Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.C(O)(=O)C.CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[CH:13][C:12](=[O:23])[N:11]2[CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:8][CH2:7]2)=[CH:16][CH:17]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CS5)CC3)c2c1
Reaction time: 3 h
Yield: 28.1 %

Procedure:
To 2 mL of an N,N-dimethylformamide solution containing 63 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride, 36 mg of 3-oxo-3,4-dihydro-2H-pyrido(3,2-b)(1,4)thiazine-6-carbaldehyde, 0.14 mL of acetic acid and 0.12 mL of triethylamine were added, and stirred for 3 hours, thereafter 53 mg of sodium triacetoxyborohydride was added, and stirred at room temperature for 45 min. Aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography [eluent; chloroform:methanol=10:1], to give 25 mg of 6-(((1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2H-pyrido(3,2-b)(1,4)thiazin-3(4H)-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[F-].[K+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:28](Br)Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]2[O:11][CH2:28][O:10][C:9]=12)[CH:5]=[O:6]
Reactant: BrCBr
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2c(c1)OCO2
Yield: 76 %

Procedure:
To a stirred solution of 3-bromo-4,5-dihydroxybenzaldehyde (10.50 g, 48.38 mmol) in DMF (145 mL) was added anhydrous KF (14.02 g, 241.9 mmol, dried for 24 hours under high vacuum/P2O5). After 15 minutes CH2Br2 was added all at once and the resulting mixture heated to 100–105° C. for 4 hours. The mixture was evaporated under reduced pressure and the residue was taken up in ether and water. The layers were separated, the aqueous layer was washed with ether (3×). The combined ether layers were washed with water (2×), brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to give 8.42 g of 3-bromo-4,5-methylenedioxybenzaldehyde (76%) as a brownish solid. 1H NMR (500 MHz; CDCl3): δ 6.16 (s, 2H); 7.26 (s, 1H); 7.55 (s, 1H); 9.77 (s, 1H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:16])[CH:13]([OH:15])[CH3:14].C(N(CC)CC)C>ClCCl.C(OCC)C.CNC>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:16][CH2:12][CH:13]([OH:15])[CH3:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CNC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
p-Toluenesulphonyl chloride (19.4 g, 102 mmol) was added to a stirred solution of propane-1,2-diol (30 ml), triethylamine (15 ml, 106 mmol), N,N-dimethylamine (108 mg, 0.87 mmol) in dichloromethane (100 ml) at +5° C. The mixture was stirred for 2 hours at +5° C. and overnight at room temperature then diluted with diethyl ether (300 ml) and washed 2M aqueous hydrochloric acid, water (twice) and brine. The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (22.8 g, 97%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20]C)[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])[CH3:2].Cl>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 54 %

Procedure:
Treat dl-13-ethyl-3-methoxygona-2,5(10)-dien-17-one with hydrochloric acid in aqueous methanol to obtain dl-13-ethylgon-4-ene-3,17-dione (25.6, 54% from dl-13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol), m.p. 156°-157.5°; ultraviolet absorption peak in 95% ethanol at 240.5 mμ (15,900), infrared maxima (potassium bromide) at 5.77 μ, 5.98 μ . Recrystallize dl-13-ethylgon-4-ene-3,17-dione (1.0 g) three times from ethyl acetate to obtain 484 mg., 157°-159.5°; ultraviolet absorption peak (95% ethanol) at 240 mμ (ε17,200), infrared maxima (potassium bromide) at 5.77 μ, 5.98 μ.
Reaction SMILES: O=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[OH:17][N:16]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: NC(=O)NC1CCC(=NO)c2sccc21

