Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1.CS(C)=O>CN(C=O)C>[ClH:25].[CH3:37][O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH3:39])[N:29]=[CH:28][N:27]=[C:26]2[CH:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:12])=[O:11])[CH:14]=2)[NH:18][C:17]1=[O:22]
Reactant: O=C1Cc2cc(S(=O)(=O)NCCN3CCOCC3)ccc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3C(=O)Nc4ccc(S(=O)(=O)NCCN5CCOCC5)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A solution of 5-(2-morpholinoethylaminosulphonyl)oxindole (364 mg, 1.1 mmol), (prepared as described for the starting material in Example 48), in DMF (3.5 ml) was added dropwise to a suspension of sodium hydride (90 mg, 2.2 mmol, prewashed with hexane) in DMF (1.5 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-6,7dimethoxyquinazoline (84 mg, 0.37 mmol), (prepared as described for the starting material in Example 1), was added as a solid followed by DMSO (2 ml). The mixture was stirred for 45 minutes at 60° C., allowed to cool and partitioned between methylene chloride and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 92/8). The purified solid was triturated with ether, collected by filtration; washed with ether and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 2M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed bv evaporation, the solid residue triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(5-(2-morpholinoethylaminosulphonyl)oxindol-3-yl)quinazoline hydrochloride (106 mg, 50%).
Reaction SMILES: N[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][NH:16][CH3:17]>CO>[CH3:15][N:16]([CH3:17])[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CNC
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 2.3 g of 5-chlorosulfonyl-2-oxindole (O-17) in 10 mL of 2 M dimethylamine in methanol was stirred at room temperature for 4 hours at which time a white solid was present. The precipitate was collected by vacuum filtration, washed with 5 mL of 1 N sodium hydroxide and 5 mL of 1 N hydrochloric acid and dried under vacuum at 40° C. overnight to give 1.9 g (79% yield) of 5-dimethylaminosulfonyl-2-oxindole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[CH3:25][N:26]([CH3:44])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1>>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]2[CH:19]=[CH:20][C:21]3[NH:22][C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][C:30]5[CH:31]=[CH:32][C:27]([N:26]([CH3:44])[CH3:25])=[CH:28][CH:29]=5)=[CH:43][CH:42]=4)=[N:1][C:4]=3[CH:5]=2)=[O:18])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: CN(C)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Product: CN(C)c1ccc(NC(=O)c2ccc(-c3nc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 193 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and 4-(4-dimethylaminophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C31H30N6O2: 519.24; found: 519.04.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: O=CCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.300 g, 1.19 mmol), hydrocinnamaldehyde (0.192 g, 1.43 mmol), and sodium cyanoborohydride (0.188 g, 2.99 mmol) were combined in CH2Cl2 and stirred overnight at room temperature. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([CH:3]([N:7]1[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)([CH3:12])[C:10](=[O:21])[N:9](CC2C=CC(OC)=CC=2)[C:8]1=[O:31])[C:4]([O-:6])=[O:5])C.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:54][C:55]#N>O>[CH2:54]([O:6][C:4](=[O:5])[CH2:3][N:7]1[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)([CH3:12])[C:10](=[O:21])[NH:9][C:8]1=[O:31])[CH3:55]
Reactant: CCC(C(=O)[O-])N1C(=O)N(Cc2ccc(OC)cc2)C(=O)C1(C)c1cc(F)cc(F)c1
Reactant: CC#N
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)CN1C(=O)NC(=O)C1(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-ethyl[5-(3,5-difluorophenyl)-3-(4-methoxybenzyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate from Step C (11.4 g, 26.3 mmol) in CH3CN (150 mL) was added drop wise a solution of ammonium cerium (IV) nitrate (43.2 g, 78.8 mmol) in water (100 mL) and the resulting mixture was stirred at ambient temperature for 3 h. The reaction was diluted with water (300 mL) and extracted with EtOAc (3×250 mL). The combined organic extracts were washed with water (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the racemic title compound. The enantiomers were resolved by HPLC, utilizing a ChiralPak AD column and eluting with hexane:EtOH:DEA 40:60:1. The first major peak to elute was ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate, isomer A, the title compound, and the second major peak to elute was ethyl[5-(3,5-difluorophenyl)-5-methyl-2,4-dioxoimidazolidin-1-yl]acetate, isomer B. MS: m/z=313 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:29]([O:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:29]([O:36][C:37](=[O:42])[CH2:38][C:39]([NH:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)CC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
