC(C)(C)C)=[C:4]([C:17](=[O:20])[NH:18][CH3:19])[CH:3]=1.[C:21]([C:25]([OH:27])=[O:26])([F:24])([F:23])[F:22]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:25]([OH:27])=[O:26].[NH2:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=1[C:17]([NH:18][CH3:19])=[O:20]
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(F)ccc1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-(methylcarbamoyl)benzylcarbamate (7.70 g, 27.3 mmol; prepared from 2-bromo-5-fluorobenzoic acid using literature methods) in CH2Cl2 (100 mL) was added CF3CO2H (25 mL) and the mixture stirred at room temperature for 15 min. This was concentrated in vacuo and the residue triturated with diethyl ether to obtain 8.0 g (Yield 99%) of the title compound as a white powder. 1H NMR (300 MHz, D2O) δ ppm: 2.93 (3H, s) 4.20 (2H, s) 7.35 (1H, dt, J=8.5, 3 Hz) 7.42 (1H, dd, J=9.0, 2.7 Hz) 7.57 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 183 (M+H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[C:4]([CH3:14])[N:3]=1)[NH2:17]
Reactant: NN
Reactant: COc1nc(C)nc(F)c1C(F)(F)F
Solvent: O
Solvent: CCO
Product: COc1nc(C)nc(NN)c1C(F)(F)F

Procedure:
Next, a reaction flask was loaded with 4-fluoro-6-methoxy-2-methyl-5-(trifluoromethyl)-pyrimidine (22 g) and ethanol (40 ml), followed by dropwise addition of hydrazine monohydrate (10.5 g) to the flask in one hour with stirring. Then, after stirring for one hour, the reaction mixture was filtrated to give 4-hydrazino-6-methoxy-2-methyl-5-(trifluoromethyl)pyrimidine. By GC/MS analysis, a molecular ion peak of 222 was confirmed for this compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(O)cc4)[nH]c3cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(OS(C)(=O)=O)cc4)[nH]c3cc21

Procedure:
2 g. (6.5 mmole) 8,8-dimethyl-2-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolin-6-one (see Example 30 d)) were suspended in 10 ml. water and, while cooling with ice, 5 ml. (65 mmole) methanesulphonic acid chloride and 50 ml. 2N aqueous sodium hydroxide solution were alternatingly added dropwise thereto in such a manner that a pH value of about 10 to 13 was always present. When the reaction was completed, the reaction mixture was filtered off with suction, the product was washed with water and purified by column chromatography (elution agent: methylene chloride/ methanol/acetic acid; 10:1:0.2 v/v/v). The evaporation fractions were suspended in water, rendered ammoniacal and washed with water to give 1.5 g. (68% of theory) of the title compound; m.p. 209°-215° C.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[K+].[Br:22]Br>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])=[C:8]([Br:22])[C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C#N)cc1CC(C)(C)O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCCn1nc(C#N)c(Br)c1CC(C)(C)O
Temperature: 0 °C
Yield: 53.5 %

Procedure:
The method described in Part F of Examples 1 through 4 was used to treat 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (18 g, 81 mmol) with potassium acetate (16.7 g, 171 mmol) and bromine (4.6 mL, 89 mmol). After the acetic acid was removed under reduced pressure, the residue was diluted with dichloromethane (100 mL) and adjusted to pH 12 with the addition of 50% w/w aqueous sodium hydroxide and ice while maintaining the temperature at 0° C. The resulting mixture was extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (60I cartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 13 g of 1-butyl-4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]([CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2S)-2-(((2-methylpropyl)amino)methyl)-1,4-piperazinedicarboxylate (0.77 g, 2.1 mmol), DMAP (0.0287 g, 0.235 mmol) and DIPEA (1.45 mL, 8.29 mmol) and CH2Cl2 (10 mL). Methanesulfonyl chloride (0.321 mL, 4.15 mmol) was added drop wise at room temperature. The mixture was stirred for 30 min and partitioned between water (30 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (30 mL) and the combined organic phases were washed with saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 10 to 70% EtOAc in hexanes) to afford di-tert-butyl (2R)-2-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.842 g) as a white solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrCCBr.C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N+:13]12[CH2:14][C:15]([C:18]([O-:20])=[O:19])([CH2:16][CH2:17]1)[CH2:2][CH2:1]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Reactant: [Li]CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: CCCCCC
Product: O=C([O-])C12CC[N+](Cc3ccccc3)(CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To DIPA (3.6 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (8.93 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzyl-pyrrolidine-3-carboxylate (5.0 g), followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 1,2-dibromoethane (6.05 g) in THF, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The aqueous layer was concentrated under reduced pressure, and to the residue was added EtOH, followed by stirring at room temperature for 30 minutes. The insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added EtOH, followed by stirring at room temperature for 10 minutes. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1-benzyl-1-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) as a colorless solid.
