Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:41])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:27][CH2:26][C@@H:25]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH2:24]5)=[C:19]([O:39][CH3:40])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:41])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]5)=[C:19]([O:39][CH3:40])[CH:18]=4)[CH2:13][CH2:14][C:15]=3[N:16]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1N1CC[C@@H](O)C1
Product: Cl

Procedure:
Dissolve (R)-2-(4-chloro-phenyl)-5-[3-methoxy-4-(3-triisopropylsilanyloxy-pyrrolidin-1-yl)-phenyl]-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (370 mg, 0.610 mmol) in dry THF (2 mL). Add TBAF (1.0M in THF, 610 μl, 0.610 mmol) and stir 2 h. Absorb the reaction mixture on silica gel and remove organic solvent via reduce pressure. Purify by silica gel chromatography using 0-100% EtOAc in hexanes to give the title compound. Dissolve the compound in a minimal amount of CH2Cl2 and add HCl/Et2O solution to give precipitated product. Remove the organic solvent via reduced pressure and triturate with MeOH to give the desired product as white solid HCl salt (144 mg, 48%). MS (ES+) 456.0 (M+1)+. 1H NMR (CD3OD): δ 8.01 (d, J=8.8 Hz, 2H), 7.71 (br d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.35 (br s, 1H), 7.16 (br d, J=8.8 Hz, 1H), 4.73-4.67 (m, 1H), 4.19 (br t, J=6.6 Hz, 2H), 4.02 (br s, 3H), 3.97-3.85 (m, 3H), 3.66 (br d, J=11.0 Hz, 1H), 3.31 (t, J=7.0 Hz, 2H), 2.49-2.36 (m, 1H), 2.26-2.17 (m, 1H).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][O:16][C:17]1[N:18]=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1.C(O)C.C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[ClH:23].[ClH:23].[CH3:9][N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][O:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN1CCC[C@H]1COc1ccc(Cl)nn1
Agent: [Pd]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC[C@H]1COc1cccnn1
Product: Cl
Reaction time: 0.5 h

Procedure:
A 92.8 mg (0.27 mmol) sample of 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridazine fumarate, from Example 12 above, was dissolved in 10 mL of a 4:1 mixture of ethyl acetate:ethanol, and 0.124 mL (0.89 mmol) of triethylamine and 5 mg of 10% Pd/C were added. The mixture was hydrogenated under 1 atm of H2 for 30 minutes, then the catalyst was removed by filtration. The solvents were removed under vacuum, to the residue was added 20 mL of satd NaHCO3 solution, and the mixture was extracted with methylene chloride. The solution was dried over MgSO4 and taken to dryness, the residue was azeotroped with ethanol several times to remove residual triethylamine. The residue was treated with HCl in ether according to Example 14c to afford 40 mg of the title compound. mp 176-177° C. MS (DCI/NH3) m/e: 194 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 8.89 (dd, 1H, J=4.6, 1.3 Hz), 7.75 (dd, 1H, J=9.0, 4.6 Hz), 7.38 (dd, 1H, J=9.0, 1.3 Hz), 4.84 (dd, 1H, J=12.3, 3.1 Hz), 4.67 (dd, 1H, J=12.3, 6.1 Hz), 3.98 (m, 1H), 3.76 (m, 1H), 3.26 (m, 1H), 3.04 (s, 3H), 2.41 (m, 1H), 2.23 (m, 1H). Anal. Calc. for C10H17Cl2N3O.0.3 HCl: C, 43.34; H, 6.29; N, 15.11; Found C, 43.23; H, 6.19; N, 14.78.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]1([CH3:23])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([O:21][NH2:22])(=[O:20])=[O:19]>C(Cl)Cl>[NH2:22][N:7]1[C:6](=[NH2+:8])[C:5]([CH3:9])=[CH:4][N:3]=[C:2]1[CH3:1].[CH3:17][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:23])[C:11]=1[S:18]([O-:21])(=[O:20])=[O:19]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1ncc(C)c(N)n1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1cnc(C)n(N)c1=[NH2+]
Temperature: 25 °C

