Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:53][S:54]([CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)(=[O:56])=[O:55]>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:60]1[CH2:61][CH2:62][CH:57]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:58][CH2:59]1)[CH2:21][CH2:20]2
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 51.1 %

Procedure:
To a flask containing a suspension of the crude ethyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.055 g, 0.094 mmol) in 1,4-dioxane (2 mL) was added Hunig's base (0.098 mL, 0.561 mmol) followed by 4-(methylsulfonyl)piperidine (0.076 g, 0.468 mmol). The mixture was heated to 100° C. for 20.5 h then was cooled to rt and was purified by flash chromatography using a 20-80% ethyl acetate in hexanes gradient and a 12 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.036 g, 0.048 mmol, 51.2% yield) as an off-white solid. LCMS: m/e 751.7 (M+H)+, 2.29 min (method 1).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH2:22][O:23]C(=O)CC)[O:9][CH2:8][C:7]2([CH2:14][O:13][C:12]([CH3:21])([CH2:15][O:16]C(=O)CC)[O:11][CH2:10]2)[CH2:6][O:5]1>O.CO>[CH3:21][C:12]1([CH2:15][OH:16])[O:11][CH2:10][C:7]2([CH2:6][O:5][C:4]([CH3:3])([CH2:22][OH:23])[O:9][CH2:8]2)[CH2:14][O:13]1
Reactant: CCC(=O)OCC1(C)OCC2(CO1)COC(C)(COC(=O)CC)OC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CO)OCC2(CO1)COC(C)(CO)OC2
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 76.1 %

Procedure:
To a solution of sodium hydroxide (3 g, 0.075 mol) in water (25 ml) and methanol (25 ml), 3,9-dimethyl-3,9-bis(propionyloxymethyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (6.5 g, 18 mmol) was slowly added, followed by stirring for 40 minutes at 60° C. After the solvent was distilled off under reduced pressure, the resultant concentrate residue was dissolved in acetonitrile/brine. The separated-off organic layer was concentrated under reduced pressure, and then ethyl acetate was added thereto. After the insoluble material was filtered out, the resultant filtrate was concentrated again under reduced pressure. The resultant concentrate residue was recrystallized from ethyl acetate/hexane, to give 3,9-dimethyl-3,9-bis(hydroxymethyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (3.4 g, 13.7 mmol, yield 76%).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:27][CH:26]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1.O1CCCC1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:37])[O:6][C@@H:5]2[O:7][C@H:8]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[CH:32]=[N:33][CH:34]=[N:35][CH:36]=4)=[CH:29][CH:30]=3)[C@H:9]([CH2:10][CH2:11][N:12]3[C:17](=[O:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=[N:13]3)[C@@H:4]2[O:3]1
Reactant: [H][H]
Reactant: CC1(C)O[C@@H]2O[C@H](/C=C/c3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cncnc4)cc3)[C@H](CCn3nnc4ccccc4c3=O)[C@@H]2O1

Procedure:
To the solution of the compound obtained from step k above (0.3 g) in a solvent mixture of tetrahydrofuran: methanol (10 mL, 1:1), 10% palladium on charcoal (0.15 g) was added at room temperature and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.3 g).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (2.5 g, 14.56 mmol) and anhydrous potassium carbonate (7 g, 50.64 mmol) in dry DMF (25 mL) was stirred for 30 min at room temperature. Benzyl bromide (2 mL, 16.82 mmol) was added dropwise into the reaction mixture and heated at 65° C. for 14 h. The reaction mixture was cooled to room temperature, filtered and quenched with ice water (25 mL). The resulting mixture was extracted in ethyl acetate (2×20 mL) and the combined organic layers were washed with water (2×15 mL) followed by brine (20 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated. The crude product obtained was purified by crystallisation using 2% methanol in chloroform to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([C:19]1[C:20]([N:25]=[CH:26][N:27]([CH3:29])C)=[N:21][CH:22]=[CH:23][CH:24]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:7]2[CH:6]=[CH:5][C:4]([OH:16])=[CH:3][C:2]=2[NH:1][C:29]2[C:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=3[N:25]=[CH:26][N:27]=2)=[CH:10][CH:11]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: Nc1cc(O)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(O)cc2Nc2ncnc3ncccc23)cc1
Yield: 35.4 %

Procedure:
The product of Example 16B (380 mg, 1.63 mmol) was reacted with the product of Example 15A (284 mg, 1.63 mmol) using the procedure of Example 15E substituting the product of Example 16B for the product of Example 15D to provide a solid which was triturated with methanol to provide the title compound (209 mg, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=C(C(F)(F)F)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.NO.[C:20](=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:9][OH:10])[NH2:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2noc(C(F)(F)F)n2)cc1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(N)=NO)cc1
Yield: 20 %