Reaction SMILES: [CH3:1]C(C1C=CC(CBr)=CC=1)(S(OCC)(=O)=O)C.[C:18]([O:22][C:23](=[O:39])[CH2:24]N=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:21])([CH3:20])[CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].ClC(OCC1C=CC=CC=1)=O.OS(O)(=O)=O>C1COCC1.O>[C:18]([O:22][C:23](=[O:39])[CH2:24][CH3:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CCOS(=O)(=O)C(C)(C)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(Cl)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 250.2 %

Procedure:
To a solution of ethyl 1-methyl-1-(4-bromomethylphenyl)ethanesulfonate (0.64 g, 1.89 mol) and N-diphenylmethyleneglycine t butyl ester (0.586 g, 1.98 mmol) in THF (6.5 mL) cooled on ice was added sodium bis(trimethylsilyl)amide (2M in THF, 1.04 mL). After 30 minutes the solvent was evaporated, the residue was taken up in acetic acid (2 mL), water (2 mL) and methanol (4 mL), and stirred at rt for 4 hours. The methanol was evaporated, water was added, and the mixture was washed with hexane/ether 1/1 (2×20 mL). The organic phase was washed with water. The combined aqueous phase was cooled on ice, and adjusted to pH 7 with sodium bicarbonate. Dioxane was added followed by benzyl chloroformate (0.38 mL, 2.65 mmol) and the mixture was stirred coming to rt overnight. Water was added, and the mixture was acidified to pH 3 with 1N H2SO4. The mixture was extracted with ethyl acetate, and the organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (10% to 20% ethyl acetate/hexane) gave crude 2-(R,S)-benzyloxycarbonylamino-3-[4'-(1"-ethyloxysulfonyl-1"-methyl)ethyl)benzene]propanoic acid t butyl ester (0.645 g, 68%). To a solution of the crude ester in methylene chloride (9 mL) cooled on ice was added trifluoroacetic acid (1.5 mL). The mixture was stirred for 4 hours, warming to rt. The reaction was quenched with cold aqueous sodium bicarbonate, and extracted with methylene chloride. The solvent was evaporated, and chromatography of the residue over silica gel (methylene chloride to 10% methanol/methylene chloride) gave 2-(R,S)-benzyloxycarbonylamino-3-[4'-(1"-ethyloxysulfonyl-1"-methyl)ethyl)benzene]propanoic acid (0.396 g, 0.88 mmol, 69%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH:16][NH2:17])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[C:5]1([C:8]2([C:14]3[N:27]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:17][N:16]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COC1=NCCCCCC1
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(C2(c3nnc4n3CCCCCC4)CCCCC2)cc1
Temperature: 120 °C

Procedure:
Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-51) as a white solid.
