Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxy-4-methylpentanoic acid (140 mg, 1.06 mmol) and HATU (403 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one (265 mg, 77%). LC/MS: m/z 421.30 (M+H)+ at 2.57 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J=8.3, 1.7 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H) 7.88 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.39 (m, 1H), 3.95 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.43 (m, 2H), 0.92 (q, J=3.8 Hz, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](C2C=C(C)C=CC=2C2C=NN(C)C=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.NC[C@@H]1[C@H](C)CCCN1C([C:46]1[C:51]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:50][CH:49]=[C:48]([CH3:59])[N:47]=1)=O>>[F:58][C:55]1[CH:54]=[CH:53][C:52]([C:51]2[C:46]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]3[CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][N:26]=3)=[O:9])=[N:47][C:48]([CH3:59])=[CH:49][CH:50]=2)=[CH:57][CH:56]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-(4-fluorophenyl)-6-methylpyridin-2-yl)methanone. ESI-MS (m/z): 487 [M+1]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nccs2)cc1

Procedure:
Using 2-bromothiazole (5.0 g, 30.482 mmol) and (4-fluorophenyl)boronic acid (8.528 g, 60.964 mmol) as reactants and following the procedure described in Example 7 step 1, the title compound was obtained after purification by flash chromatography (60-120μ; 4% ethyl acetate in hexane) as colorless liquid (5.0 g, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.89 (m, 2H), 7.90 (d, 1H), 7.76 (d, 1H), 7.32 (t, 2H); LC-MS m/z calculated for [M+H]+180.02. found 180.1.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]2=[O:19])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:21]([O-])=O)[N:3]=1>CN(C=O)C.[OH-].[OH-].[Pd+2]>[NH2:21][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:20])[N:11]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:2]([CH3:1])=[N:3]2
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 12 h
Yield: 68.9 %

Procedure:
A mixture of 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (250 mg) and Pd(OH)2 on carbon (110 mg) in DMF (40 mL) was shaken under hydrogen (50 psi) for 12 hrs. The suspension was filtered through a pad of Celite and washed with DMF (10 mL). The filtrate was concentrated in vacuo and the resulting oil was purified by flash column chromatography (silica gel, methanol/methylene chloride) to give 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (156 mg, 69% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 3.52 min (99.9%); mp: 293-295° C.; 1H NMR (DMSO-d6) δ 2.10-2.17 (m, 1H, CHH), 2.53 (s, 3H, CH3), 2.59-2.69 (m, 2H, CH2), 2.76-2.89 (m, 1H, CHH), 5.14 (dd, J=6, 11 Hz, 1H, NCH), 6.56 (d, J=8 Hz, 1H, Ar), 6.59 (d, J=8 Hz, 1H, Ar), 7.02 (s, 2H, NH2), 7.36 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.98, 23.14, 30.52, 55.92, 104.15, 110.48, 111.37, 134.92, 148.17, 150.55, 153.62, 162.59, 169.65, 172.57; LCMS: MH=287; Anal. Calcd. for C14H14N4O3+0.3H2O: C, 57.65; H, 5.05; N, 19.21. Found: C, 57.50; H, 4.73; N, 19.00.
Reaction SMILES: [C:1]1([C@H:7]2[N:10](CC3C=CC(OC)=CC=3OC)[C:9](=[O:22])[C@H:8]2[N:23]=[N+:24]=[N-:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C.O>[C:1]1([C@H:7]2[NH:10][C:9](=[O:22])[C@H:8]2[N:23]=[N+:24]=[N-:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](N=[N+]=[N-])[C@H]2c2ccccc2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1c1ccccc1
Yield: 65.1 %

