Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)CCl.C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2[nH]ncc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
5-Methoxyindazole (1.7 g, 11.5 mmol), (Tetrahedron, 1994, 50, 3529), was dissolved in ethylene chloride (35 ml) and cooled in an ice/water bath. Boron tribromide (57.4 ml of a 1M olution in methylene chloride, 57.4 mmol) was added over 10 minutes and then the mixture allowed to warm to ambient temperature. The mixture was stirred for 2 hours and then re-cooled in an ice/water bath. 2N Sodium hydroxide was slowly added until pH 8. The precipitated solid was filtered off and dried under vacuum at 60° C. overnight. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 5-hydroxyindazole (1.0 g, 65%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])/[C:8]([O:10]CC)=[O:9])[N:6]=1.O>CO.[OH-].[Na+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:15][CH2:16][N:17]=[N+:18]=[N-:19])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\OCCN=[N+]=[N-])c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCO/N=C(\C(=O)O)c1csc(N)n1
Reaction time: 20 h
Yield: 89 %

Procedure:
8.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetate are dissolved in 150 ml of methanol and 45 ml of 2N aqueous sodium hydroxide solution. After 20 hours, 50 ml of water are added thereto. The methanol is then removed in vacuo. The aqueous solution is treated with 90 ml of 1N aqueous hydrochloric acid and concentrated to dryness. The residue is taken up in 200 ml of dimethylformamide. The sodium chloride is removed by filtration and the solution is concentrated to 50 ml. The acid is precipitated by the addition of acetonitrile. There are obtained 6.5 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetic acid. Yield: 6.5 g of melting point 180° C.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[C:31]([CH2:42]Br)[CH:30]=1)=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[C:31]([CH2:42][O:24][C:21]2[CH:20]=[CH:19][C:18]([C:8]3[CH:9]=[N:10][C:11]4[N:12]([N:13]=[CH:14][C:15]=4[C:16]#[N:17])[C:7]=3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[CH:30]=1)=[O:28]
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)c1

Procedure:
Alkylation of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile with 2-bromomethyl-4′-chloro-biphenyl-4-carboxylic acid methyl ester was carried out in dimethylformamide (DMF) using cesium carbonate and following a previously described experimental procedure to give 4′-chloro-2-[4-(3-cyano-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-6-yl)-phenoxymethyl]-biphenyl-4-carboxylic acid methyl ester. This compound was converted to its corresponding tetrazole 4′-chloro-2-{4-[7-cyclohexyl-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidin-6-yl]-phenoxymethyl}-biphenyl-4-carboxylic acid methyl ester (475) via a previously described procedure. Finally, 4′-chloro-2-{4-[7-cyclohexyl-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidin-6-yl]-phenoxymethyl}-biphenyl-4-carboxylic acid (490) was obtained following a standard LiOH saponification protocol.
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:31][CH3:32])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([CH:22]([C:24]3[N:28]([CH3:29])[C:27]([CH3:30])=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.ClCCl>O1CCOCC1.[O-2].[O-2].[Mn+4]>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:31][CH3:32])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[N:28]([CH3:29])[C:27]([CH3:30])=[N:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 2.25 h

Procedure:
A heterogeneous mixture of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (625 mg, 1.32 mmol, Intermediate 21: step a) and manganese dioxide (809 mg, 7.91 mmol) in dioxane (13 mL) was heated to 100° C. After 135 minutes, the flask was allowed to cool to 23° C. Dichloromethane (40 mL) was added and the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (3 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with 30% ethyl acetate-hexanes initially, grading to 100% ethyl acetate provided the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([Cl:37])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:38])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[C:29]([Cl:37])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:38])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1ccc(C(F)(F)F)c(Cl)c1)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 30.3 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-acrylonitrile (2.5 g, 6.9 mmol) prepared in Example 71a, AgF (1 g, 8 mmol), and triethylamine (2.4 mL, 17 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:35](=[O:36])[CH2:34][C:32]#[N:33])[N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:11][CH:10]=3)[C:20]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
Into a 100 mL, round-bottom flask, was placed 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (185 mg, 0.44 mmol, 1.00 equiv), 2-cyanoacetic acid (30.7 mg, 0.36 mmol, 0.80 equiv), HATU (138 mg, 0.36 mmol, 0.80 equiv), triethylamine (91 mg, 0.90 mmol, 2.00 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. and then extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 101 mg (47%) of 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a off-white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22](OCC(C)C)=O)[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[N:37]#CBr>C(Cl)(Cl)Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:37])[CH2:18][CH2:17]3)=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step B, Example 1; 300 mg, 0.958 mmol) and potassium carbonate (492 mg, 3.57 mmol) were stirred in chloroform (10 mL). Cyanogen bromide (122 mg, 1.15 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (99:1, 1 L) to provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.89 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 4.11 (t, J=6.5 Hz, 2H), 3.50-3.25 (m, 2H), 3.10-2.90 (m, 2H), 2.25-2.10 (m, 1H), 1.90-1.75 (m, 2H), 1.65-1.40 (m, 3H), 1.10-0.80 (m, 2H), 0.80-0.60 (m, 2H), −0.09 (q, J=4.7 Hz, 1H). MS (Multimode) m/z 339 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15]>>[N+:8]([C:7]1[C:2]([O:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: OCC(CO)CO
Reactant: O=[N+]([O-])c1cccnc1F
Product: O=[N+]([O-])c1cccnc1OCC(CO)CO

