Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C. solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10.4 g, 55.5 mmol) and triethylamine (15.5 mL, 0.1111 mole) in CH2Cl2 (150 mL) was added dropwise methanesulfonyl chloride (5.2 mL, 0.06665 mole). When the addition was complete, the reaction mixture was allowed to warm to room temperature, then stirred overnight. The reaction mixture was concentrated under reduced pressure to give a residue that was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% hexane to 70:30 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to give (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate. 1H NMR (300 MHz, CD3OD) δ ppm 1.47 (s, 9H), 2.14-2.29 (m, 2H), 3.12 (s, 1H), 3.36-3.67 (m, 4H), 5.24-5.30 (m, 1H); MS (DCI/NH3) m/z 266 (M+H)+, 283 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[S:47][CH:48]=[CH:49][N:50]=1>>[CH3:44][C:2]([CH3:1])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:46]3[S:47][CH:48]=[CH:49][N:50]=3)=[CH:17][CH:18]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: Brc1nccs1
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2nccs2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 2-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.19; m/z found, 549.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J=8.5, 1H), 8.35 (d, J=8.6, 1H), 8.20 (d, J=8.0, 1H), 8.07-7.86 (m, 5H), 7.85-7.77 (m, 2H), 7.62 (d, J=9.1, 1H), 7.50 (d, J=2.3, 1H), 7.40 (d, J=8.3, 2H), 7.34 (dd, J=9.1, 2.3, 1H), 5.89 (s, 2H), 5.72 (s, 2H), 3.55 (s, 2H), 1.33 (s, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1(=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.Cl>C(OCC)C>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:20]1
Reactant: O=C1CCc2ccccc21
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C1=C(c2ccccc2Cc2ccccn2)c2ccccc2C1
Temperature: -20 °C
Yield: 33.5 %

Procedure:
A mixture of 3.23 ml (0.02 mol) of 2-benzylpyridine in 15 ml of diethyl ether was cooled to −20° C. and 13 ml of n-butyllithium (1.6M in hexane, 0.02 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled to −60° C. A solution of 2.8 g (0.021 mol) of 1-indanone in 10 ml of diethyl ether was subsequently added while maintaining the temperature. The mixture was allowed to warm to room temperature, stirred for a further 3.5 hours and hydrolyzed with 40 ml of dilute hydrochloric acid. The solid which had precipitated was filtered off, the organic phase was separated off and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was then neutralized with aqueous ammonia solution and extracted three times with 30 ml each time of methylene chloride. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. Recrystallization of the residue obtained in this way from hexane gave 1.9 g (34%) of [2-(1H-inden-3-yl)(phenyl)-methyl]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[C:18](C)[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C(O)(=O)C.[Pd].[C]>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[C:13]1[CH:24]=[CH:23][C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(=Cc1ccc(C(C2=C(C)C(=O)C(C)=C(C)C2=O)c2cccnc2)cc1)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)C(C(c2ccc(CCC(=O)O)cc2)c2cccnc2)=C(C)C1=O
Reaction time: 2 h
Yield: 44.2 %

