Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:42]I>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=2)[C@H:10]([CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:42])[CH:32]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)C[C@H]1Cc1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (1.15 g) in dimethylformamide (60 ml) was added 60% sodium hydride (0.1 g) under nitrogen atmosphere, and the mixture was stirred for 5 minutes. After addition of methyl iodide (0.13 ml), the reaction mixture was stirred for 40 minutes. The reaction was quenched with 0.5N hydrochloric acid (60 ml) and diluted with dichloromethane (80 ml). The organic layer was washed with water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column eluting with a mixture of toluene and ethyl acetate (10:1) to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(N-methyl-1H-indol-3-yl-methyl)piperazine (1.12 g) as a syrup.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:24][C:23]=2[CH3:31])=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].O>ClCCl>[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[C:24]([Br:1])[C:23]=2[CH3:31])=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(C(=O)c2c(C)cc3ccccn23)ccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Reaction time: 2 h
Yield: 89.4 %

Procedure:
0.492 g (2.73 mmol) of N-bromosuccinimide is added, under an inert atmosphere at ambient temperature, to 0.812 g (2.6 mmol) of methyl 2-amino-5-[(2-methylindolizin-3-yl)carbonyl]benzoate in 17 ml of dichloromethane. The reaction medium is stirred for 2 hours and then hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase obtained is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 0.9 g of a yellow solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.C(OCC)C.[BrH:24]>>[Br:24][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCCCCCCCc1ccc(Cl)c(Cl)c1
Reactant: Br
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(CCCCCCCCBr)cc1Cl

Procedure:
A solution of 8-(3,4-dichlorophenyl)octan-1-ol (0.66 g) in 48% hydrobromic acid (7 ml) was stirred under reflux for 2 h. Water (20 ml) and diethyl ether (20 ml) were added. The organic layer was separated and the aqueous layer reextracted with diethyl ether (10 ml). The combined organic extracts were washed with water (10 ml), sodium hydrogen carbonate solution (10 ml) and brine (10 ml) and dried over magnesium sulfate. The solution was treated with charcoal, filtered and evaporated under reduced pressure to give 1-bromo-8-(3,4-dichlorophenyl)octane (0.74 g). 1H-NMR (CDCl3) δ 1.2-1.8 (12H, m), 2.55 (2H, t), 3.41 (2H, t), 7.00 (1H, dd), 7.25 (1H, dd) and 7.33 (1H, d).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30][CH2:31][CH3:32])[C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CO.[OH:35]OS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30]([CH2:31][CH3:32])=[O:35])[C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(SCC)cc3n2COCCOC)c1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)CC)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 44 h
Yield: 45 %