Procedure:
3-(4-hydroxyphenyl)-5-trifluoromethyl-1,2,4-oxadiazole 13.32 g (0.1 mol) 4-methoxybenzonitrile, 20.85 g (0.3 mol) of hydroxylamine hydrochloride and 41.40 g (0.3 mol) potassium carbonate was added to 400 mL absolute ethanol and refluxed 21 hours. The product was filtered and recrystallized from methanol to give 3.12 g (0.02 mol) of 4-methoxybenzamide oxime.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)(=O)C>C(O)C.[Fe]>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccccc1-n1cccc1
Yield: 92.2 %

Procedure:
To a solution of 2-(1-pyrrolyl)nitrobenzene (1.11 g) in ethanol (30 ml) were added iron powder (1.65 g) and acetic acid (3.54 g) and the mixture was refluxed for 1 hour. The reaction mixture was filtered through a bed of celite and the. filtrate was concentrated in vacuo. The residue was diluted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution and the mixture was filtered through a bed of celite again. The organic layer was separated and washed with water and brine. The solution was dried over sodium sulfate and the solvent was evaporated in vacuo to give 2-(1-pyrrolyl)phenylamine (860 mg).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:8]=[C:7]([CH:6]=[CH:5][C:3]=1[OH:4])[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Oc1ccccc1O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)c(O)c3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 1.1 g of pyrocatechol in 6 ml of trifluoroacetic acid is mixed with 0.8 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene, the mixture is evaporated to dryness under reduced pressure, and the residue is twice triturated with 30 ml portions of diethyl ether to remove the excess pyrocatechol. The residue is worked up in accordance with the process described in example 6 and yields 3-(3,4-dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid which after crystallisation from a mixture of acetic acid ethyl ester and acetone is obtained in the form of colourless crystals, melting point 114°C; thin layer chromatogram (silica gel): Rf = 0.71 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.73 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.44 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (methanol): λmax 222 mμ (ε = 17600), 250 mμ (ε = 6800) and 283 mμ (ε = 3700); infrared absorption spectrum (in mineral oil): characteristic bands at 3.01μ, 5.72μ, 5.87μ and 6.06μ.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([O-])([OH:15])=[O:14].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc(C)c2ncccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])cc(C)c2ncccc12
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
5,8-dimethylquinoline (1.25 g), in a 250 mL round bottom flask is cooled to 0° C. in an ice-NaCl bath under argon. Concentrated sulfuric acid (50 mL) is added slowly via addition funnel so that the internal temperature does not exceed 5° C. The solution is allowed to stir a few minutes then cooled to -15° C. in an ethylene glycol-dry ice bath. Nitric acid (1.7 mL, 69-71%) in sulfuric acid (50 mL) is added dropwise (via syringe) at such a rate that the reaction temperature does not exceed -3° C. After 10 minutes, the reaction is poured into a beaker of ice and basified slowly to pH 10 by the addition of ammonium hydroxide solution (28-30%). The product is extracted with ethyl acetate (3×500 mL). The organic layer is dried over MgSO4, filtered, and rotary evaporated to yield crude product (2.6 g) which is flash chromatographed on silica gel eluting with 15% ethyl acetate/hexane. Compound-containing fractions are combined and rotary evaporated to yield 5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[H-].[Na+].CN(C)C=O.Cl[CH2:38][C:39](=[O:41])[CH3:40]>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:38][C:39](=[O:41])[CH3:40])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)=O)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (3 g), sodium hydride (0.47 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-chloropropan-2-one (0.75 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.49 g, 14%).
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
Formaldehyde (37% in H2O; 15.6 μL, 0.210 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (25 mg, 0.053 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.111 g, 0.525 mmol) was then added in one portion to the reaction mixture. The reaction was stirred at room temperature for 1.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (25 mL) and saturated aq. NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL), the combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The solvent was removed under reduced pressure yield a white solid. The solid was suspended in DCM (2 mL) and cyclohexane (10 mL) then filtered to afford the title compound (16) (19 mg, 73%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.70-7.61 (m, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.14-2.97 (m, 4H), 2.88 (d, J=10.6 Hz, 2H), 2.46-2.36 (m, 1H), 2.22 (s, 3H), 2.07-1.93 (m, 2H), 1.78-1.58 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][C:18]([CH:20]1[NH:25][C:24](=[O:26])[CH:23]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:22]([OH:31])[C:21]1=[O:32])=[O:19])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([C:20]1([C:18]([O:17][CH2:15][CH3:16])=[O:19])[NH:25][C:24](=[O:26])[CH:23]([CH2:27][CH:28]([CH3:29])[CH3:30])[N:22]([O:31][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:21]1=[O:32])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1NC(=O)C(CC(C)C)N(O)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)NC(=O)C(CC(C)C)N(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.60 g of potassium carbonate and 6.3 ml of benzyl chloride were added to 100 ml of a solution of 9.57 g of 3-ethoxycarbonyl-1-hydroxy-6-isobutylpiperazine-2,5-dione in anhydrous N,N-dimethylformamide, on ice-cooling. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 450 ml of ethyl acetate, then washed three times with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The resulting solution was subjected to distillation to remove the solvent. The residue was allowed to stand. The resulting crystals were collected by filtration and washed with methanol to obtain 4.51 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-dione as colorless columnar crystals.
Reaction SMILES: C(OC(N1[C:12](=[O:13])[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=2)([CH3:14])[N:10](C(OC(C)(C)C)=O)C1=O)=O)(C)(C)C.[OH-:30].[Na+]>CCOC(C)=O.CO>[NH2:10][C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=1)([CH3:14])[C:12]([OH:13])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C(=O)N(C(=O)OC(C)(C)C)C(C)(c2cccc(Br)n2)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(N)(C(=O)O)c1cccc(Br)n1
Reaction time: 0.5 h