Procedure:
4-[3,5,6-trimethyl-1,4-benzoquinone-2-yl-(3-pyridyl)methyl]-α-methylcinnamic acid, 0.7 g (1.75 mmol), was hydrogenated with 0.2 g of 5% Pd-carbon in 6 ml of acetic acid (the reaction completed in about 2 hours). The catalyst was filtered off, and the filtrate was concentrated, to which water was added and neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The resultant substance was extracted with ethyl acetate, and oxidized by shaking with an aqueous solution of ferric chloride. After the organic phase was washed with water and dried, the solvent was evaporated off and the residue was purified with silica gel column chromatography (ethyl acetate-ethanol (9:1)) and recrystallized from ethyl acetate, to give 0.3 g (44.2%) of 3-(4-[3,5,6-trimethyl-1,4-benzoquinone-2-yl-(3-pyridyl)methyl]phenyl)propionic acid. The physical data are shown in Table 1.
Reaction SMILES: C([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:26]4[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]4)[CH:22]=[CH:23][C:24]=3[Cl:25])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([C@H:26]2[C@H:31]([OH:32])[C@@H:30]([OH:33])[C@H:29]([OH:34])[C@@H:28]([CH2:35][OH:36])[O:27]2)=[CH:20][C:19]=1[CH2:18][C:15]1[CH:16]=[CH:17][C:12]2[O:11][CH2:10][CH2:9][NH:8][C:13]=2[CH:14]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-[3-(4-benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-chloro-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (2.4 g, 4.68 mmol) in methanol (15 mL) was added 10% palladium on charcoal (240 mg) and 0.05 mL conc. H. The reaction mixture was stirred under hydrogen atmosphere for 2 h then filtered through celite bed (which was washed with methanol). The resulting filtrate was concentrated to a residue which was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (1.6 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C=O.[CH3:23][N:24]([CH2:26]N(C)C)[CH3:25].Cl>CCO.C1C=CC=CC=1>[CH3:23][N:24]([CH2:26][C:8]1[C:9]([OH:20])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:5]([C:6]=2[CH:7]=1)[CH2:4][CH2:3][C@@:2]1([CH3:1])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:19])[CH3:25]
Reactant: CN(C)CN(C)C
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: CN(C)Cc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 80 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
To a suspension of estrone (11, 5.40 g, 20 mmol) in EtOH (100 mL) and benzene (60 mL) were added paraformaldehyde (0.600 g, 20 mmol) and N,N,N',N'-tetramethyldiaminomethane (5.5 mL, 40 mmol), and stirred for 20 h at 80° C. After the reaction mixture was cooled to 0° C., 5 N HCl was added. The aqueous layer was washed with Et2O, and basified with aqueous NH4OH. The precipitate was collected by filtration and washed with H2O, and recrystallized from EtOH to afford 4.37 g of 72 (67% yield) mp: 172-173° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:16])[NH:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.Cl>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:16][C:22](=[O:23])[O:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2noc(=O)[nH]2)C1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Crude (R)-3-(N-hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (887 mg, 3.86 mmol) and CDI (94 mg, 5.8 mmol) were dissolved in dioxane (30 mL) and heated to reflux. After 1 h, the reaction was concentrated in vacuo. The crude reaction mixture was dissolved in CH2Cl2 and the pH was adjusted to 3 by adding 1M HCl to the solution. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to yield 872 mg of crude (R)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11][CH:10]([CH2:18]O)[CH2:9]2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:44]=[N+:45]=[N-:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:44]([CH2:18][CH:10]1[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:21]([F:24])([F:23])[F:22])[CH:4]=2)([CH3:20])[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH2:11]1)=[N+:45]=[N-:46]
Reactant: COC(=O)C1=CCC(CO)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=CCC(CN=[N+]=[N-])CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 19.5 h
Yield: 51.6 %

