Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@H:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[O:26][C:20](=[O:21])[NH:19]2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)c2cccc(Br)n2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Optically-enriched tert-butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-hydroxy-2-(3-methoxyphenyl)ethylcarbamate (860 mg, 1.02 mmol) was dissolved in trifluoroacetic acid (15% in dichloromethane, 25 mL) and stirred at room temperature for 1 h. The reaction was concentrated, dissolved in methanol, and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (20 mL), cooled to 0° C., and treated with carbonyldiimidazole (201 mg, 1.24 mmol) in a single portion. The resulting suspension was stirred at 0° C. for 5 min. The ice bath was removed and stirring continued for 1 h. Upon warming to room temperature, everything went into solution. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was dissolved in a minimum of ethyl acetate and poured into water. The organics were diluted with several volumes of diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%-->50% EtOAc/Hex) gave 92 mg (26%). 1H-NMR (CDCl3, 500 MHz) δ 7.64 (dd, J=7.9, 7.6, 1H), 7.51 (d, J=7.9, 1H), 7.40 (d, J=7.6, 1H), 7.35 (dd, J=8.2, 8.2, 1H), 7.03 (m, 2H), 6.93 (m, 1H), 6.84 (bs, 1H), 5.60 (d, J=5.5, 1H), 4.91 (d, J=5.8, 1H), 3.85 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.2, 159.9, 159.1, 142.6, 139.8, 139.7, 130.2, 128.2, 119.7, 117.8, 114.8, 111.0, 83.4, 64.4, 55.5. Mass spec.: 349.04 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH2:12].C(O)CCCC.[CH2:19]([CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]=O)[CH2:20][CH2:21][CH2:22]CC.O=O>CN1C(=O)CCC1>[C:10]([C:5]1[C:6]([C:8]#[N:9])=[CH:7][C:2]2[N:1]=[C:26]([CH:25]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[NH:12][C:3]=2[CH:4]=1)#[N:11]
Reactant: CCCCCCC(C=O)CCCCCC
Reactant: N#Cc1cc(N)c(N)cc1C#N
Agent: O=O
Solvent: CCCCCO
Solvent: CN1CCCC1=O
Product: CCCCCCC(CCCC)c1nc2cc(C#N)c(C#N)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A 100 mL round-bottom flask was charged with 3 (1.32 g, 8.37 mmol), pentanol (42 mL), 2-hexyl-1-octanal (1.77 g, 8.37 mmol), and a magnetic stirring bar. The flask was fitted with a Hickman still and placed in an oil bath heated to 120° C. NMP (4.0 mL) was added to fully dissolve the solid material. The mixture was heated and stirred for 2 h. Then FeCl3.6H2O (113 mg, 0.42 mmol) was added to the reaction vessel and oxygen was bubbled through the mixture as it was heated and stirred for an additional 12 h. The reaction mixture was then removed from heat and added to 200 mL diethyl ether. The ether solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was chromatographed (silica, CHCl3), yielding a tan solid (2.37 g, 81%): 1H NMR δ 0.82 (t, J=7.6 Hz, 6H), 1.10-1.30 (m, 16H), 1.77-1.87 (m, 2H), 2.90-3.04 (m, 1H), 8.07 (br s, 2H), 10.36 (br s, 1H); 13C NMR δ 14.2, 22.8, 27.7, 29.4, 31.8, 34.9, 41.3, 108.4, 117.0, 165.3; FAB-MS obsd 351.2551, calcd 351.2549 (C22H30N4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][CH2:28][CH2:27][C:26]=2[CH:30]=1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:35]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:29][CH2:28][CH2:27][C:26]=4[CH:30]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 5e (6.3 g, 14.44 mmol) was dissolved in 60 mL pyridine, followed by addition of 4-dimethylamino pyridine (353 mg, 2.89 mmol) and tert-butyl-dimethyl-chloro-silane (2.61 g, 17.32 mmol) in turn. The reaction mixture was stirred for 16 hours and concentrated under reduced pressure. The resulting residue was dissolved in 200 mL ethyl acetate and partitioned. The organic extract was washed with water (50 mL) and saturated sodium chloride solution (50 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 5f (7.96 g, pale yellow solid), which was used directly in the next step without purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([NH:24]C(=O)OC(C)(C)C)[CH:20]=[CH:21][C:22]=2[CH3:23])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH:18]=1)[O:16][C:11]1[N:10]=[C:9]2[S:8][C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:15][C:14]2=[CH:13][CH:12]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To tert-butyl [3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]carbamate (0.80 g, 1.82 mmol) produced in Example C46(v) were added anisole (0.5 mL) and trifluoroacetic acid (5.0 mL) at 4° C. to give a solution, and the solution was stirred at the same temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (80 mL) was added to the obtained oily residue, and the mixture was extracted with ethyl acetate (80 mL)/tetrahydrofuran (8 mL). The organic layer was washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure. The residue was triturated with hexane to give the title compound (525 mg, 85%) as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[C:12]=2[OH:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:26]([C:28]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1)=[O:29])[NH2:27]>C(O)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:27][NH:26][C:28]([C:30]3[CH:31]=[CH:32][C:33]([S:36]([NH:39][CH3:40])(=[O:37])=[O:38])=[CH:34][CH:35]=3)=[O:29])[C:12]=2[OH:25])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CNS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: Cn1nc(C(=O)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 21.9 %