Procedure:
A mixture of 2,5-dimethylpyrimidin-4-amine (15.2 g, 49.0 mmol) in DCM (30 in L) was stirred at room temperature, and O-(mesitylsulfonyl)hydroxylamine (2.0 g, 16.0 mmol) was added slowly. The reaction mixture was stirred at room temperature for 12 h, then the solvent was removed under reduced pressure. The crude product was used for the next step without further purification. ESI MS: m/z 139 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (800 mg) was dissolved in DMF (8 mL) and tert-butyl bromoacetate (452 mg) was added. Potassium carbonate (336 mg) was further added, and the mixture was stirred at room temperature overnight. After water was added carefully to the reaction solution, ethyl acetate (200 mL) was added, followed by extraction. The resulting organic layer was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further recrystallization with IPE afforded 704 mg of white crystals.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[O:29]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1cnc(Oc2ccccc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
In a flask, 64 g of 2,3-dichloro-5-trifluoromethyl pyridine, 250 ml of dimethyl sulfoxide, 81.8 g of anhydrous potassium carbonate and 33.4 g of phenol were charged. The flask was heated in an oil bath at 100° C. to react them with stirring for 4 hours. The reaction mixture was poured into suitable amount of water and the reaction product was extracted with methylene chloride. The extracted phase was washed with water, with 5% sodium hydroxide aqueous solution and then, with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure and the residue was distilled to obtain 49 g of 2-phenoxy-3-chloro-5-trifluoromethyl pyridine. The product was mixed with 100 ml of 98% sulfuric acid and the mixture was cooled with ice water. A mixture of 11.3 g of 60% nitric acid and 30 ml of 98% sulfuric acid was added dropwise to the sulfuric acid solution of the reaction product at a temperature of 0° to 10° C. A mild exothermic reaction was performed. After the reaction, the reaction mixture was poured into suitable amount of ice water and neutralized with 10% sodium hydroxide aqueous solution. The reaction product was extracted with methylene chloride. The extracted phase was dried over anhydrous sodium sulfate. Methylene chloride was distilled off under a reduced pressure to obtain 38.5 g of the object compound having a melting point of 90° to 91° C.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=1[F:19].N1C=CN=C1>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[F:19])[O:20][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(F)c(F)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1ccc(F)c(F)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Triisopropylsilyl chloride (166 mL, 961.5 mmol) was slowly added to a mixture of 3,4-difluorophenol (125 g, 961.5 mmol) and imidazole (65.4 g, 961.5 mmol) in N,N-dimethylformamide (500 mL), and the resulting solution stirred overnight at room temperature. The reaction mixture was diluted with water (1500 mL) and extracted with dichloromethane (3×300 mL). The combined organic layers washed with water (3×200 mL) and brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with petroleum ether) to afford (3,4-difluorophenoxy)triisopropylsilane (220 g, 80%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:12][N:11]([CH3:13])[C:8]1[CH:7]=[C:3]2[C:4]([O:6][C:16](=[O:15])[NH:1][C:2]2=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)c1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(C)c1ccc2[nH]c(=O)oc(=O)c2c1

Procedure:
To the mixture of 8.9 g of 2-amino-5-dimethylaminobenzoic acid in 60 mL of dioxane, under stirring and external cold water cooling 10 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 mL of ether. The product is stirred for 5 minutes in the mixture of 50 mL of methanol and 5 mL of triethylamine, filtered off, washed with 30 mL of methanol. After drying 7 g of the title product is obtained, m.p.: 258° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:41])[O:13][CH2:14][C@@H:15]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[Cl:39])=[O:29])[CH2:16][C:17](=O)[NH:18][CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:2]=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:41])[O:13][CH2:14][C@@H:15]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[Cl:39])=[O:29])[CH2:16][C:17]2[N:21]3[CH:22]=[CH:23][N:24]=[CH:25][C:20]3=[CH:19][N:18]=2)[N:2]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)NCc1cnccn1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a mixture of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-oxo-4-(pyrazin-2-ylmethylamino)butyl isoquinolin-3-ylcarbamate (650 mg, 1.12 mmol) and DCM (50 mL) were added phosphoryl chloride (0.514 mL, 0.00561 mol). The resulting mixture was stirred at RT for overnight. The resulting solution was concentrated. The resulting residue was purified on prep-HPLC (ACN/H2O with 0.1% HCOOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(imidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (0.27 g, 43%). LRMS (M+H+) m/z 562.1
Reaction SMILES: [NH2:1][C@H:2]([C:7](O)=O)[CH2:3][CH:4]([CH3:6])C.[NH:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14].[CH2:26]=O>>[NH:10]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14].[CH3:25][C:22]([O:21][C:19]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][C:13]1[NH:1][C:2]2[CH:3]=[CH:4][CH:6]=[CH:26][C:7]=2[CH:15]=1)=[O:20])([CH3:23])[CH3:24].[NH:10]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C@H:11]([CH:16]=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: C=O
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc2ccccc2[nH]1)C(=O)O
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C

