Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[CH:13]1([CH2:18][C:19]([OH:21])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH:13]1([CH2:18][C:19]([O:21][CH2:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC1CCCC1
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CC1CCCC1)OCc1ccccc1
Temperature: 25 °C
Yield: 703 %

Procedure:
p-Toluene sulfonic acid monohydrate (1.48 g, 7.82 mmol) was added to a solution of cyclopentylacetic acid (10.0 g, 78.2 mmol) and benzyl alcohol (8.42 g, 78.2 mmol) in toluene (100 ml) at room temperature, a Dean-Stark water separator was mounted, and the mixture was refluxed for 4 hr. The mixture was allowed to cool to room temperature and was concentrated under reduced pressure, the residue was dissolved in ether, the solution was washed with saturated sodium bicarbonate and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=97:3) to give the title compound as a light yellow oil (12.0 g, yield 70%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([NH:39][C:40]([NH:42][CH2:43][CH2:44][F:45])=[O:41])[CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO.COCCOC>[F:23][C:24]1[CH:25]=[C:26]([NH:39][C:40]([NH:42][CH2:43][CH2:44][F:45])=[O:41])[CH:27]=[CH:28][C:29]=1[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 9.9 %

Procedure:
A solution of (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) (100 mg, 0.31 mmol), 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 31) (450 mg, 1.38 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (16 mg, 0.02 mmol) and sodium carbonate (49 mg, 0.46 mmol) in 2 ml of a 7:3:2 mixture of DME:EtOH:H2O respectively was heated in the microwave at 130° C. for 1 hour. The reaction was filtered through celite and purified via preparative HPLC at high pH then low pH to yield the title compound (15 mg, 10%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][NH2:12])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH2:13]([O:15][C:16](=[O:20])[C:17](=O)[CH3:18])[CH3:14]>C(O)C>[N+:2]([C:5]1[CH:6]=[C:7]([NH:11]/[N:12]=[C:17](\[CH3:18])/[C:16]([O:15][CH2:13][CH3:14])=[O:20])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)/C(C)=N/Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3-Nitrophenyl)hydrazine hydrochloride (30 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22 g, 0.19 mol) were dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h before the solvent was evaporated under reduced pressure to give (E)-ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate, which was used directly in the next step.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH:16]=[CH:17][C:18](=[N:20][OH:21])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([O-])(O)=O.[Na+]>O.C1COCC1.OS([O-])=O.[Na+]>[CH3:19][C:18]1[CH:17]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[O:21][N:20]=1
Reactant: CC(C=C[C@@H]1CCCN1C(=O)OCc1ccccc1)=NO
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2CCCN2C(=O)OCc2ccccc2)on1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A 169 mg sample (0.59 mmol) of the product from step 23d above, 344 mg (2.07 mmol) of Kl, 156 mg ((0.61. mmol) of 12, and 198 mg (2.36 mmol) of NaHCO3 were dissolved in 3 mL of water and 3 mL of THF. The mixture was heated at reflux for 6 hr, then cooled to room temperature. The mixture was diluted with 20 mL of 1.7 M NaHSO3 solution, then extracted with ether. The combined extracts were washed with brine and dried over MgSO4, then concentrated to give 143 mg of crude product. Chromatography on silica gel, eluting with 20% ethyl acetate in hexane afforded 102 mg of the title compound after removal of the solvent.
Reaction SMILES: [CH2:1]([CH:3]1[C:18](=[O:19])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:20])[CH3:2].[C:21]([S:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22]>>[C:21]([S:24][CH2:25][CH2:26][C:3]1([CH2:1][CH3:2])[C:18](=[O:19])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[N:5]2[C:4]1=[O:20])(=[O:23])[CH3:22]
Reactant: CC(=O)SCCBr
Reactant: CCC1C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O
Product: CCC1(CCSC(C)=O)C(=O)N2CCCC(C(=O)OC(C)(C)C)N2C1=O

Procedure:
In a manner analogous to that described in Example 1(D)(c), from 4 g of tert.butyl 2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate and 5.43 g of S-(2-bromoethyl) thioacetate there was obtained tert.butyl 2-(2-acetylthioethyl)-2-ethyl-hexahydro-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Chromatography gave 1.1 g (20%) of diastereomer A having a melting point of 82°-84° C. (from diethyl ether/hexane) and 0.4 g (7%) of diastereomer B in the form of a colorless oil.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:16]([CH3:29])[C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH3:29])[C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 77 %