Procedure:
Prepared analogously to example XII.1 using 2-fluoro-3-nitropyridine (142 mg) and 2-(hydroxymethyl)-1,3-propanediol (148 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[C:30]([OH:37])[CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(=O)c1ccc(OCCCBr)cc1O
Product: CC(=O)c1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1O

Procedure:
Following the procedure of Example 1, ]α,α-bis(p-fluorophenyl)-4-piperidinemethanol and 1-[4-(3-bromopropoxy)-2-hydroxyphenyl]ethanone are reacted to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[CH:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:27]([O:30][N:31]([CH:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH:15]=[C:14]1[CH2:16][O:17][CH3:18])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1O
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a stirred solution of Intermediate 118 (6.2 g, 16.00 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (4.34 g, 16.80 mmol) and triphenylphosphine (5.03 g, 19.20 mmol) in toluene (140 mL), was added (E)-diisopropyl diazene-1,2-dicarboxylate (3.67 g, 17.60 mmol) at rt. The reaction was stirred at rt over the weekend. The mixture was then concentrated and the residue was purified by silica gel column (120 g, 0-100% Hex/EA) to give the title compound (8.80 g, 88%) as an oil
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[C:19](O)=[O:20])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:58][O:59][C:60]([C:62]1([NH2:67])[CH2:66][CH:65]=[CH:64][CH2:63]1)=[O:61]>CN(C=O)C>[CH3:58][O:59][C:60]([C:62]1([NH:67][C:19]([C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]=2[O:8][CH2:7][C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:1])([F:25])[F:24])=[CH:4][CH:5]=2)=[O:20])[CH2:66][CH:65]=[CH:64][CH2:63]1)=[O:61]
Reactant: COC(=O)C1(N)CC=CC1
Reactant: O=C(O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)cc2)CC=CC1
Reaction time: 0.5 h
Yield: 118 %

Procedure:
To a solution of 200 mg 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid in 2 ml abs. DMF under inert atmosphere 72 mg 1-hydroxybenzotriazole, 285 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 288 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 229 mg of 1-amino-cyclopent-3-enecarboxylic acid methyl ester hydrochloride, followed by 223 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate and concentrated to yield 320 mg of 1-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-cyclopent-3-enecarboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[CH:1]1([CH2:6][O:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1CC=CC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCC1CC=CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
In a flask under argon was placed cyclopent-3-enyl-methanol (7.86 g, 80 mmol) and pyridine (100 mL). To this mixture was slowly added benzoyl chloride (9.30 mL, 80 mmol). After addition was complete, the mixture was stirred at 25° C. for 1.5 h. After this time, the mixture was slowly treated with water (15 mL) and concentrated in vacuo to remove most of the pyridine. The mixture was taken up into chloroform (400 mL) and washed with water (300 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford benzoic acid cyclopent-3-enylmethyl ester (15.86 g, 98%) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH3:37])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:34]([O:33][CH:29]([O:30][CH2:31][CH3:32])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH3:37])[CH3:36])[CH3:35]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 68 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:18]=[C:17]([NH:19]C(OC(C)(C)C)=O)[S:16][N:15]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:18]=[C:17]([NH2:19])[S:16][N:15]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)ns1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1nsc(N)n1)C(=O)O
Yield: 52.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (114 mg, 0.173 mmol), DCM (1.7 mL) and TFA (800 μl, 10.4 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (46 mg, 46%) as a white powder. LCMS: Rt=0.42 min, m/z=504.0 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J=8.6 Hz, 1H), 8.65 (s, 1H), 8.21 (br s, 2H), 8.10 (s, 1H), 5.22 (dd, J=8.6, 5.5 Hz, 1H), 4.67-4.58 (m, 1H), 4.56-4.47 (m, 1H), 4.28 (q, J=5.5 Hz, 1H), 1.39 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:29][CH3:30]>C1COCC1>[CH2:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:34][CH:33]=1)[CH2:29][CH3:30]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCOc1ccc(C=CCCCC(=O)O)cc1
Yield: 75.5 %