Procedure:
A solution of methyl (4RS,6RS)-6-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-6-methylcyclohex-1-enecarboxylate (Example 7, Step 9; 38.2 mg, 0.105 mmol) in THF (0.8 mL) was treated sequentially with triphenylphosphine (83 mg, 0.316 mmol), hydrazoic acid (ca. 2M in benzene, 0.211 mL, 0.421 mmol) and diethyl azodicarboxylate (0.050 mL, 0.316 mmol). The resulting mixture was stirred at rt for 19.5 h and then an additional amount of triphenylphosphine (83 mg, 0.316 mmol), diethyl azodicarboxylate (0.050 mL, 0.316 mmol) and hydrazoic acid (ca. 2M in benzene, 0.211 mL, 0.421 mmol) were added. The resulting mixture was stirred for a total of 43 h. After this time, the mixture was concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 5-50% ethyl acetate-hexanes, to provide methyl (4RS,6RS)-4-(azidomethyl)-6-(4-chloro-3-(trifluoromethyl)-phenyl)-6-methylcyclohex-1-enecarboxylate (21 mg, 51%). Mass spectrum m/z 405.0 (M+NH4+). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=2.4 Hz, 1 H), 7.40 (d, J=8.4 Hz, 1 H), 7.31 (dd, J=8.4, 2.4 Hz, 1 H), 7.25 (dd, J=5.5, 2.4 Hz, 1 H), 3.65 (s, 3 H), 3.17 (d, J=5.3 Hz, 2 H), 2.45 (m, 1 H), 2.01 (m, 1 H), 1.73 (m, 1 H), 1.66 (s, 3 H), 1.58 (m, 2 H).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH2:16][C:15]1=[O:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Anhydrous chromium trioxide (CrO3) (1.94 g, 19.4 mmol) is added to a solution of anhydrous pyridine (3.07 g, 38.8 mmole) in anhydrous methylene chloride (CH2Cl2) (50 ml). The resulting mixture is stirred at room temperature for 15 mins. A solution of N-(t-butyldimethylsilyl)-4-(2-hydroxyethyl)-azetidin-2-one (0.74 g, 3.23 mmol) in anhydrous CH2Cl2 (5 ml) is added all at once. After stirring at room temperature for 5 mins, the mixture is decanted and the dark, gummy residue is washed with more CH2Cl2. The combined CH2Cl2 supernatant is evaporated i.v. The residue is taken up in diethylether and filtered to remove chromium salts. The ethereal filtrate is washed with 5% NaHCO3, 5% HCl, 5% NaHCO3 and brine, dried with MgSO4, filtered, and evaporated i.v. to yield N-(t-butyldimethylsilyl)-4-(2-oxoethyl)-azetidin-2-one (0.54 g) as an off-white solid: ir(CHCl3) 5.77, 5.80, 7.36, 7.60, 7.99, 8.50 and 11.95 cm-1 ; nmr (CDCl3) δ0.23(s, 3), 0.27 (s, 3), 0.98 (s, 9), 2.63 (ddd, 1), 2.65 (dd, 1), 3.07 (ddd, 1), 3.37 (dd), 3.97 (m, 1), and 9.78 (t, 1); mass spectrum m/e 170 and 128.
Reaction SMILES: Cl[O-:2].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])C>>[C:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)([OH:8])=[O:2]
Reactant: [O-]Cl
Reactant: CCC(C(=O)O)c1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCC(C(=O)O)c1ccc(C(=O)O)cc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a solution of sodium hypochlorite (330 mL, 17.32 g, 0.234 mol) in a solution of sodium hydroxide (50%, 172 mL), warmed to 55° C., was added, portionwise as a solid, 4-acetylphenylbutyric acid (16.0 g, 0.078 mol) while keeping the temperature between 60°-70° C. All was stirred at 55° C. over 20 hours. The cooled solution was quenched by the dropwise addition of a solution of sodium bisulfite (25%, 330 mL). The mixture was then transferred to a beaker and acidified by the careful addition of concentrated hydrochloric acid. The resulting solid was collected, washed with water and dried, then triturated sequentially with chlorobutane and hexane to give 4-carboxyphenylbutyric acid (15.31 g, 0.074 mol, 95%) as a white solid. mp=190°-195° C.; 1H NMR (DMSO) d 12.55 (bs, 1H), 8.1 (s, 1H), 7.85 (d, 2H, J=8.1 Hz), 7.3 (d, 2H, J=8.1 Hz), 2.7 (t, 2H, J=7.5 Hz), 2.2 (t, 2H, J=7.4 Hz), 1.8 (quintet, 2H, J=7.5 Hz).
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][CH2:12][OH:13])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N+]=[N-]>[C].[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][CH2:12][OH:13])[C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2c(N=[N+]=[N-])ncnc2OCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2c(N)ncnc2OCCO)cc1
Yield: 89.7 %

Procedure:
A mixture of 2-{6-azido-5-(4-methylphenyl)pyrimidin-4-yloxy}-ethanol (19.6 g), 10% palladium-carbon (50% moist) (4.0 g) and ethanol (240 ml) is subjected to catalytic hydrogenation at room temperature under hydrogen atmosphere (1 atm) for one hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is recrystallized from ethyl acetate/n-hexane to give 2-{6-amino-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (15.9 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:20]([O:22][C:23]([C@:25]1([NH2:37])[CH2:30][C@H:29]([OH:31])[C@@H:28]2[C@H:26]1[C@H:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:24])[CH3:21]>ClCCl>[CH2:20]([O:22][C:23]([C@:25]1([NH:37][C:17](=[O:19])[CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:30][C@H:29]([OH:31])[C@@H:28]2[C@H:26]1[C@H:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:24])[CH3:21]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O
Yield: 87 %