Procedure:
Leu-psi -Tpi-BHA resin is made by reacting Boc-Leu-psi -Trp-BHA resin with formaldehyde in accordance with the procedures as follows: Boc-Leu-psi -Trp-BHA resin is obtained from 1.0 g BHA resin (0.9 m mode NH2 g) with coupling Boc-Trp and Boc-Leu-CHO successively by the method indicated in Operation I and Operation II. 10 ml. DMF containing 1% acetic acid is added to the above peptide resin and then reacted with 1 ml 10% formaldehyde at room temperature for 60 minutes and washed with DMF, MeOH and DCM.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(I)cc1
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccc(Oc2cnccn2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of chloropyrazine (124 mg, 1.08 mmol), K2CO3 (749 mg, 5.42 mmol), and 4-iodophenol (263 mg, 1.20 mmol) in DMF (24 mL) was heated at 100° C. for 9.5 h and then stirred at rt overnight. The reaction was diluted with EtOAc and washed with H2O (40 mL). The aqueous wash was back extracted with EtOAc (20 mL). The organic extracts were combined, washed with H2O (2×40 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (0%-20% EtOAc in hexanes) to give 289 mg of 2-(4-iodophenoxy)pyrazine (containing 15% of 4-iodophenol) as a white semi-solid. 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, 1H), 8.41 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 2H), 7.07 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:6].ClC1C=C(Cl)C=C(Cl)C=1[O:24][C:25](=O)[CH:26]([CH3:39])[C:27](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:28]>BrC1C=CC=CC=1>[CH:8]1([N:7]2[C:25](=[O:24])[C:26]([CH3:39])=[C:27]([OH:28])[C:4]([C:3]([O:2][CH3:1])=[O:14])=[C:5]2[CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)C=C(C)NC1CCCCC1
Solvent: Brc1ccccc1
Product: COC(=O)c1c(O)c(C)c(=O)n(C2CCCCC2)c1C
Temperature: 170 °C
Yield: 21.3 %

Procedure:
To a solution of 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) was added 2-methylmalonic acid bis-(2,4,6-trichloro-phenyl)ester (2.71 g, 5.72 mmol) and the reaction mixture was heated at 170° C. for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 94:6 methylene chloride/MeOH) and recrystallization from hot MeOH provided methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate as pale yellow crystals (0.34 g, 21%): 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 4.00-3.90 (m, 1H), 3.76 (s, 3H), 2.75-2.60 (m, 2H), 2.31 (s, 3H), 1.81 (s, 3H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 3H), 1.40-1.20 (m, 2H), 1.15-1.05 (m, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][CH:6]([CH:12]([CH3:14])[CH3:13])[C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH2:15](O)[CH3:16]>>[ClH:3].[CH2:15]([O:10][C:9](=[O:11])[C@H:7]([CH:6]([OH:5])[CH:12]([CH3:14])[CH3:13])[NH2:8])[CH3:16]
Reactant: CC(C)C(O)[C@H](N)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CCO
Product: CCOC(=O)[C@@H](N)C(O)C(C)C
Product: Cl

Procedure:
Into a 100 mL round-bottomed flask equipped with reflux condenser is added 50 mL ethanol and stirred using magnetic stirrer under positive nitrogen pressure. The flask is cooled using a dry ice/IPA bath to −35° C. Using an addition funnel 8.5 mL (0.12 mol) of thionyl chloride is added over 10 min. To the flask is then added 14.7 g (0.1 mol) of β-Hydroxy Leucine. The cooling bath is then removed and the flask heated using a heating mantle to reflux for 10 h. The reaction mixture is concentrated to 20 mL and then precipitated by adding 50 mL of ether. The product is isolated by filtration and washed with ether. The product β-Hydroxy Leucine ethyl ester hydrochloride is characterized by proton NMR and elemental analysis.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:11]([CH:14]1[N:18](CCO)[CH2:17][CH2:16][O:15]1)([CH3:13])[CH3:12].NC([O:25][CH2:26][CH3:27])=O>>[CH:11]([CH:14]1[N:18]([N:8]([C:9]([O:25][CH2:26][CH3:27])=[O:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][O:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)C1OCCN1CCO
Reactant: CCOC(N)=O
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)N(Cc1ccccc1)N1CCOC1C(C)C