Procedure:
This compound was synthesized from 4-carboxybutyltriphenylphosphonium bromide (8.87 g, 20 mmol) and p-propoxybenzaldehyde (3.28 g, 20 mmol, synthesized from p-hydroxybenzaldehyde and 1-iodopropane) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (3.75 g, 76%) as white crystals (mp, 49-50° C.). IR: 3400-2500, 1725 cm-1 ; 1H-NMR: 1.00 (t, 3H), 1.75 (m, 4H), 2.35 (m, 4H), 3.90 (t, 2H), 5.55 (m, 1H), 6.35 (m, 1H), 7.00 (q, 4H), 11.30 (bs, 1H). Anal. Calcd. for C15H20O3 : C, 72.55, H, 8.12%; Found: C, 72.45, H, 8.13%. Z:E=35:65.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:34]([NH:36][NH2:37])[CH3:35].CCOC(C)=O>CCN(CC)CC>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[N:36]([CH2:34][CH3:35])[N:37]=1
Reactant: CCNN
Reactant: O=C(CC(=O)C1CCN(Cc2ccccc2)CC1)Cc1ccc(F)c(F)c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCn1nc(Cc2ccc(F)c(F)c2)cc1C1CCN(Cc2ccccc2)CC1
Reaction time: 0.06 h

Procedure:
The title compound was prepared from 1-(1-benzylpiperidin-4-yl)-4-(3,4-difluorophenyl)butane-1,3-dione and ethylhydrazine oxalate using a procedure similar to that described in Example 1, Step B. RF: 0.29 (2:1 EtOAc to hexanes with 1% (v/v) Et3N). It was the fast-eluting isomer on silica gel. 1H NMR (500 MHz, CDCl3): δ7.29˜7.33 (m, 4H), 7.23˜7.28 (m, 1H), 7.05˜7.14 (m, 2H), 6.97˜7.01 (m, 1H), 5.86 (s, 1H), 4.06 (q, 7.2 Hz, 2H), 3.84 (s, 2H), 3.55 (s, 2H), 2.97 (br d, 11.9 Hz, H), 2.64 (tt, 12.1 & 3.7 Hz, 1H), 2.12˜2.16 (m, 2H), 1.83 (br d, 13.1 Hz, 2H), 1.62˜1.71 (m, 2H), 1.35 (t, 7.2 Hz, 3H); ESI-MS 396.2 (M+H), HPLC A: 3.43 min., compared with 3.54 min. for its isomer.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:23](O)[C:24]#[CH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.CCCCCC>[CH2:1]([C:16]1[CH:17]=[C:18]([O:22][CH2:25][C:24]#[CH:23])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: C#CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: O
Product: C#CCOc1cccc(CCCCCCCCCCCCCCC)c1
Reaction time: 4.5 h

Procedure:
To a solution of 24.4 g (80 mmol) of 3-pentadecylphenol, 4.93 g (88 mmol) of propargyl alcohol and 23.1 g (88 mmol) of triphenylphosphine cooled to 15° C. is added dropwise 15.3 g (13.9 ml, 88 mmol) of diethyl azodicarboxylate. The mixture is stirred for 4.5 hours and then is diluted with water and extracted with hexane (3 times). The hexane extracts are combined, washed with 1N sodium hydroxide and are dried over magnesium sulfate overnight. Filtration and evaporation gives crude oil which is subjected to flash chromatography using hexane as eluting solvent. The appropriate fractions are combined to give the title compound as an oil which solidifies upon standing: mp. 26°-27° C. The product is used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C([O-])=S)=C(CC4CCCO4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(CC2CCCO2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 25.3 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-tetrahydrofurfurylthio-3-cephem-4-carboxylate (50 mg) was reacted with iodomethyl pivalate (36 mg) and post-treated in the same manner as in Example 4, yielding the titled compound (15 mg; 25%) as colorless crystals.