(2-Amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (570 mg) was dissolved in CH2Cl2 (15 ml) and DMF (5 ml) prior to the addition of DIEA (2.3 ml) and malonic acid monobenzyl ester (400 mg). After cooling to 0° C., HATU (940 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Flash chromatography of the resulting residue gave N-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid benzyl ester (570 mg), MS found: (M−H)−=451.2. (20b) The above derivative (20a) (860 mg) was dissolved in THF (9.5 ml) prior to the addition of HOAc (28.5 ml). The resulting solution was heated in an oil bath at 65° C. for 3 h. After cooling, the solution was concentrated. Flash chromatography of the resulting residue gave (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid benzyl ester (343.3 mg). MS found: (M+H)+=335.2. (20c) A portion (142 mg) of the above derivative (20b) was dissolved in THF (1 ml) prior to the addition of a solution of LiOH (10 mg) in H2O (1 ml) and several drops of MeOH. After stirring at rt for 0.5 h, the reaction was concentrated. The resulting residue was dissolved in water and this was extracted with EtOAc to remove BnOH. The water layer was freeze-dried to give (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt. 1H NMR (CD3OD, δ ppm, 300 mHz) 3.3 (s, 2H), 7.43 (d, 1H), 7.61 (d, 1H), 7.79 (s, 1H). (20d) (±)(1S*,2R*,4R*)—N4-Isopropyl-N4-methyl-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexane-1,4-diamine TFA salt, from example (19g), (34 mg) was dissolved in DMF (2 ml) prior to the addition of DIEA (61 μl) and example (20c) (19 mg). After cooling to 0° C., HATU (53 mg) was added. The resulting mixture was warmed to rt and stirred overnight before being concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (15 mg). MS found: (M+H)+=597.3
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O-:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-])=O)(=[O:3])[CH3:2].[CH2:17](O)[CH3:18].[H][H]>[Pd].O>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:7][C:6]=1[NH2:14])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)[O-])cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Solvent: O
Product: CCOC(=O)c1ccc(NC(C)=O)c(N)c1
Temperature: 10 °C
Yield: 40.3 %

Procedure:
A mixture of wet crystals of 4-(acetylamino)-3-nitrobenzoate (45.3 g, purity: 66.2%), ethanol (191.6 g), water (31.9 g), and palladium-on-carbon (palladium content: 5%, water content: 50%, 3.0 g) was stirred at 40° C. for 19 hours at a hydrogen atmosphere. The catalyst was collected by filtration and washed with a mixed solvent of water and ethanol (1/9, 30.0 g). The filtrate was concentrated, and t-butyl methyl ether (33.0 g) was added dropwise thereto at 50° C., and the mixture was cooled to 10° C. to effect crystallization. Crystals were collected and washed with t-butyl methyl ether (30.0 g), and dried at 60° C. under reduced pressure. Thus, ethyl 4-(acetylamino)-3-aminobenzoate (18.2 g) was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:9][CH:8]=1)(=O)=O.[C:26]([C:28]1[CH:29]=[C:30]([Sn](C)(C)C)[CH:31]=[N:32][CH:33]=1)#[N:27].C(N(CC)CC)C.[Cl-].[Li+]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C)C=O>[C:26]([C:28]1[CH:29]=[C:30]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[C:14]3[N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:9][CH:8]=2)[CH:31]=[N:32][CH:33]=1)#[N:27]
Reactant: CN1CCN(c2cccc3ccc(OS(=O)(=O)C(F)(F)F)cc23)CC1
Reactant: C[Sn](C)(C)c1cncc(C#N)c1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc3ccc(-c4cncc(C#N)c4)cc23)CC1
Yield: 34 %

Procedure:
A mixture of 7-trifluoromethylsulfonyloxy-1-(4-methylpiperazin-1-yl)naphthalene (0.527 g, 1.53 mmol), bis(triphenylphosphine)palladium[II]chloride (0.537 g, 0.77 mmol), 5-cyano-3-trimethylstannylpyridine (0.0.450 g, 1.69 mmol, from preparation 7), triethylamine (1.02 mL, 7.34 mmol), lithium chloride (0.194 g, 4.59 mmol), 2,6-di-tert-butyl-4-methylphenol (approximately 0.01 g), and N,N-dimethylformamide (6 mL) was heated between 100° C. to 115° C. under nitrogen for 1.5 hours. The resulting mixture was concentrated via evaporation under reduced pressure, and the residue was column chromatographed using silica gel (approximately 25 g) and elution with 5% methanol in ethyl acetate to afford the title compound (0.170 g, 0.52 mmol, 34%) as a pale yellow foam: Rf =0.40 in 5% methanol in ethyl acetate; 1H (CD3OD) δ 9.08 (d, J=2.2 Hz, 1H), 8.82 (d, J=2.2 Hz, 1H), 8.43 (t, J=2.0 Hz, 1H), 8.36 (br s, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.70 (dd, J=1.8 and 8.5 Hz, 1H), 7.57 (br d, J=8.2 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.3 Hz, 1H), 3.20-3.00 (br s, 4H), 2.85-2.65 (br s, 4H), 2.40 (s, 3H); LRMS (m/z, relative intensity) 328 (M+, 100); HRMS m/e calculated for C21H20N4 328.1690. Observed m/e 328.1715