Procedure:
4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylurea (5 g., 0.0238 mole) and hydroxylamine hydrochloride (2 g., 0.028 mole) in dry pyridine (50 ml.) are stirred together at room temperature under nitrogen overnight. The resulting clear solution is evaporated and the residual gum triturated with water (50 ml.) and the brown solid obtained is collected, washed with water and air dried (5.15 g.). The solid is recrystallized from hot methanol to afford 2.95 g. of the title compound m.p. 232°-233° C. dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1I
Reactant: Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 8.33 g of 4-bromotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to -78° C. in a nitrogen atmosphere, and the mixture was then stirred at -78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at -78° C., and the mixture was stirred at room temperature for 1 hour. This solution was added to a solution of 7.22 g of 2-fluoroiodobenzene and 0.52 g of tetrakis(trifluorophosphine)palladium (O) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.05 g of oily 2-fluoro-4'-methylbiphenyl.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.[CH3:13][NH2:14]>>[CH3:13][NH:14][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Product: CNc1cc(O)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
To a pressure vessel was added 3-fluoro-4-nitro-phenol (5.0 g, 31.82 mmol) and a 40% aqueous solution of methylamine (10 mL). The reaction mixture was stirred at 85° C. for 5 h, then it was cooled to room temperature, poured on water, and acidified to pH 1 with 1 N aqueous HCl. The resulting precipitate was filtered, washed with water, and dried in vacuo to give 5.23 g of 3-methylamino-4-nitro-phenol as an orange solid (98% yield): 1H NMR (DMSO-d6) δ 2.88 (d, 3H), 6.14 (dd, 1H), 6.17 (d, 1H), 7.96 (d, 1H), 8.25 (q, 1H), 10.8 (broad s, 1H); MS (m/z) 167 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]C)=[O:10])[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]([OH:11])=[O:10])[CH3:1]
Reactant: COC(=O)c1ncoc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ocnc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
To a solution of methyl 5-(1-methylethyl)-1,3-oxazole-4-carboxylate (0.55 g) in methanol (10 ml) was added sodium hydroxide (10 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue dissolved in water (10 ml) then acidified using 2M hydrochloric acid. The mixture was concentrated until precipitation commenced when the mixture was extracted with ethyl acetate, dried over sodium sulphate and evaporated to give the title compound (0.45 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:4]([CH3:20])([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)C(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN1CCNCC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of 568 (1.137 g, 3.79 mmol) and TFA (15 ml) in DCM (30 ml) was stirred at rt for 2.5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 1 h, and the pH was adjusted to around 9-10 with 1N NaOH. The alkaline solution was extracted with DCM. The extract was dried over anhydrous magnesium sulfate, filtered, concentrated and dried under high vacuum to afford the desired product 569 (667 mg, 3.33 mmol, 88% yield) as a pale-yellow viscous liquid. The crude material was used in the next step without any further purification. MS (z): 201.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:30]=[C:26]1[N:27]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[C:16]4[C:10]([CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15]4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:28][CH2:29][O:25]1
Reactant: O=C1NCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(Br)cc3)nc2CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCOC4=O)cc3)nc2CC1
Reaction time: 2 h