Procedure:
(±)-(cis)-4-Phenyl-1-(2,4-dimethoxybenzyl)-2-oxo-3-azidoazetidine (737 mg) is dissolved in 25 ml of acetonitrile and heated to 80°-83° C. under nitrogen. To the resulting solution are added over a 1 hour period 943 mg of potassium persulfate and 570 mg of potassium monohydrogen phosphate, both dissolved in 25 ml of water. After the addition, the mixture is further heated at 80°-83° C. for 7 hours. The mixutre is cooled and the pH is adjusted to 6-7 by adding solid potassium monohydrogen phosphate. Most of the acetonitrile is removed under reduced pressure and the resulting mixture is extracted with 60 ml of chloroform. The chloroform layer is washed with water (60 ml), dried over anhydrous sodium sulfate and stripped of solvent to give a crude product as an oil. The crude product is chromatographed on 40 g of silica gel eluting with 1:1 petroleum ether-ethyl acetate. The combined fractions yield crystals and the product is recrystallized from petroleum ether-ethyl acetate to give 267 mg of the title compound.
Reaction SMILES: C(OC([NH:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)C.C[O-].[Na+].CO>O>[NH2:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)NC1=C(C(=O)OCC)CCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C1=C(N)CCC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution containing ethyl 2-[(ethoxycarbonyl)amino]-1-cyclopentene-1-carboxylate (72 g, 0.32 moles) and 25 wt % sodium methoxide in methanol (91.5 mL, 0.40 moles) was refluxed for about 18 hours. Methanol (200 mL) was added during the course of the reaction. The reaction mixture was allowed to cool to ambient temperature then diluted with water and extracted with diethyl ether (5×100 mL). The ether extracts were combined, treated with activated charcoal, dried over sodium sulfate then evaporated to provide 43.8 g of ethyl 2-amino-1-cyclopentene-1-carboxylate as an ivory solid, m.p. 90°-92° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:1]([O:6][C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(C)C(=O)O
Solvent: ClCCl
Product: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 96.8 %

Procedure:
The anion exchange resin used in Example 7 was regenerated by washing with 500 ml of a 4% aqueous caustic soda solution and then with methanol and acetonitrile to remove water. 0.43 g (0.005 mol) of methacrylic acid and 1.39 g (0.005 mol) of triphenylmethyl chloride were dissolved in methylene chloride and reacted together batchwise in the presence of the above regenerated resin to give 1.59 g (yield: 96.0%) of triphenylmethyl methacrylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:3][N:2]=1
Reactant: O=C(Nc1ccnnc1)Oc1ccccc1
Reactant: NC1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)NC1CCCC1

Procedure:
A stirred solution of 2.0 grams (0.009 mole) of phenyl N-(4-pyridazinyl)carbamate and 1.0 ml of cyclopentylamine in tetrahydrofuran was heated under reflux for 18 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel. Elution was accomplished with 10% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.2 gram of N-(4-pyridazinyl)-N'-cyclopentylurea. This material were combined with the identical product from a previous reaction to yield 0.5 gram; m.p. 192°-195° C. dec. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([C:13]([OH:15])=O)[CH2:10][O:11][CH3:12])=O)(C)(C)C.C([N:19](CC)CC)C.ClC(OCC)=O.[OH-].[NH4+].[Cl-].[NH4+]>O1CCCC1>[CH3:6][NH:8][C@H:9]([C:13]([NH2:19])=[O:15])[CH2:10][O:11][CH3:12]
Reactant: CCN(CC)CC