Reaction SMILES: C(OC)(=O)C(C)=C.C(O)(=O)C(C)=C.CN([C:17]1[CH:18]=[CH:19][C:20]([C:23]([C:25]2[CH:26]=[CH:27][C:28](N(C)C)=[CH:29][CH:30]=2)=[O:24])=[CH:21][CH:22]=1)C>C(OCCO)C>[C:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OC
Solvent: CCOCCO
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
A mixture iof 2.5 g of a 9:1 copolymer of methyl methacrylate and methacrylic acid, 3.50 g of Epocryl® DRH 303, 0.24 g of 2-(o-chlorophenyl)-4,5-diphenylimidazolyl dimer, and 0.06 g of Michler's ketone was dissolved in 25.20 g of 2-ethoxyethanol (Solution A). Solutions B, C and D were prepared by varying the quantities of Michler's ketone and 2-ethoxyethanol as follows:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:33][C@@H:32]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([CH2:34]OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:31]2)[CH2:26][N:25]1[C:48]([O:50][CH3:51])=[O:49])=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:33][C@@H:32]2[C@@H:27]([CH2:28][CH2:29][C@H:30]([CH2:34][N:5]3[C:4]([CH3:3])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=[CH:6]3)[CH2:31]2)[CH2:26][N:25]1[C:48]([O:50][CH3:51])=[O:49])=[O:23])[CH3:20]
Reactant: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](COS(=O)(=O)c3cccc([N+](=O)[O-])c3)CC[C@H]2CN1C(=O)OC
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(C[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)c1C
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
Sodium hydride (0.24 g, 1.2 eq) was washed with hexanes (3×10 ml) and suspended in dry THF (10 ml). To this was added a solution of 0.848 g of ethyl 4-methyl-5-imidazolecarboxylate in THF (5 ml) dropwise. The reaction mixture was stirred at 20° C. for 1.5 h and DMF (10 ml) was added. To the resulting solution was slowly added a solution of 2.43 g of [3S,4aR,6S,8aR]-ethyl-6-((3-nitrophenylsulfonyloxy)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate in THF (10 ml). The reaction was stirred at ambient temperature over night under N2. The reaction was quenched with saturated aqueous sodium bicarbonate. The resulting white solid was removed by filtration and the filtrate was extracted with ethyl acetate (3×10 ml). The combined organic extract was washed with brine, dried (MgSO4), filtered, and evaporated to a light brown oil. The crude product was chromatographed over silica gel eluting with ethyl acetate to give 1.09 g of the intermediate title compound: MS m/z: 456.3 (m++1);
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[CH3:36][NH:37][C:38](=[O:50])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[NH2:40]>C(Cl)Cl.CN(C=O)C>[CH3:36][NH:37][C:38](=[O:50])[C@H:39]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[NH:40][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of BOC-L-Leucine (5.26 g, 0.021M) in CH2Cl2 (40 ml) and DMF (10 ml) stirred at 0° was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (4 g, 0.021M). After 15 min., N-methyl morpholine (0.021M) was added followed by, after a further 10 min. at 0°, a solution of O-methyl-L-tyrosine N-Methylamide (4.3 g, 0.019M) in CH2Cl2. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo, and the residue in CH2Cl2, washed in turn with H2O (200 ml), saturated aq. NaHCO3 (200 ml), dilute HCl (1M; 200 ml), saturated aq. NaHCO3 (200 ml) and water (150 ml), dried (Na2SO4) and evaporated in vacuo to a solid. Recrystallisation from ethyl acetate/hexane gave N-(Tertiarybutoxycarbonyl)-L-leucyl-O-methyl-L-tyrosine N-methylamide as a white crystalline solid, (4.5 g), m.p. 159-161; (Found: C, 62.65; H, 8.33; N, 9.96. C22H35N3O5 requires C, 62.69; H, 8.37; N 9.97%). νmax (CDCl3) 3400, 1700 and 1662 cm-1 ; δ(CDCl3) 0.91 (6H, dd, J=7 and 14 Hz, CH(CH3)2); 1.37 (9H, s, OC(CH3)3); 1.47-1.7 (3H, m, CH2CH(CH3)2); 2.71 (3H, d, J=4.7 Hz, NHCH3), 2.98 and 3.14 (each 1H, each m, CH2C6H4); 3.78 (3H, s, OCH3); 4.0 and 4.61 (each 1H, each m, 2×α-CH); 4.86, (1H, br s, OCONH); 6.40 and 6.55 (each 1H, each br s, CONH×2); 6.82 (2H, d, J=8.4 Hz, Tyr H-3 and H-5); 7.08 (2H, d, J=8.4 Hz, Tyr H-2 and H-6); m/e 422 (70%, [m+1]+), 365 (70%, [m-58]+).