Procedure:
133 g (1 mol) of benzylisocyanate is added dropwise to 159 g (1 mol) of 2-(2-isopropyl-1,3-oxazolidin-3-yl)-ethanol with vigorous stirring and the temperature is maintained at from 20° to 25° C with cooling. An almost colorless product with a viscosity of 460 cP (25° C) is obtained. It shows no NCO bands in the IR spectrum, but does show the expected urethane bands (1700 cm-1, 1540 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:25])[CH2:24][O:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:41]=[CH:40][C:33]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:25])[CH2:22][O:23][CH2:24]3)[C:17]([NH:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])=[CH:40][CH:41]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C)COC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: C=CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1ccc(NC(=O)C(CC2(C)COC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
115 mg (285 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoic acid (racemate), 51 mg (285 μmol) of allyl 4-aminobenzoate, 40.6 mg (285 μmol) of Oxima and 45 μl (0.29 mmol) of DIC in 2 ml of dimethylformamide were reacted according to General Method 5B. Preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 25 mg (16% of theory)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Solvent: Cc1ccccc1C
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 110 °C
Yield: 62.1 %

Procedure:
A suspension of 14.8 g (0.10 mole) of phthalic anhydride, 10.5 g (0.05 mole) of 2-phenylindole and 82 ml of xylene was heated to 110° C. briefly, cooled to and maintained at 95° C. for approximately two hours. The solution was cooled to ambient temperature and the solid which separated was collected by filtration and dried to obtain 10.6 g of 2-[(2-phenyl-3-indolyl)carbonyl]benzoic acid (Formula VIII: R0 =R1 =R2 =R3 =R6 =Y1 =H; R5 =C6H5) which melted at 106°-107° C. and had a nuclear magnetic resonance spectrum consistent with the assigned structure.
Reaction SMILES: COC(=O)[C@@H](C1C=CC=[CH:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)O.C(C(C(C([O-])=O)O)O)([O-])=[O:28].[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:25][C:21]1[CH:20]=[C:19]([C@@H:7]([O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:8][OH:28])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: COC(=O)[C@H](O)C1C=CC=CC1(OC1CCCCO1)c1cccc(Cl)c1
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OC[C@H](OC1CCCCO1)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
Into toluene (15 ml) were added (R)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)-mandelic acid methyl ester (7.0 g) obtained in 2) above and then, under ice cooling and dropwise, a 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution (7.67 g). The resulting mixture was stirred at the same temperature for 1 hour. Then the reaction mixture was added into a 30% aqueous (+)−potassium sodium tartrate solution (27.6 g), the resulting mixture was stirred for 1 hour and then the organic layer was separated. The organic layer obtained was washed with water and further with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desciccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (6.2 g, 98.1%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@@:11]2([CH2:26][OH:27])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28](OC([C@@H]1C[C@@]2(COC)[C@H](C2)N1C(OC(C)(C)C)=O)=O)C.[OH-].[Na+].O[Li].O>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[CH2:12][C@@:11]2([CH2:26][O:27][CH3:28])[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: CCOC(=O)[C@@H]1C[C@]2(COC)C[C@@H]2N1C(=O)OC(C)(C)C
Agent: [Li]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC[C@@]12C[C@@H]1N(C(=O)OC(C)(C)C)[C@H](C(=O)NCc1cccc(Cl)c1F)C2

Procedure:
were obtained using the same protocols as described in Scheme B28 steps D and E for the preparation of (1R,3S,5S) and (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester starting from (1R,3S,5S) and (1S,3S,5R)-5-methoxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester. NaOH was replaced by LiOH.H2O in step D. The diastereoisomers were separated by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to EtOAc) to give (1S,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-methoxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester as a colorless oil: TLC, Rf (c-hexane/EtOAc 1:1)=0.50; MS (UPLC/MS): 413.3/415.2 [M+H]+, 457.3/459.3 [M+HCOO]−; tR (HPLC conditions a): 3.74 min and (1R,3S,5S)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-5-methoxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester as a colorless oil: TLC, Rf (c-hexane/EtOAc 1:1)=0.30; MS (UPLC/MS): 413.2/415.3 [M+H]+, 457.3/459.3 [M+HCOO]−; tR (HPLC conditions a): 3.57 min.