Procedure:
[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl](phenyl)methanone (0.254 mmol, 85 mg), 4-(hydrazinocarbonyl)-N-methylbenzenesulfonamide (0.254 mmol, 58 mg) and p-tosylic acid monohydrate (30 mol %, 13 mg) were dissolved in isopropyl alcohol (8.5 mL) and stirred at 100° C. for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (30.3 mg, yield 22%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccc(Br)c1F
Temperature: -78 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (0.150 g, 0.739 mmol) in THF (3.21 mL) cooled to −78° C. was added (4-fluorophenyl)magnesium bromide (0.443 mL, 0.887 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature slowly over 2 hr. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with CH2Cl2 and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). Organics were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a yellow residue.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.CS[CH:8]1[N:11]([C:12](=[C:17]2[S:21][C:20]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:19][S:18]2)[C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:27])[CH2:9]1>C(Cl)Cl>[Cl:4][CH:8]1[N:11]([C:12](=[C:17]2[S:21][C:20]([C:23]([F:26])([F:25])[F:24])([OH:22])[CH2:19][S:18]2)[C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:27])[CH2:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)C(=C1SCC(O)(C(F)(F)F)S1)N1C(=O)CC1SC
Solvent: ClCCl
Product: COC(=O)C(=C1SCC(O)(C(F)(F)F)S1)N1C(=O)CC1Cl

Procedure:
Sulphuryl chloride (59.7 mg, 35.8 μl, 0.442 mmole) was added to a solution of methyl 2-(4-methylthio-2-azetidinon-1-yl)-2-(4-trifluoromethyl-4-hydroxy-1,3-dithiolan-2-ylidene)acetate (166 mg, 0.442 mmole) in methylene chloride (3 ml) at room temperature, with stirring. After this addition, the solution was stirred for 3 minutes and then the solvent was distilled off to give the crude methyl 2-(4-chloro-2-azetidinon-1-yl)-2-(4-trifluoromethyl-4-hydroxy-1,3-dithiolan-2-ylidene)acetate. This 4-chloroazetidinone compound was dissolved in methylene chloride (3 ml) without purification, and triethylamine (185 μl) was added thereto, after which the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The resulting residue was dissolved in ethyl acetate and washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulphate. The solvent was distilled off under reduced pressure and the residue was purified by preparative thin layer chromatography (eluent: a 3:2 by volume mixture of benzene and ethyl acetate), to give 63 mg of the desired product as crystals.
Reaction SMILES: [CH:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2)=[CH2:2].C(=O)([O-])[O-:14].[Na+].[Na+]>ClCCl>[O:14]1[CH2:2][CH:1]1[C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: O=C([O-])[O-]
Reactant: C=CC12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Solvent: ClCCl
Product: C1C2CC3CC1CC(C1CO1)(C2)C3
Yield: 123.4 %