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][S:15][CH2:16][CH2:17][O:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:8][CH:7]=1.C(O)C.[OH-].[K+]>O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[O:18][CH2:17][CH2:16][S:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:7][CH:8]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(OCCSCCOC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 98 %

Procedure:
A mixture of 3-[4-[2-[2-[Bis(4-chlorophenyl]methoxy]ethylthio]ethoxy]phenyl]propionic acid methyl ester (2.76 g, 5.31 mmol) and 80% aqueous ethanol (50 ml) was treated with a solution of potassium hydroxide (0.7 g, 10.6 mmol) in water (3 ml) and the resulting mixture was heated at 60° C. for 1 h. The solvent was then concentrated in vacuo and the residue was diluted with water (30 ml) and dichloromethane (50 ml) and acidified to pH4 with 2N hydrochloric acid. The aqueous phase was extracted a second time with dichloromethane and the combined organic extracts were washed with brine and dried (magnesium sulfate). Evaporation of the solvent under reduced pressure gave 2.63 g (98%) of the title acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:63])[CH2:60][O:61][CH3:62])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2([C:27]([NH:63][C@H:59]([C:56]3[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=3)[CH2:60][O:61][CH3:62])=[O:28])[CH2:25][CH2:26]2)=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[CH:10]=1
Reactant: COC[C@H](N)c1ccc(F)cc1
Reactant: Cn1cc(-c2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)cc3F)ccn2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)C1(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of Example B3 (65 mg, 0.164 mmol), TBTU (79 mg, 0.246 mmol) and (R)-1-(4-fluorophenyl)-2-methoxyethanamine (40.5 mg, 0.197 mmol; prepared according to the published method: J. Med. Chem. (1999), 42(24), 4981) in DMF (2 ml) was added DIEA (0.171 ml, 0.984 mmol). The resulting clear solution was stirred at RT overnight. After stirring overnight, the reaction was diluted with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with satd. NaHCO3 (1×), satd. LiCl (2×), and brine (1×), dried (MgSO4), evaporated in vacuo and purified by reverse phase chromatography. Pure fractions were pooled, treated with satd. NaHCO3 (pH 8) and extracted with EtOAc (3×). The combined organics were washed with satd. NaHCO3 (1×), brine (1×), dried (MgSO4), and evaporated to afford N-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-((R)-1-(4-fluorophenyl)-2-methoxyethyl)cyclopropane-1,1-dicarboxamide as an oil. This was dissolved in 4:1 MeCN/H2O, treated with certified 0.1N HCl (1.37 ml, 1.0 eq), frozen and lyophilized to afford 63 mg (66% yield) of the HCl salt as a solid. 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 8.49-8.48 (m, 2H), 8.44-8.42 (m, 1H), 8.18 (brs, 1H), 7.89-7.85 (m, 1H), 7.54 (brs, 1H), 7.48-7.35 (m, 4H), 7.16-7.11 (m, 2H), 6.92 (brs, 1H), 5.13-5.06 (m, 1H), 3.89 (s, 3H), 3.61-3.56 (m, 1H), 3.49-3.46 (m, 1H), 3.25 (s, 3H), 1.45-1.33 (m, 4H); MS (ESI) m/z: 516.1 (M+H+).