Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O.O>[CH:22]1([O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
(S)-2-Benzyloxycarbonylamino-3-tert-butoxy-propionic acid (4 g, 0.014 mol) was dissolved in DMF (40 ml). Cyclopentanol (2.54 ml, 0.027 mol) and dimethylaminopyridine (0.165 g, 0.014 mol) were added. The solution was cooled to 0° C. using an ice bath and to it was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.73 g, 0.014 mol, 1.05 eq.). The mixture was stirred at 0° C. for 10 minutes and then allowed to warm to r.t. and stirred for a further 18 hours. To the reaction mixture was added water (20-30 ml) followed by EtOAc (40 ml). The layers were separated and the aqueous layer re-extracted with EtOAc (15 ml). The combined organic layers were washed with water (4×20 ml), dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by column chromatography (1:1 EtOAc/heptane) gave the product as a colourless oil (3.82 g, 78% yield). 1H NMR (300 MHz, CDCl3), δ: 1.15 (9H, s, CH3×3), 1.50-1.90 (8H, m, CH2×4), 3.57 (1H, dd, J=7.4, 1.2 Hz, CH), 3.85 (1H, dd, J=7.4, 1.2 Hz, CH), 4.45 (1H, m, CH), 5.15 (2H, s, CH2), 5.25 (1H, m, CH), 5.65 (1H, d, CH, J=7.6 Hz), 7.30-7.50 (5H, m, ArH×5).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:22]=[C:21]4[C:16]([C:17]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:18][C:19](=O)[NH:20]4)=[CH:15][CH:14]=3)[CH:7]=2)[CH2:3][CH2:2]1.C(N)=O>C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:22]=[C:21]4[C:16]([C:17]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)=[N:18][CH:19]=[N:20]4)=[CH:15][CH:14]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3)nc(=O)[nH]c2c1
Solvent: CC(=O)O
Solvent: NC=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3)ncnc2c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
The mixture of 3′-Amino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide from Example 15 (20 mg, 0.054 mmol) and formamide (2.9 mg, 0.065 mmol) in 0.7 mL acetic acid was stirred at 180° C. for 10 minutes in microwave. The solvents were removed under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and was washed with sat. aqueous NaHCO3 (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by preparative TLC sheet (methylene chloride:methanol=10:1) to give a colorless solid (4.6 mg, 22%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Cl:28][C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:15]2[CH:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([F:12])([F:11])[F:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=[C:17]([CH3:19])[N:16]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1cc(-c2cc(C)nc(OS(=O)(=O)C(F)(F)F)c2)ccc1C(F)(F)F
Reactant: OB(O)C1(Cl)C=CC=CN1
Product: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-pyridin-2-yl ester (example A.59) (2.0 g, 5.0 mmol) and commercially available 2-chloropyridine boronic acid (0.758 g, 5.0 mmol) according to the general procedure IVb. Obtained as an off-white solid (1.50 g, 82%). MS (ISP) 379.2 [(M+H)+] and 381 [(M+2+H)+].
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]2[N:7](O)N=NC=2C=1.CN(C=O)C.N1CC[CH2:19][CH2:18][CH2:17]1.[CH3:22]N(C=O)C>CN(C=O)C>[CH3:17][CH:18]([N:7]=[C:4]=[N:5][CH:6]([CH3:1])[CH3:22])[CH3:19]
Reactant: C1CCNCC1
Reactant: On1nnc2cccnc21
Reactant: CN(C)C=O
Product: CC(C)N=C=NC(C)C

Procedure:
After 4.44 g (0.45 mmol/g) of Rink Amide MBHA resin commercially available was swollen in DMF, the resin was treated with 50 mL of 20% piperidine/DMF solution for 20 minutes to remove the Fmoc group. The resulting resin was washed with DMF and treated in DMF with 4.21 g (8 mmol) of Fmoc-Trp(Boc)-OH, 1.27 mL (8 mmol) of DIPCDI and 1.31 g (8 mmol) of HOOBt at room temperature for 90 minutes, whereby Trp(Boc) was introduced to give the Fmoc-Trp(Boc)-Rink Amide MBHA resin. In a similar manner, Orn(Mtt) was introduced to give 2 mmol of the Fmoc-Orn(Mtt)-Trp(Boc)-Rink Amide MBHA resin. After the resin obtained was washed and swollen in toluene, 30 mL of TFA/TIS/TFE/toluene (1/5/47/47) was added, followed by shaking for 30 minutes and removing the solution by filtration. This procedure was repeated until yellow color caused by free Mtt group in a TFA/TIS/TFE/toluene (1/5/47/47) solution disappeared when the solution was added; thus the Mtt group was removed. The resulting Fmoc-Orn-Trp(Boc)-Rink Amide MBHA resin was neutralized with 5%-DIEA/toluene solution. After washing with toluene, 15 mL of toluene-TFE (4:1) and 1.95 g (6 mmol) of N-methyl-N,N′-bis-Boc-1-guanylpyrazole obtained in REFERENCE EXAMPLE 1 were added to the resin. DIEA was added to the mixture to adjust pH of the solution to 10. The solution was shaken for 15 hours to give Fmoc-Arg(Boc2,Me)-Trp(Boc)-Rink Amide MBHA resin (2 mmol). After the resin obtained was dried in MeOH, 0.03 mmol was weighed and reswollen in DMF. Leu was introduced in the same manner as described above to give 0.03 mmol of Fmoc-Leu-Arg(Boc2,Me)-Trp(Boc)-Rink Amide MBHA resin. After Fmoc deprotection in 20% piperidine/DMF solution, the resin was treated in DMF with 51.5 mg (0.12 mmol) of Fmoc-Phe-Ψ(CH2CH2)-Gly-OH obtained in REFERENCE EXAMPLE 3, 19.1 μl (0.12 mmol) of DIPCDI and 240 μl of 0.5 M HOAt/DMF solution at room temperature for 150 minutes. The resin was washed with DMF and then treated with 10.9 μl of (0.12 mmol) of Ac2O and 20.9 μl (0.12 mmol) of DIEA for capping of residual amino groups. Subsequently, the resin was shaken overnight in 2 mL of DMF solution of Ac-D-Tyr-Hyp-Asn-Thr-OH (0.06 mmol) synthesized in a conventional manner of the liquid-phase process, 31.2 mg (0.06 mmol) of PyAOP, 120 μl (0.06 mmol) of 0.5 M HOAt/DMF solution and 10.5 μl (0.06 mmol) of DIEA to give Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ψ(CH2CH2)-Gly-Leu-Arg(Boc2,Me)-Trp(Boc)-Rink Amide MBHA resin. After drying, 1.5 mL of TFA/PhSMe/m-cresol/H2O/TIS/EDT (80/5/5/5/2.5/2.5) was added to the resin and stirred for 90 minutes.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([O:16]CC)=O)[C:4]1=[O:19])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:25][CH2:24][C:23]([O:22][CH3:21])=[O:26])=[O:16])[C:4]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC)c1=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(C(=O)NCC(=O)OC)c(O)c2ccccc21
Yield: 11 %