Procedure:
Condensation of BocProOH (4.30 g.) and HMePheOMe (2.74 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MePheOMe in 77% yield. Demethylation of BocPro-MePheOMe (3.0 g.) using aqueous sodium hydroxide gave BocPro-MePheOH in 83% yield. Condensation of BocPro-MePheOH (1.71 g.) and HPheOBz (2.14 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MePhe-PheOBz in 76% yield. Debenzylation of BocPro-MePhe-PheOBz (2.0 g.) by hydrogenation with palladium catalyst gave BocPro-MePhe-PheOH in 100% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:23](=[O:24])[CH:22]([N:8]2[CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[CH:7]2[CH2:6][C:5]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC2CC2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with cyclopropylamine.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:28])([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[N+:29]([O-:31])=[O:30])C.[OH-].[Na+].Cl>C(O)C.O>[F:28][C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([N+:29]([O-:31])=[O:30])[CH:8]=2)=[CH:17][CH:16]=1)([CH3:27])[CH2:19][NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of {4′-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-3-nitro-biphenyl-4-yl}-acetic acid ethyl ester. (0.341 g, 0.731 mmol, prepared in example 47) in Ethanol (5.0 mL) is added a solution of 6.7% NaOH (15.0 mL) and the resulting mixture is stirred under N2 at ambient temperature for 72 h. The mixture is diluted with H2O (100 mL) and acidified with 37% HCl. Extraction with EtOAc followed by drying (MgSO4), filtration, and evaporation of the filtrate in vacuo gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19]C(=O)CC4C=CC=CC=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:5][CH:4]=1.CN1CCOCC1.N1C=CC=CC=1.[C:47]([O:51][C:52]([NH:54][C:55]1[S:56][CH:57]=[C:58]([C:60](=[N:64][O:65][CH3:66])[C:61](Cl)=[O:62])[N:59]=1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>ClCCl.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:61](=[O:62])[C:60]([C:58]4[N:59]=[C:55]([NH:54][C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:53])[S:56][CH:57]=4)=[N:64][O:65][CH3:66])[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30][Cl:31])=[O:10])=[CH:32][CH:33]=1
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a suspension of 7β-amino-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (1) p-toluenesulfonate (4.33 g; 8 mMol.) in dichloromethane (40 ml) is added at 0° C. N-methylmorpholine (0.88 g; 1 Eq.), pyridine (0.8 ml; 1.2 Eq.) and 2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetyl chloride (1.2 Eq.). After keeping at 0° C. for 30 minutes, the reaction mixture is diluted with water and ethyl acetate and ethyl acetate layer is taken. This is washed with ##STR19## water, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography (using toluene:ethyl acetate) to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (2) (4.89 g).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].CO.OS(O)(=O)=O.[C:17]([O-])(O)=O.[Na+]>C1COCC1>[CH3:17][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C([O-])O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A 500 g sample of L-pyroglutamic acid was added to 2.8 L of anhydrous methanol, 28 mL of H2SO4 was added, and the mixture was stirred for 4 hr at 60° C. The reaction mixture was cooled to room temperature, 262 g of NaHCO3 was added, and the mixture was stirred for an additional 16 hr. The mixture was dried by addition of 314 g of Na2SO4 with stirring for 1 hr, then the mixture was filtered and the solvent was evaporated under vacuum to yield a pale yellow oil. The oil was dissolved in THF, and a small amount of unreacted acid was filtered off. The THF was removed under vacuum, and the residual oil was dried by azeotropic distillation with toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][NH:38][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CI)C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNCC2OCCN(C(=O)OC(C)(C)C)CC2c2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (1.4 g) in DMF (5 mL) were added potassium carbonate (1.2 g) and 4-methoxybenzylamine (0.79 g), and the mixture was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2ccc3ccccc3c2)ncn1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(C)c(-c2cc(-c3ccc4ccccc4c3)ncn2)c1
Yield: 97 %

Procedure:
Next, into a recovery flask equipped with a reflux pipe were put 3.3 g of 4-chloro-(6-naphthalen-2-yl)pyrimidine, 2.1 g of 2,5-dimethylphenylboronic acid, 1.5 g of sodium carbonate, 0.11 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, into the flask were further put 1.0 g of 2,5-dimethylphenylboronic acid, 0.73 g of sodium carbonate, 0.050 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 2:1, so that a pyrimidine derivative Hdmp2npm was obtained (pale yellow oil, yield of 97%). A synthesis scheme (s-2) of Step 2 is shown below.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:17])[C:14](O)=[O:15])=[CH:9][CH:8]=1)=[O:6].[N:18]1(C(N)=O)[CH2:22]CC[CH2:19]1>>[CH3:19][N:18]([CH3:22])[C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:8][CH:9]=1)[CH3:17]
Reactant: CC(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Reactant: NC(=O)N1CCCC1
Product: CC(C(=O)N(C)C)c1ccc(C(=O)CCCCl)cc1