Reactant: COC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN[C@@H](COC)C(N)=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
N-(tert-Butoxycarbonyl)-N,O-dimethyl-L-serine (1.5 g, 6.43 mmol) and triethylamine (0.99 ml, 7.07 mmol) in tetrahydrofuran (20 ml) were cooled to −15 to −17° C. Ethyl chloroformate (0.68 ml, 7.07 mmol) was added drop wise followed by concentrated ammonium hydroxide (12 ml). The mixture was stirred at 0 to 5° C. for 2 hours. Saturated ammonium chloride solution was added and the layers separated. The aqueous layer was re-extracted with ethyl acetate and the combined organics dried (MgSO4) and concentrated under reduced pressure. The residues were dissolved in dioxane (10 ml) and 4M hydrogen chloride in dioxane (10 ml) was added and the mixture stirred for 1 hour. The mixture was evaporated and the residue dissolved in methanol, absorbed onto an SCX column, washed with methanol and eluted with 7N ammonia in methanol. Appropriate fractions were combined and evaporated to give N2,O-dimethyl-L-serinamide (576 mg, 68%) as a white, crystalline solid; 1H NMR spectrum: (DMSO d6) 1.92 (brs, 1H); 2.21 (s, 3H); 2.98 (t, 1H); 3.21 (s, 3H); 3.37 (m, 2H); 7.07 (brs, 1H); 7.30 (brs, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([OH:1])[C:3]=1[F:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(F)c(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A solution of 3-hydroxy-2,4,5-trifluorobenzoic acid (50 g, 0.26 mol) (prepared in an analogous manner to that described in Eur. Pat. Publication 271275) in methylene chloride (500 mL) was added oxalyl chloride (79 g, 0.62 mol). This solution was stirred at room temperature for 18 hours, cooled to 5° C. and then treated dropwise with methanol (100 mL). The mixture was stirred at room temperature for 2 hours, refluxed for 0.5 hour, cooled and concentrated. The residue was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated to provide 16.7 g of the desired 3-hydroxy-2,4,5-trifluorobenzoic acid methyl ester. Acidification of the bicarbonate layer, extraction with ether and concentration provided an additional 37 g of desired product as indicated by NMR, This material was not purified further but carried into the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4].[F:14][C:15]1[CH:16]=[C:17]([N:34]2[CH2:38][C@H:37]([CH2:39][N:40]3[CH:44]=[CH:43][N:42]=[N:41]3)[O:36][C:35]2=[O:45])[CH:18]=[CH:19][C:20]=1[C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH2:31][C@@H:30]([CH2:32]O)[O:29][N:28]=2)=[CH:25][CH:26]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([N:5]([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:32][C@H:30]1[O:29][N:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:20]3[CH:19]=[CH:18][C:17]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[CH:43][N:42]=[N:41]5)[O:36][C:35]4=[O:45])=[CH:16][C:15]=3[F:14])=[CH:22][N:23]=2)[CH2:31]1)=[O:11])=[O:4]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COC(=O)N(C)CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N(C)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The carbamate prepared as above (0.175 g, 0.93 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 0.25 g, 0.57 mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 3.5 hours at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.18 g), melting point: 82° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>Cl>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: COC(=O)CCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Yield: 80.1 %