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]([C:16]1C=[CH:22][CH:21]=[CH:20][C:17]=1C#N)[CH2:8][CH2:7]2.ClCCl.[CH2:27]([OH:30])[CH2:28]O>O>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[N:9]([C:16]1[CH:17]=[CH:20][CH:21]=[CH:22][C:28]=1[C:27]([OH:30])=[O:1])[CH2:8][CH2:7]2
Reactant: OCCO
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)N(c1ccccc1C#N)CC2
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(c([N+](=O)[O-])c1)N(c1ccccc1C(=O)O)CC2
Temperature: 175 °C
Yield: 32 %

Procedure:
A stirred solution under nitrogen of potassium hydroxide (30 g, 0.53 mole) in ethylene glycol (250 ml) and water (35 ml) was heated to 175° C., at which temperature there was added 2-(5-methyl-7-nitroindolin-1-Yl)benzonitrile (26 g, 0.093 mole). After heating at 175° C. for 3 hours, the reaction mixture was cooled to room temperature and dichloromethane (1 liter) and water (500 ml), were added, with stirring. The aqueous phase was separated and extracted with two 250 ml-portions of dichloromethane. The aqueous phase was then cooled in an ice-bath and acidified with concentrated hydrochloric acid. The product was extracted out with three 500 ml-portions of dichloromethane. The combined organic extracts were washed twice with brine, dried, filtered, and concentrated to afford 9.0 g (32%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:25](=[O:26])[C@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:28]([CH3:30])[CH3:29])[CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC1(C)CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-(4-chlorophenyl)-2,2-dimethylpiperazine (0.76 g, 3.38 mmol) in DMF (10 mL), was added (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (0.735 g, 3.38 mmol), BOP (1.496 g, 3.38 mmol) and DIPEA (0.588 mL, 3.38 mmol). The mixture was stirred at rt for 2 h, quenched with aq. NaHCO3, extracted with EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by a flash column chromatography using 30% EtOAc in hexanes as an eluent. The product containing fractions were concentrated and dried to give (R)-tert-butyl 1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (1.36 g, 3.21 mmol, 95% yield) as a yellow oil. To (R)-tert-butyl 1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was added 4N HCL in dioxane and the resulting mixture stirred at room temperature until the starting material had been consumed. The volatile solvents were removed and the product dried to give (R)-2-Amino-1-(4-(4-chlorophenyl)-3,3-dimethylpiperazin-1-yl)-3-methylbutan-1-one hydrochloride as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39].C(N(CC)CC)C.[CH2:51](O)[CH2:52][CH2:53][CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH3:60]>C1COCC1>[CH2:51]([O:34][C:35]1[CH:36]=[C:37]([C:38]([NH2:40])=[O:39])[CH:41]=[CH:42][CH:43]=1)[CH2:52][CH2:53][CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCC/C=C\CCCCO
Reactant: NC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC/C=C\CCCCOc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a suspension of polymer-supported triphenyl phosphine (1.4 g, 3 mmol, based on a loading of 2.15 mmol/g [purchased from Argonaut], 1.5 equiv.) swollen in THF (20 ml) at room temperature was added diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.). The mixture was shaken for 5 min before 3-hydroxybenzamide (274 mg, 2 mmol, 1 equiv.), triethylamine (0.28 ml, 2 mmol, 1 equiv.) and cis-5-decenol (313 mg, 2 mmol, 1 equiv.) were added. The resulting suspension was shaken at room temperature for 16 h and then filtered. The resin was washed with additional THF (×3) and then the combined filtrate and washings were concentrated under reduced pressure, to give the crude product as a colourless semi-solid. It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient) to give the desired compound as a white solid (390 mg, 71%), mp 98-100° C. HPLC-MS (method 1): m/z 276 [M+H]+, Rt=5.00 min. 1H NMR (CDCl3) δ=7.35 (s, 1H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 (t, J=6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34-1.28 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).