Procedure:
To a mixture of 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (EXAMPLE 95, product from Step A) (0.501 g, 1.14 mmol) and methanol (5.7 mL) was added a solution of Oxone®/potassium peroxymonosulfate (1.47 g, 2.40 mmol) in water (5.7 mL). The mixture was stirred for 44 h at 23° C. EtOAc (50 mL) and water (30 mL) were added and the biphasic mixture was stirred. The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-80% EtOAc/hexanes) to yield the tiled compound (0.260 g, 48% yield, 5:2 mixture of regioisomers) and 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfinyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.232 g, 45% yield, 2:1 mixture of regioisomers). MS (ESI/CI): mass calcd. for C13H23ClN4O6S, 470.1; m/z found, 471.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.91 (d, J=0.6 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.82 (s, 1H), 6.21 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.72-3.67 (m, 2H), 3.53-3.42 (m, 4H), 3.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H), 1.30 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(CCc2cccc(OC)c2)C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCc3cc(OC)ccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.31 g(7.7 mmol) of 2-(4-methoxyphenyl)-4-(3-methoxyphenyl)butyric acid was dissolved in 30 mL of CH2Cl2 and cooled to 0° C. To this solution was added 3.4 mL (23.1 mmol) of trifluoroacetic acid, the reaction was allowed to proceed for 30 minutes. The reaction was quenched by pouring into an aqueous solution of NaHCO3. The organic layer was separated, washed twice with NaHCO3 solution washed twice with brine, dried with Na2SO4, and evaporated to a solid. This yielded 1.5 g of the title compound as a tan amorphous solid.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.[CH3:15]OC(OC)(C)C>>[NH2:1][C@H:2]([C:11]([O:13][CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(C)(C)OC
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3.30 g L-tyrosine (3A) suspended in 50 mL 2,2-dimethoxypropane, 5 mL of concentrated 36% HCl was added. The resulting mixture was stirred overnight at room temperature and then concentrated to dryness to afford crude methyl tyrosinate. 1H NMR (CDCl3, 500 MHz): δ 7.02 (d, J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 3.76-3.71 (m, 4H), 3.04 (dd, J1=13.8 Hz, J2=5.1 Hz, 1H), 2.82 (dd, J1=13.8 Hz, J2=7.7 Hz, 1H). The mixture was then dissolved in a 20 mL N,N-dimethylformamide solution containing 8.0 mL N,N-diisopropylethylamine. This solution was chilled in an ice-water bath, mixed with 4.78 g N-(benzyloxycarbonyloxy)succinimide in 10 mL N,N-dimethylformamide and stirred at room temperature for 3 hours before it was concentrated by rotary evaporation. The residue was dissolved in ethyl acetate and water, acidified to pH 3 and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and rotary evaporated to dryness. Flash column purification afforded a white solid (3B) in 4.65 g (78%). 1H NMR (CDCl3, 500 MHz): δ7.40-7.34 (m, 5H), 6.96 (d, J=7.8 Hz, 2H), 6.73 (d, J=7.8 Hz, 2H), 5.28 (s, 1H), 5.14 (d, J=12.4 Hz, 1H), 5.10 (d, J=12.4 Hz, 1H), 4.65 (m, 1H), 3.70 (s, 3H), 3.09 (dd, J1=13.8 Hz, J2=5.5 Hz, 1H), 3.02 (dd, J1=13.8 Hz, J2=5.7 Hz, 1H). 13C NMR (CDCl3, 500 MHz): δ172.2, 162.8, 155.7, 154.9, 136.2, 130.4, 128.6, 128.2, 128.1, 127.5, 115.5, 67.1, 55.0, 52.4, 37.5.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2Br)[C@@H:6]1[O:23]C(=O)C)(=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[OH-].[Na+]>>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[N:11]([C@@H:7]3[CH2:8][CH2:9][CH2:10][C@@H:5]([OH:4])[C@H:6]3[OH:23])[C:12]([NH:30][CH:27]3[CH2:29][CH2:28]3)=[N:13][C:14]=2[CH:19]=1
Reactant: NC1CC1
Reactant: CC(=O)O[C@H]1[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: O[C@@H]1[C@H](O)CCC[C@H]1n1c(NC2CC2)nc2cc(Cl)c(Cl)cc21
Yield: 76 %

Procedure:
(±)-(1R*,2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclohexanediyl diacetate (464 mg, 1.00 mmol) and cyclopropylamine were reacted as in example 46. The solution was cooled and 1 N sodium hydroxide (one equivalent) was added. Volatiles were evaporated in vacuo and the residual solid was crystallized from methanol to provide title compound as off-white powder (271 mg, 76%), m.p. >25° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 7.62, 7.44 (both s, each 1, 2 aromatic CH), 7.00-6.95 (m, 1, NH), 4.66 (d, J=6.2 Hz, 1, OH), 4.56 (d, J=2.7 Hz, 1, OH), 4.3-3.9 (m, 3, 2 OCH and NCH), 2.8-2.65 (m, 1, NCH), 2.1-1.4 (m, 6, 3 CH2), 0.75-0.45 (m, 4, 2 CH2 of cyclopropyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[CH:7][C:8]=1[CH3:9])[NH2:6].[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[Br:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(Br)c(C)cc1N
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C(C)(C)C)c(C)cc1Br
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2,5-xylidine (8 g) in pyridine (60 ml) was added pivaloyl chloride (4.7 ml) at room temperature. After 30 minutes, the mixture was poured into dilute hydrochloric acid/ice solution. The precipitate was filtered and washed with water to give the title product.
Reaction SMILES: C([O:8][CH:9]1[CH2:12][CH:11]([N:13]2[C:21](=[O:22])[C:20]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)[C:18]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=4)=[N:17][C:16]=3[N:15]([CH3:43])[C:14]2=[O:44])[CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:19]2[C:20]3[C:21](=[O:22])[N:13]([CH:11]4[CH2:10][CH:9]([OH:8])[CH2:12]4)[C:14](=[O:44])[N:15]([CH3:43])[C:16]=3[N:17]=[C:18]2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:40])[F:41])[CH:33]=2)=[CH:29][CH:28]=1
Reactant: Cn1c(=O)n(C2CC(OCc3ccccc3)C2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C2CC(O)C2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
To a solution of 1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (110 mg, 0.175 mmol) in methanol was added 5% Pd/C (15 mg). The mixture was hydrogenated at 45 psi for 30 min. The reaction was filtered and concentrated to give a crude product which was purified via preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxycyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (11 mg, 17.7% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][CH2:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31]>C(#N)C>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:30](=[O:31])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][CH2:21][S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:12][C:3]=2[CH:4]=1
Reactant: COc1cc(N)c(CCNCCCN(C)CCCSc2ccccc2)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1cc2c(cc1OC)NC(=O)N(CCCN(C)CCCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(2-(2-amino-4,5-dimethoxyphenyl)-ethylamino)-propyl]-N-[3-(phenylthio)-propyl]-methylamine and carbonyldiimidazole in acetonitrile analogously to Example 56.
Reaction SMILES: C([NH:8][C@H:9]([C:22]([NH:24][CH2:25][CH2:26][NH:27][C:28]([CH:30]=[CH:31][CH3:32])=[O:29])=[O:23])[CH:10]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:13])[OH:12])(OC(C)(C)C)=O>O1CCOCC1>[CH2:15]([O:14][CH:10]([C:11](=[O:12])[OH:13])[C@@H:9]([C:22]([NH:24][CH2:25][CH2:26][NH:27][C:28]([CH:30]=[CH:31][CH3:32])=[O:29])=[O:23])[NH2:8])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC=CC(=O)NCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(OCc1ccccc1)C(=O)O
Solvent: C1COCCO1
Product: CC=CC(=O)NCCNC(=O)[C@@H](N)C(OCc1ccccc1)C(=O)O
Yield: 113.1 %