Procedure:
6-(4-nitrophenoxy)-hexanoic acid methyl ester 21 (125 g, 468.16 mmol) was refluxed in conc. HCl (1250 ml) for 16 hours. The reaction mixture was cooled to room temp., filtered, dried and recrystallised from a mixture of ethyl acetate:hexane (1:6) to get pure 35 (95 g, 80.2%) as a white powder with an m.p. between 104-107° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:12](OC(=O)C)=[O:13].[OH-].[Na+]>C1COCC1>[C:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccccc1
Reactant: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)N(C=O)c1ccccc1
Yield: 74.2 %

Procedure:
A solution of 1a (1.2212 g, 8.18 mmol) and acetic formic anhydride (1.2 mL, 15 mmol) in THF (10 mL) was stirred for 7 h at room temperature. To the reaction solution was added an aqueous NaOH solution (1.0 M, 20 mL) The organic phase was extracted with Et2O (30 mL×2) and was chromatographed (4:1 hexanes/EtOAc) to give 2a (1:1 mixture of isomers, 1.076 g, 74.2%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.72 (s, 0.5H), 8.16 (s, 0.5H), 7.51-7.29 (m, 3H), 7.19-6.99 (m, 2H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 163.4, 162.6, 141.0, 138.2, 130.3, 130.1, 129.3, 129.2, 128.4, 57.7, 56.7, 31.0, 29.2. HRMS-ESI (m/z): [M+H]+ calcd for C11H15NO, 178.1226. found: 178.1228.
Reaction SMILES: C(O)(=O)C.NN.C([S:10][C@@H:11]1[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:57])[CH2:26][NH:27][C:28]([NH:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=3)=[O:45])=[N:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[CH2:20]2)=[O:18])[CH2:12]1)(=O)C.[OH:58][C@@H:59]([C@H:61]1[C:96](=[O:97])[N:63]2[C:64]([C:83]([O:85][CH2:86][C:87]3[CH:92]=[CH:91][C:90]([N+:93]([O-:95])=[O:94])=[CH:89][CH:88]=3)=[O:84])=[C:65](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:66]([CH3:67])[C@H:62]12)[CH3:60].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:32][C:30]([N:29]=[C:28]([NH:43][C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])[NH:27][CH2:26][C:25]([NH:24][C@H:21]2[CH2:22][CH2:23][N:19]([C:17]([C@@H:13]3[CH2:12][C@H:11]([S:10][C:65]4[C@H:66]([CH3:67])[C@@H:62]5[C@@H:61]([C@H:59]([OH:58])[CH3:60])[C:96](=[O:97])[N:63]5[C:64]=4[C:83]([O:85][CH2:86][C:87]4[CH:88]=[CH:89][C:90]([N+:93]([O-:95])=[O:94])=[CH:91][CH:92]=4)=[O:84])[CH2:15][N:14]3[CH3:16])=[O:18])[CH2:20]2)=[O:57])=[O:31])=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CC[C@H](NC(=O)CNC(=NC(=O)OCc3ccc([N+](=O)[O-])cc3)NC(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)CNC(=NC(=O)OCc5ccc([N+](=O)[O-])cc5)NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
Hydrazine acetate (652 mg) was added to a solution of (2S,4S)-4-acetylthio-2-[(3S)-3-[2-[2,3-bis(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]-1-methylpyrrolidine (4.3 g) in N,N-dimethylformamide (86 ml) and stirred at room temperature for 4 hours. To the resulting mixture was added 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-diphenylphosphoryloxy-1-carbapen-2-em-3-carboxylate (3.53 g) and N,N-diisopropylethylamine (1.34 ml) and allowed to react at −30° C. for 3 days. At the end of this time, to the reaction mixture was added 1% aqueous sodium hydrogencarbonate solution and the resulting precipitate was filtered, washed with water, and dissolved in a mixture of tetrahydrofuran and ethyl acetate (3:7). The resulting solution was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a silica gel column using 10% methanol/ethyl acetate and 20% methanol/ethyl acetate as the eluant to afford the crude desired product. The product was dissolved in tetrahydrofuran and reprecipitated with a mixture of ethyl acetate and ether (1:1) to give the desired compound (4.02 g) as a pale yellow powder.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][C:20]=1[O:28][CH3:29]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([F:30])[F:15])=[C:20]([O:28][CH3:29])[CH:21]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: COc1cc(C(C)N)ccc1OCC(F)F
Agent: Cl
Product: COc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (154 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)ethanamine hydrochloride (152 mg, 0.57 mmol, Amine-31, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a solution of methyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenyl]propanoate (0.755 g, 1.64 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (0.736 g, quant.) as a pale-yellow oil.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].C(O)(=O)C.C([O:19][C:20]1[C:21]([CH2:30]O)=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)(=O)C>CN(C)C=O>[OH:19][C:20]1[C:21]([CH2:30][S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1
Reactant: OCc1ccccc1S
Reactant: CC(=O)Oc1cc2c(cc1CO)OCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: OCc1ccccc1SCc1cc2c(cc1O)CCCO2
Reaction time: 0.5 h

Procedure:
To a solution of o-mercaptobenzylalcohol (289 mg, 2.06 mmol) in dry dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 83 mg, 2.07 mmol) portionwise and the mixture allowed to stir for 30 minutes. To the resulting solution was added dropwise a solution of 6-acetoxy-7-hydroxymethyl-3,4-dihydrobenzopyran acetate (543 mg, 2.06 mmol) in dry dimethylformamide and the mixture allowed to stir at room temperature under nitrogen for three hours, heated to 50° for 30 minutes, then allowed to cool and stir overnight. The reaction was quenched with 2.5N sodium hydroxide (2 mL) and after stirring for 30 minutes, the mixture was poured into water (75 mL). The aqueous mixture was neutralized with 2N hydrochloric acid (2.5 mL), extracted with ether (2×100 mL) and the ether extract washed with brine (3×100 mL), dried (Na2SO4) and concentrated. The crude product was purified by preparative HPLC (2:1 hexane/ethyl acetate as eluant) to afford 6-hydroxy-7-(2-hydroxymethylphenyl)thiomethyl-3,4-dihydrobenzopyran as a pale off-white solid, m.p. 140°-141° C.