Procedure:
A mixture of 1,1-dimethylethyl 2-(4-bromophenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (150 mg, 0.38 mmol) (may be prepared as described in Description 12), 1,3-oxazolidin-2-one (100 mg, 1.15 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.0 mg, 0.02 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (35.0 mg, 0.06 mmol) and cesium carbonate (195 mg, 0.60 mmol) in dioxan (4 ml) was heated at reflux under argon for 3 hours and then in the microwave for 2 hours at 150° C. The mixture was diluted with ethyl acetate, filtered through celite and washed with 2×20 ml of water. The combined ethyl acetate layers were dried over magnesium sulphate, filtered and evaporated. The crude product was purified by column chromatography eluting with a mixture of ethyl acetate/pentane (50-100%) to afford the product (D26); MS (ES+) m/e 399 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C.O>ClCCl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0-5° C.) suspension of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (50.2 g, 186 mmol) in dichloromethane (200 mL) was slowly added a solution of tert-butyl piperidin-4-ylcarbamate (39.0 g, 195 mmol) and triethylamine (56 mL, 390 mmol) in dichloromethane (200 mL). The resulting mixture was stirred overnight at room temperature. Water (400 ml) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, eluent: dichloromethane/heptanes 4:6-1:0). Two fractions were obtained: 38.7 g of tert-butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate as a yellow solid, and a less pure fraction (26.1 g) that was purified by recrystallization from methanol to yield tert-butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate. Both fractions were combined (17.0 g, 69%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[S:15]([C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26])(=[O:17])=[O:16])C>CO.O>[Cl:25][C:21]1[C:22]([CH3:24])=[CH:23][C:18]([S:15]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][CH2:7][C:6]([OH:27])=[O:5])(=[O:16])=[O:17])=[C:19]([CH3:26])[CH:20]=1
Reactant: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(S(=O)(=O)N2CCCCC2CCC(=O)O)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
KOH (10.5 g) was added to a solution of 3-(1-(4-chloro-2,5-dimethylphenyl-sulfonyl)piperidin-2-yl)propionic acid ethyl ester (33 g) in methanol/water (230 ml/100 ml) and the mixture was stirred at room temperature for 15 hours. The reaction was observed by thin layer chromatography. When the reaction was complete, the methanol was distilled off and the aqueous phase was extracted with ethyl acetate (2×75 ml). The aqueous phase was then adjusted to pH=4 with HCl, while cooling with ice, and extracted with MC. The combined organic phases were dried with Na2SO4 and concentrated in vacuo. The yield was 30.6 g (100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
A solution of 1120 g. of N-methylpiperazine and 755 g. of p-fluoroacetophenone in 1920 ml. of dimethyl-sulfoxide is heated at 95° for 16 hours, then evaporated at reduced pressure. The residue is poured into 8 liters of water and the solution is basified with 440 g. of 50% aqueous sodium hydroxide and cooled. The precipitate of p-(4-methyl-1-piperazinyl)acetophenone is collected by filtration, washed with water and dried; m.p. 97°-99°.
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:40])[CH2:30][C:31]2[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([Cl:39])[N:32]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O.C(Cl)Cl>[Cl:39][C:33]1[N+:32]([O-:2])=[C:31]([CH2:30][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)=[O:40])[C:36]([C:37]#[N:38])=[CH:35][CH:34]=1
Reactant: N#Cc1ccc(Cl)nc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(Cl)[n+]([O-])c1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
Solid sodium percarbonate (555 mg, 5.30 mmol H2O2) (Na2CO3.1.5 H2O2, approximately 25% H2O2, Aldrich) was added in one portion under air with stirring to a rt solution of (6-chloro-3-cyano-pyridin-2-yl)-acetic acid 4-nitro-phenyl ester (566 mg, 1.78 mmol), as prepared in the previous step, in CH3CN (13.5 mL) and the slurry was then stirred on an ice bath for 5-10 min. The flask was fitted with an argon needle outlet to prevent pressure build-up, and triflic anhydride (7.58 g, 26.9 mmol) was added dropwise with stirring at 0° C. over about 4 min. The reaction was stirred at 0° C. for 3.5 h, and was then poured into 0° C. saturated NaHCO3 (80 mL), with the residual yellow reaction mixture transferred with DCM (2×10 mL). The ice-cold bilayer was stirred at 0° C. for 30 min, and the light yellow organic layer was saved. The dark yellow upper aqueous layer was extracted with DCM (2×40 mL), the organic layers were combined, dried (Na2SO4), and concentrated to provide 463 mg of the crude title compound as a tan solid. This material was combined with a separately-prepared batch of crude title compound (250 mg), and the whole was dissolved in EtOAc (˜20 mL) and concentrated under reduced pressure in the presence of silica gel (2.7 g) to afford a free-flowing powder. This silica-adsorbed material was flash chromatographed (2:1 toluene/EtOAc eluent) to afford the title compound as a beige solid [319 mg, 35% (calculated from the 463 mg crude)].
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11](OC)=[O:12])[O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[CH2:11][OH:12])[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCCCC12OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCCCC12OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 1,4-dioxaspiro[4.5]decane-6-carboxylate (3.00 g, 15.0 mmol) in THF (45 mL) at 0° C. was added LiAlH4 (2M in TI-IF (9.00 mL, 18.0 mmol) dropwise. The mixture was then allowed to warm to rt and stirred overnight. The mixture was then cooled to 0° C. and 1.36 mL of H2O was added very slowly. The reaction mixture was basified by adding 0.682 mL of 15% NaOH and then 3.41 mL of H2O. The resulting mixture was filtered through a pad of celite, washed with Et2O, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.95-4.05 (m, 4H), 3.71-3.79 (m, 1H), 3.52-3.59 (m, 1H), 2.81 (dd, 1H, J=3.9 Hz, 7.1 Hz), 1.78-1.91 (m, 2H), 1.61-1.73 (m, 3H), 1.41-1.53 (m, 2H), 1.24-1.40 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][C:5]=1[C:41]([F:44])([F:43])[F:42].[OH-].[Na+]>CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C@@:16]2([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:39])([CH3:38])[CH3:40])[NH:14][C@@H:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:45])=[O:2])=[C:5]([C:41]([F:43])([F:44])[F:42])[CH:6]=3)=[O:12])[C@@H:17]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[F:25])=[C:29]([F:35])[CH:30]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
Rac 4 {[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-trifluoromethyl-benzoic acid methyl ester (36 mg) was dissolved in MeOH (10 mL). To the stirred solution was added NaOH (1N, 3 mL) and the mixture was stirred at 50° C. for 3 hrs. The solvent was removed and the residue was treated with 1 N HCl to make the mixture acidic. The white suspension was filtered to collect the white solid as the title compound (29 mg, 82% yield).
Reaction SMILES: [K+:1].[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][C:11](=[CH2:15])[C:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.[H][H]>[Rh]>[K+:1].[C:2]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10][C@@H:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: [Rh]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C

Procedure:
100 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid potassium salt (2-a, R1=Boc, R2=H, R3=CO2K) (prepared according to procedure in Example 42) is added to isopropyl acetate (1 ml). 5% Rhodium on carbon (10 mg) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with isopropyl acetate (2×1 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-a, R1=Boc, R2=H, R3=CO2K) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid potassium salt (1-b, R1=Boc, R2=H, R3=CO2K). Spectroscopic data as in Example 42, Method 1.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([NH2:30])[N:16]=[C:15]([O:14][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH3:13])[N:23]=2
Reactant: CCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 5 h
Yield: 98.7 %

Procedure:
N-Bromosuccinimide (12.16 g, 68.3 mmol) was added portionwise over 5 mins. to a stirred solution of 2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (14.9 g, 48.8 mmol) in chloroform (80 ml) at <5° C. under an atmosphere of nitrogen. The reaction mixture was stirred at <5° C. for 5 hours then washed with saturated sodium hydrogen carbonate solution (80 ml) then water (80 ml). The foam was dissolved in DCM (50 ml) and washed with water (50 ml) then brine (50 ml). The combined aqueous phases were washed with DCM (50 ml). The combined organic layers were dried through a hydrophobic frit, and the solvent removed in vacuo to yield the title compound as an orange foam (18.5 g).