Procedure:
A solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2,5-dioxo-imidazolidine-1,3-dicarboxylic acid di-tert-butyl ester (31.53 g, 67.0 mmol) in 2.5M aq. NaOH soln. (215 ml) was refluxed for 40 h. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrates were separated and the org. layer was washed with H2O. The combined aq. layers were evaporated to dryness to leave a solid that was suspended in MeOH (350 ml) and stirred for 30 min. The suspension was filtered and the white precipitate was washed with MeOH. The filtrates were evaporated to leave a pale orange solid which was used for the next step without further purification.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH2:17][CH2:16]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(C=Cc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[1H-indene-1,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. mp 119°-120°. FDMS m/e=374 (M+ of free base). α[D]589 =-5.51 (c=0.47, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]=12)#[N:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:25])=S.[Na+].[Na+]>CO.O>[C:1]([C:3]1[CH:4]=[CH:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:7]=12)(=[O:25])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCn2ccc(C#N)c2C1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2ccc(C(N)=O)c2C1
Temperature: 55 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
To a solution of 26.7 g (108 mmol) of tert-butyl 8-cyano-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 490 ml of methanol are added 80 ml (864 mmol) of concentrated aqueous 32% sodium hydroxide and 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution. The reaction medium is heated at 55° C. for 2 hours. 4 times 4.0 g (41 mmol) of aqueous 35% hydrogen peroxide solution are then added every 2 hours and heating is then continued at 55° C. for 18 hours. The medium is then treated with an aqueous solution of 30 g (190 mmol) of sodium thiosulfate in 250 ml of water and the reaction mixture is stirred for 1 hour and then partially concentrated under reduced pressure. The product is extracted with 350 ml and then twice 100 ml of dichloromethane, and the organic phases are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in a mixture of dichloromethane and ethyl acetate and then precipitated by slow concentration to give 21.1 g of tert-butyl 8-carbamoyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after drying in an oven at 60° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:19][OH:20])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:20][CH2:19][CH:16]2[CH2:15][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:9])[C:18]=3[O:17]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 74.2 %

Procedure:
Treatment of 2,4,6-trichlorobromobenzene (14.5 g, 55.69 mmol) with 2-methoxybenzeneboronic acid (12.69 g, 83.54 mol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.656 g, 0.835 mmol), and potassium carbonate (19.21 g, 139.22 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (61%) of 2′ 4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether (9.8 g, 34.08 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (9.38 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided provided 9.2 g of a yellow solid. Treatment of 2′,4′,6′-trichloro-1,1′-biphenyl-2-ol (9.17 g, 33.52 mmol) with potassium carbonate (18.53 g, 134.1 mmol) and allyl bromide (4.46 g, 36.87 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. (10.35 g, 33.00 mmol) with 3-chloroperoxybenzoic acid (17.08 g, 99.00 mmol, 77%) followed by potassium carbonate (11.40 g, 82.51 mmol) generally according to the procedure described for Intermediate 9 afforded 10.4 g (95%) of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (10.38 g, 31.49 mmol) with p-toluenesulfonyl chloride (7.20 g, 37.79 mol) generally according to the procedure described for Intermediate 10 gave 10.5 g (68%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 178-180° C.