Procedure:
To a mixture of 16.2 g of 1-vinyladamantane, 120 ml of dichloromethane, and 5.3 g of sodium carbonate, 36.9 g of 70-m-chloroperbenzoic acid was added over 30 minutes on a water bath. The resultant mixture was stirred at room temperature for further 2 hours, was washed with a 5% sodium sulfite aqueous solution and saturated aqueous sodium bicarbonate, and the obtained organic layer was then concentrated. The residue was purified by column chromatography on a silica gel (SiO2400 g, developing solution: hexane/ethyl acetate=15/1) to give 11.0 g of 1-(1,2-epoxyethyl)adamantane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25]C(=O)C)=[CH:18][C:17]=2[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[OH:29])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 101.2 %

Procedure:
A mixture of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-acetamido-5-nitrobenzamide (1 g; 0.0024 moles) [prepared as described in Example 2], sodium hydroxide (0.2 g; 0.0048 moles), water (25 ml) and ethanol (12.5 ml) was boiled under reflux for 3 hours. Then the mixture was diluted with water, neutralized with diluted hydrochloric acid and the precipitate collected by filtration. This precipitate was washed with water and then with diethyl ether to give 0.9 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide. This compound was treated with a saturated solution of hydrogen chloride in methanol to give the hydrochloride which was recrystallized from ethanol. N-(1-Benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide hydrochloride was obtained, m.p. 248°-250° C. (dec).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[N:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][NH:18][C:12](=[O:14])[C:11](=[N:10][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:8][CH:7]=2)[CH3:15])=[CH:21][CH:22]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Yield: 78 %

Procedure:
2-(4-Trifluoromethylphenyl hydrazono) propionic acid (12.31 g, 50.0 mmol) was dissolved in dichloromethane (250 ml) and N,N-dimethylformamide (25 ml), and 5-aminomethyl-2-chloropyridine (7.13 g, 50.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloric acid salt (9.59 g, 50.0 mmol) were added thereto. 30 hours later, the mixture was washed with 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, and dried on sodium sulfate and then filtrated. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 63) (14.47 g, 39.02 mmol, 78%).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:7]=32)[CH2:3]1.[ClH:17].[H][H]>C(O)C.[Pd]>[ClH:17].[NH2:14][C:12]1[CH:11]=[CH:10][C:7]2[N:8]3[CH2:9][CH:2]([OH:1])[CH2:3][C:4]3=[N:5][C:6]=2[CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)nc1n2CC(O)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)nc1n2CC(O)C1

Procedure:
A mixture of 0.3 g (1.36 mmol) of the 2,3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo[1,2-a]benzimidazole obtained in step IX-2 and of 100 mg of palladium-on-charcoal at 10% in 15 ml of ethanol and 2 ml of 1N hydrochloric acid is stirred for 5 hours at 20° C. under 4 bar of hydrogen. After this period of time, the reaction mixture is filtered over a celite buffer, the filtrate is concentrated under reduced pressure, and 0.35 g of the expected product is obtained in the form of a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][C:44]([CH:51]=[CH2:52])([C:48]([OH:50])=[O:49])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.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:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][O:45][C:44](/[CH:51]=[CH:52]/[C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[CH3:25])[NH:18]4)=[O:16])[CH3:13])=[N:9]3)=[CH:4][CH:3]=2)([C:48]([OH:50])=[O:49])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: C=CC1(C(=O)O)CN(C(=O)OC(C)(C)C)CCO1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)CN(C(=O)OC(C)(C)C)CCO4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (95 mg, 0.178 mmol), 2-vinyl-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester (45.7 mg, 0.178 mmol), tri(o-tolyl)phosphine (11 mg, 0.036 mmol) and triethylamine (0.08 mL, 0.534 mmol) in 1,4-dioxane (5 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (16.3 mg, 0.018 mmol). After stirring at 100° C. for 50 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 711.3 [M+H], Tr=2.14 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C)=[O:10].ClC1C=CC2N=[C:24](C3C=CC=CC=3)[O:25]C(=O)C=2C=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:25][CH3:24])=[O:10]
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Product: COc1ccccc1C(=O)c1cc(Cl)ccc1N
Yield: 84 %