Procedure:
2-[4-(4-Chloro-butyryl)-phenyl]-propionic acid, pyrroldineamide;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][C:27]([F:30])([F:29])[F:28])[N:11]=2)[CH2:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:33]([CH3:35])=O.[Na+].C(=O)C.C([O-])(O)=O.[Na+]>CC(O)=O.CO>[CH2:33]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][C:27]([F:29])([F:30])[F:28])[N:11]=2)[CH2:6][CH2:7]1)[CH3:35]
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C#N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-{[(trans-4-Aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]amino}pyrimidine-5-carbonitrile (150 mg, 0.36 mmol) was dissolved in a solution of 1% AcOH in MeOH. The solution was cooled to 0° C. and to this cold solution were added NaBH(OAc)3 and acetaldehyde. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then treated with saturated NaHCO3 and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using 9:1:0.1 CH2Cl2:MeOH:NH4OH as an eluent to afford 24 mg (15%) of the title compound, m/z 449.4 (M+1)+.
Reaction SMILES: I[CH2:2][C:3](=[O:5])[CH3:4].[P:6]([O:13]CC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>>[CH2:2]([P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[C:3]([CH3:4])=[O:5]
Reactant: CC(=O)CI
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(C)=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.3 %

Procedure:
Iodoacetone (56.5 g, 0.31 mole) was added dropwise over a 20 minute period to 41.4 g (0.31 mole) of triethyl phosphite at 0° C. The mixture was allowed to warm to room temperature and held there for 90 minutes. The crude product was distilled in vacuo and the fraction boiling at 76°-86° C. (0.3-0.35 mm) was collected, giving 12.2 g of diethyl acetonylphosphonate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH2:10])=[N:6]1.[Cl:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:18]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:19])=[N:6]1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)Cn1nnc(N)n1
Product: COC(=O)Cn1nnc(NC(=O)c2ccc(Cl)s2)n1

Procedure:
63.2 Using general method D, (5-amino-tetrazol-2-yl)-acetic acid methyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give {5-[(5-chloro-thiophene-2-carbonyl)-amino]-tetrazol-2-yl}-acetic acid methyl ester. White solid. MS 302.0 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:46][NH2:47]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:46][NH:47]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Yield: 37.6 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (201 mg, 0.472 mmol), 5 mL of EtOH, Hunig's base (0.330 ml, 1.890 mmol), and hydrazine anhydrous (0.089 mL, 2.83 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum to afford the title compound (81 mg) as a light yellow solid. LC-MS (ES) m/z=457 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12-1.21 (m, 3H), 1.59-1.92 (m, 5H), 2.27-2.44 (m, 1H), 2.96 (m, 1H), 4.16-4.45 (m, 2H), 5.38 (s, 2H), 6.00-6.16 (m, 2H), 6.59 (s, 1H), 7.18-7.42 (m, 5H), 7.58 (dd, J=8.6, 1.3 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.90-8.00 (m, 1H), 8.43-8.55 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[C:7](O)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>C(CC(C)(C)C)(C)C>[C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)O
Reactant: CC(C)(C)OO
Solvent: CC(C)CC(C)(C)C
Product: CC(C)(C)OOC(=O)C(C)(C)C

Procedure:
To a reaction vial with a TEFLON fluoropolymer magnetic stirring rod, 3 ml containing 0.2 M tert-butyl hydroperoxide and 0.2 M pivalic acid in isooctane was added. The reaction was started by addition of 200 mg of Rhizomucor miehei enzyme and about 10 mg of molsieves (3 grains). After sixty-seven hours, 13% conversion to tert-butyl peroxypivalate was obtained as measured with GC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:11]2)=[C:6]([CH:9]=1)[CH:7]=[O:8].OO.Cl([O-])(=O)(=O)=[O:61].[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[C:3]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@@H:14]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:13]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:12]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:11]2)=[C:6]([CH:9]=1)[C:7]([OH:61])=[O:8]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C=O)cc2Cl)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C(=O)O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzaldehyde (0.826 g, 1.1 mmol) in t-BuOH/water (3:1, 17 mL) was added hydrogen peroxide (30%, 5.29 mL, 46.7 mmol) and sodium perchlorate (0.14 g, 1.1 mmol), and the solution was stirred overnight at RT. The volatiles were removed under reduced pressure, and the residue was quenched with water. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with water and then with brine, and then dried over anhydrous sodium sulfate. After removal of the volatiles, 0.802 g of crude solid product was obtained. MS ESI− (m/z): 841 (M+45)−.