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].C[CH:17](O)[C:18]([O-:20])=[O:19].N1C=CC=C[CH:23]=1>C(Cl)Cl>[S:3]([O:6][CH2:17][C:18]([O:20][CH3:23])=[O:19])([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: CC(O)C(=O)[O-]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Yield: 89.5 %

Procedure:
10.09 ml (60 mmol) trifluorometansulfonic anhydrid dissolved in CH2Cl2 was added dropwise to a mixture of 4.05 ml (50 mmol) methylglycolate and 4.04 ml (50 mmol) pyridin in CH2Cl2 (totally 62.5 ml) at 0° C. during 25 minutes, and thereafter stirred at 0° C. for 1H. After washing with 0.3 M KHSO4 and saturated NA2CO3, drying (Na2SO4) and filtration, evaporation of the solvent in vacuo gave 9.94 g (90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(O)C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:18]([O:17][C:15]([C:14]1[CH:20]=[N:7][C:6]2[C:8]([C:13]=1[OH:12])=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:16])[CH3:19]
Reactant: COc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 4-methoxyaniline (40 g, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A).
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:27][N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: CCCCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.5 %

Procedure:
Solid Teoc-OSu (390 mg, 1.5 mmol) was added to a vigorously stirred 2-phase mixture of (2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane (312.8 mg, 1.0 mmol), Na2CO3 (525 mg, 5.0 mmol), H2O (5.0 mL), and CH2Cl2 (25.0 mL). The mixture was stirred for 90 min at rt and the reaction was taken up in CH2Cl2 (50 mL), washed with brine (3×10 mL), dried over Na2SO4, decanted, and stripped to give a clear oil. This oil was separated on a 4 g SiO2 column to give crude (2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (486.5 mg, 106%) as a clear oil (quant). MS ESI +ve m/z 479 (M+Na). The crude product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[CH2:13][NH:14]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4].C=O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>C1COCC1.ClCCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=5)=[CH:21][CH:20]=4)[CH2:13][N:14]3[CH3:44])=[CH:9][C:8]=2[CH2:7][N:6]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:4]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a solution of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (298 mg) in THF/DCE (30 mL, 2:1) was added paraformaldehyde (90 mg, 4 eq.) and sodium triacetoxy-borohydride (208 mg) and the mixture stirred 4 hours. DCM was added to the mixture and the organic washed with 10% Na2CO3 solution and brine. The organic was dried over sodium sulfate and the solvent removed under reduced pressure to afford the crude amine. The residue was purified by flash chromatography (hexanes/ethyl acetate from 80:20 to 60:40) to provide the product (277 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([CH2:7][C:8](=[O:9])[CH2:6][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1ccccc1
Reaction time: 15 h

Procedure:
100 ml of n-tetrabutyl tin, then 120 mg of [benzyl (chloro) bis(triphenyl phosphine)]palladium were added to a solution of 40 ml of phenyl acetyl chloride in 500 ml of tetrahydrofuran. The mixture was stirred for 15 hours at reflux, filtered on clarcel and evaporated to dryness. The residue was distilled at 65° C. to 68° C. under 0.5 mm of mercury and the main fraction was chromatographed on silica (eluant: hexane - ethyl acetate (9-1)) to obtain 27.5 g of the desired product.