Procedure:
In a manner similar to that described above for compound 1m, 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1n (84% yield) MS m/z=262 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:17][C:2]([Cl:1])([Cl:16])[C:3]([NH:5][C:6]1[CH:7]=[N+:8]([O-:26])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cnc2c(c1)CCCC2)C(Cl)(Cl)Cl
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: O=C(Nc1cc2c([n+]([O-])c1)CCCC2)C(Cl)(Cl)Cl
Yield: 98.9 %

Procedure:
To a solution of 24.03 g of Compound 2 obtained in the above step (2) in 40 ml of methylene chloride is added 21.2 g of 80% m-chloroperbenzoic acid at room temperature, and the resultant mixture is stirred for 45 minutes. The reaction mixture is mixed with isopropyl ether and the crystals are filtered to give 25.06 g of the titled compound 3 as crystals. Yield: 99% mp.: 244° to 246° C. (dec.)
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)[CH2:11][CH:12]([CH3:14])[CH3:13].[C:26](OC(=N)C(Cl)(Cl)Cl)([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH2:10]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CCOc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CCOc1ccc(CC(=O)OC(C)(C)C)cc1
Reaction time: 16 h
Yield: 41.7 %

Procedure:
Boron trifluoride etherate (0.65 mL) was added in one portion to a stirred solution of [4-(isopentyloxy)phenyl]acetic acid (crude from preparation of intermediate 11; 7.31 g, 32.9 mmol) and t-butyltrichloroacetimidate (14.4 g, 11.8 mL, 65.8 mmol) in THF (70 mL) at room temperature under nitrogen. The resulting solution was stirred for 16 h then quenched with saturated aqueous sodium hydrogen carbonate solution (50 mL). The resulting suspension was extracted with ethyl acetate (3×50 mL) then the organic_extracts combined, dried_(magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (5-10% diethyl ether: cyclohexane) to give the title compound as a colourless oil (3.82 g, 42% over 2 steps). LC/MS: 3.94 min; z/e 296, calcd (M+18) 296. 1H NMR (400 MHz: CDCl3): 7.25 (2H), 6.90 (2H), 4.05 (2H), 3.55 (2H), 1.90 (1H), 1.75 (2H), 1.50 (9H), 1.05 (6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][N:14]([CH:47]2[CH2:49][CH2:48]2)[C:15](=[O:46])[CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:29][CH:28]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:55]>ClCCl>[Cl:1][C:2]1[C:3]([CH2:13][N:14]([CH:47]2[CH2:48][CH2:49]2)[C:15](=[O:46])[CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:31][CH:32]=2)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N+:6]([O-:55])[CH:7]=1
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c(Cl)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c(Cl)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (3-[{[5-chloro-2-(methoxypropyl)pyridin-4-yl]methyl}(cyclopropyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Experiment 94, Step 4 in dichloromethane (0.03 M) was added 3-chloroperoxybenzoic acid. The reaction mixture was stirred at RT for 16 h. The reaction was quenched with water and then extracted with EtOAc. The combined organic extracts were washed with 10% aq. HCl and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 1:1 (v/v) Hex:EtOAc 4 EtOAc) afforded the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:16][CH3:17])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:15])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.