Procedure:
Boc-Asp(OBzl) (12.9 g) was dissolved in tetrahydrofuran (100 ml) and added with N-methylmorpholine (4.0 g) and isobutyl chloroformate (5.44 g) with cooling at -10° C. After stirring for 15 minutes, the mixture was added with ethylenediamine monomethacrylic acid hydrochloride (4.0 g) and N-methylmorpholine (3.0 g) and stirred. One hour later, the solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate and 10% aqueous solution of citric acid and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel chromatography to collect fractions of dichloromethane/ethyl acetate=25/75 to give N-Boc-β-benzyloxy-L-aspartylaminoethylaminocarbonyl-2-methylethene (3.3 g). N-Boc-β-benzyloxy-L-aspartylaminoethylaminocarbonyl-2-methylethene (3.3 g) was dissolved in dioxane (50 ml) and the Boc group was removed by adding 4M-hydrochloric acid solution in dioxane (50 ml) to give β-benzyloxy-L-aspartylaminoethylaminocarbonyl-2-methylethene (2.9 g).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[C:6]([N:8]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]>O.CO.C1COCC1>[Cl:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[C:6]([N:8]([C@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=2)[CH2:15][CH2:14]1)[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(CC(C)C)C(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)CN(C(=O)c1ccccc1Cl)[C@@H]1CCc2ccc(C(=O)O)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
LiOH (173 mg, 4.156 mmol, 2 eq), dissolved in water (12 ml), was added dropwise to an ice-cooled (0° C.) solution of (R)-methyl 3-(2-chloro-N-isobutylbenzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-29) (0.8 g, 2.078 mmol, 1 eq) in MeOH:THF (1:1, 24 ml), and stirring was carried out for 8 h at RT. After monitoring by thin-layer chromatography, the reaction solution was concentrated and the residue was taken up in water (30 ml) and extracted with ethyl acetate (25 ml). The aqueous phase was adjusted to pH 3 with 2 M HCl and extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. Yield: 78% (600 mg, 1.62 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].[CH2:13](I)[CH3:14]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:13][CH3:14])=[C:4]([F:10])[CH:3]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A solution of 4-bromo-2,6-difluorophenol (1.04 g) in dry N,N-dimethylformamide (10 cm3) was added over 5 minutes to a well stirred mixture of sodium hydride (0.24 g of a 50% dispersion in oil) in dry N,N-dimethylformamide (5 cm3). After 30 minutes, ethyl iodide (0.78 g) was added in one portion. After stirring the reaction mixture for 30 minutes, analysis by gas liquid chromatography appeared to show no reaction; further ethyl iodide (5 g) was therefore added, and the reaction mixture was heated at 80° C. for 15 minutes. Later analysis showed similar retention times for both starting material and product, and the reaction may already have been complete prior to the second addition of ethyl iodide. The reaction mixture was washed, poured into water, and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulphate and evaporated under reduced pressure to give a red oil. The oil was purified by column chromatography on a silica gel support, eluting with an 8:1 parts by volume mixture of n-hexane and ethyl acetate to give 4-bromo-2,6-difluorophenetole as a colourless oil (1.02 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(Cl)Cl.[K+].[Br-]>CO.C(Cl)Cl>[CH3:6][O:5][C:3]([CH2:2][NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:4]
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CNC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Yield: 36 %