Procedure:
Prepare according to the General Procedure A using Boc-L-phenylalanine (772 mg, 2.91 mmoles) and (1S,2S,4S,5R,6R)-2-amino-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (480 mg, 1.94 mmoles, Preparation 22). Concentrate the crude reaction mixture, dissolve in dichloromethane, flash through a short silica gel plug with ethyl acetate/DCM (1:1), and concentrate in-vacuo to give a yellow oil. Further purify the material by silica gel chromatography eluting with 30% ethyl acetate/hexanes to 80% ethyl acetate/hexanes to afford 852 mg (87%) of the title compound.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Sc1ccccc1
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: O=C1c2c(O)cccc2C(Sc2ccccc2)c2cccc(O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (3.05 g) was dissolved in dichloromethane (100 ml) and thiophenol (1.1 ml) was added. The red-brown solution became yellow-green, and was then left, with stirring, at room temperature for 5 hours. Removal of the solvent gave a yellow solid which, after recrystallisation from a hexane/chloroform mixture (10:1), afforded 1,8-dihydroxy-10-phenylthio-9-anthrone (2.89 g, 87%) as pale yellow needles, melting point 156°-157° C. (Found: C 71.8, H 4.2, S 9.95; C20H14O3S requires C 71.85, H 4.2, S 9.6%.)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:15][OH:16])([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[C:19](OC)([CH3:21])[CH3:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:20][C:19]1([CH3:21])[O:1][CH2:2][C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][O:16]1
Reactant: CCOC(=O)C(CO)(CO)c1cccnc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2cccnc2)COC(C)(C)OC1
Reaction time: 12 h

Procedure:
To a mixture of 1.25 g of ethyl 3-hydroxy-2-(hydroxymethyl)-2-(pyridin-3-yl)propanoate in 13 ml of acetone were added 0.75 ml of 2,2-dimethoxypropane and 105 mg of p-toluenesulfonic acid monohydrate, followed by stirring for 12 hours. Then, 1.06 g of p-toluenesulfonic acid monohydrate was added thereto, followed by stirring for 6 hours. Further, 0.75 ml of 2,2-dimethoxypropane was added thereto, followed by stirring at 50° C. for 30 minutes, and the solvent was evaporated under reduced pressure. To the obtained residue were added 13 ml of acetone and 0.78 ml of 2-methoxy-1-propene at room temperature, followed by stirring for 30 minutes. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.16 g of ethyl 2,2-dimethyl-5-(pyridin-3-yl)-1,3-dioxane-5-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:25]=[CH:24][C:22]([N:23]3[CH2:27][CH2:28][NH:29][C:30]3=[O:31])=[CH:21][CH:20]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCCCl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
A mixture of 4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}aniline (1.1 g, 3.26 mmol) and 2-chloroethyl isocyanate (0.369 g, 3.5 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for overnight. Sodium hydride was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. Water was added to the reaction solution, and the resulting solid was collected and washed with water, diethyl ether, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give the title compound as a solid (1.2 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[Mg+2:13].[Cl-:14].[Cl-].Cl.C(N(CC)CC)C>CCCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O-:12])=[O:11].[Cl-:14].[Mg+2:13]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C([O-])Cc1ccc(Cl)cc1Cl
Yield: 96 %

Procedure:
215 grams (1.05 moles) of 2,4-dichloro-phenylacetic acid are added to 95.2 grams (1 mole) of MgCl2 suspended in 2 liters of heptane. The suspension is brought to reflux temperature under a light stream of nitrogen and is maintained at boiling point until the complete development of HCl (8-12 hours). After cooling, the reaction mixture is treated with 10.1 g (0.1 moles) of triethylamine and filtered. 253.2 g (96% yield) of white solid are obtained from the filtrate, after evaporation and subsequent drying, with the following elemental analysis:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CCN(CC)CC.[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[CH:23]1([C:28]([CH:11]2[CH2:12][NH:13][CH2:14][CH2:15][N:10]2[C:7]2[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=2)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N2CCNCC2C(=O)C2CCCC2)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
4-Methylphenyl piperazine dihydrochloride (4.20 g, 16.9 mmol) and NEt3 (7.0 mL, 50.2 mmol) were dissolved in DCM (125 mL) at 0° C. Cyclopentanecarbonyl chloride (2.0 mL, 16.5 mmol) was added and the reaction mixture was allowed to warm to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution (3×100 mL), dried (MgSO4) and concentrated in vacuo to give cyclopentanecarbonyl 4-(methyl)phenyl piperazine (4.42 g, 98%) as a pale brown oil which was used without further purification.