Procedure:
This compound (7) was synthesized from compound 5 using a method analogous to the synthesis described in Example 4. FC (silica gel, first CH2Cl2, then 5% MeOH/CH2Cl2). Yield: 36%. IR (KBr): 3342 (N--H), 1740 (C=O), 1519,1347 (NO2), 1203 (C--O). 1N-NMR (CDCl3): 3.04 (dd, J=7.3, 13.7, 1H); 3.13 (dd, J=6.3, 13.7, 1H); 3.36 (d, J=17.3, 1H); 3.42 (d, J=17.3, 1H); 3.63 (dd, J=6.3, 7.3, 1H); 3.69 (s, 3H); 3.70 (s, 3H); 7.39 (d, J=8.8, 2H); 8.16 (d, J=8.8, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([OH:19])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH:20]([CH3:21])[CH3:22])[C:10]([C:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:23])[CH2:7][CH2:6]2)=[O:9])=[CH:18]3)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.6 %

Procedure:
To a cold (0° C.) mixture of (1,1-dioxo-1λ6-thiomorpholin-4-yl)-(5-hydroxy-1-isopropyl-1H-indol-2-yl)-methanone (890 mg, 1.0 eq.), 1-tert-butyloxycarbonyl-4-hydroxy-piperidine (659 mg, 1.2 eq.) and triphenylphosphine (858 mg, 1.2 eq.) in tetrahydrofuran (6 mL) was added dropwise a solution of di-tert-butyl-azodicarboxylate (746 mg, 1.0 eq.) in tetrahydrofuran (4 mL). The reaction mixture was stirred for 15 h at room temperature, concentrated in vacuo, then purified on silica eluting with a gradient of cyclohexane/ethyl acetate. One fraction was isolated to yield 434 mg (31.6%) of the desired product as white oil. MS (m/e): 520.7 (MH+, 100%).
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][NH:13][OH:14])(=[O:8])[O:5]CC)C.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[OH:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(COCCNO)OCC
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: O=P(O)(O)COCCNO
Temperature: 100 °C
Reaction time: 16 h

Procedure:
With reference to K -L. Yu, J. J.Bronson, H.Yang, A.Patick, M.Alam, V.Brankovan, R.Datema, M. J. M.Hitchcock, J. C.Martin, J. Med. Chem. 1992, 35, 2958-2969 0.5 mol [2-(N-hydroxyamino)-ethoxy]methylphosphonic acid diethylester and 1 mol 2,4,6-collidine in 5 ml of absolute methylenechloride are stirred under argon for one hour at a temperature of 0° C. After allowing to stand for 16 hours at room temperature the-solution is concentrated in vacuum, taken up in watery acetone and stirred for 14 hours. Subsequently it is taken up in 1 n NaOH and heated to 100° C. for 2 h. After cooling-off it is concentrated and the raw product purified by chromatography.
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:5]([O:7][CH:8]([CH3:11])[CH2:9][Cl:10])=[O:6])(=O)[CH3:2].[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26]>C(O)(C)C.C(OCC)C>[CH3:29][C:23]1[NH:22][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH:8]([CH3:11])[CH2:9][Cl:10])=[O:6])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)CCl
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)CCl)C1c1cccc([N+](=O)[O-])c1
Reaction time: 3.5 h
Yield: 64.1 %

Procedure:
A solution comprising 18.72 g of 1-methyl-2-chloroethyl α-acetyl-3-nitrocinnamate, prepared as described in Example 1, and 7.12 g of methyl 3-aminocrotonate in 48 ml of isopropanol was refluxed under stirring for 210 minutes. After cooling, the reaction mixture was evaporated to dryness under vacuum and the oil thus obtained was chromatographed on silica gel (200 g) using chloroform as eluent. Evaporating the fractions containing a sole product (TLC, chloroform: ethylacetate 95:5) gave a thick oil, which was dissolved in diethyl ether. The solvent was then evaporated off at 20°-25° C. to give 15.75 g of the title compound, m.p. 95°-102° C., which could be employed without further purification.