Procedure:
In 4 mL of toluene in a microwave vial, ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.380 g, 1 mmol), glycine methyl ester hydrochloride (0.5 g, 4 mmol) was microwaved at 180° C. for 3 minutes and then purified by silica flash chromatography with a 1-5% MeOH/DCM gradient to afford 0.050 g. Yield: 11%
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C@@H:12]4O)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=O)[CH2:32][CH3:33])(=[O:29])CC>N1C=CC=CC=1.C(Cl)Cl>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C@@H:12]4[C:26]([O:30][CH2:31][CH2:32][CH3:33])=[O:29])[CH2:2][CH2:3]1
Reactant: CCC(=O)OC(=O)CC
Reactant: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)[C@H]1C=C2NC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](OC4CC4)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a manner analogous to the procedure reported in Baer, H. et al., Can. J. Chem 1991, 69, 1563-1574, 17β-cyclopropyloxy-7β-hydroxy-4-aza-androst-5-en-3-one (1.000 g, 2.895 mmol) from Example 20A or otherwise obtained is dissolved in pyridine (20 mL). Proprionic anhydride (20.0 mL, 156.0 mmol) is added, and the mixture is stirred at room temperature under nitrogen for 12 hours. At the end of the reaction time, the solution is diluted with CH2Cl2 (150 mL) and washed with water (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4, filtered and evaporated to dryness. The residue is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH:14]([CH3:16])[CH3:15])[C:6](=[O:17])[C:5]2([CH2:20][CH3:21])[CH2:18][CH3:19]>CO.O1CCCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH:14]([CH3:15])[CH3:16])[C:6](=[O:17])[C:5]2([CH2:20][CH3:21])[CH2:18][CH3:19]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc([N+](=O)[O-])c(N)cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1(CC)C(=O)N(C(C)C)c2cc(N)c(N)cc21
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 5-amino-3,3-diethyl-1-isopropyl-6-nitro-1,3-dihydro-indol-2-one (1.9 g, 6.52 mmol) in methanol/tetrahydrofuran (THF) (1:1, 80 ml) palladium on charcoal (10%, 1.2 g) was added and the mixture hydrogenated at room temperature for 4 h. After filtration the solvent was evaporated and the residue triturated with iso-hexane to yield 1.7 g 5,6-diamino-3,3-diethyl-1-isopropyl-1,3-dihydro-indol-2-one (6.50 mmol, 99%).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C@@:2]1([CH2:12][CH2:11][C@H:7]([C:8]([OH:10])=[O:9])[C:4]1([CH3:6])[CH3:5])[CH3:3].[CH3:15]O>Cl>[CH3:15][O:9][C:8]([C@H:7]1[CH2:11][CH2:12][C@@:2]([CH3:3])([C:1]([OH:14])=[O:13])[C:4]1([CH3:6])[CH3:5])=[O:10]
Reactant: CO
Reactant: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Yield: 83 %

Procedure:
To a stirred solution of (1R,3S)-(+)-camphoric acid (5 g, 25 mmol) in 30 mL of methanol, anhydrous HCl was bubbled for 2 h at room temperature. Methanol was evaporated and the residue was mixed with 5% sodium bicarbonate solution until the effervescence ceased and then 5% sodium hydroxide was added. The diester by-product was removed by extraction with diisopropyl ether. The aqueous layer was acidified with 10% HCl and extracted with diisopropyl ether. The combined ether extracts were dried over anhydrous sodium sulfate and evaporated to obtain (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (4.38 g) in 83% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.84 (s, 3H), 1.25 (s, 6H), 1.53-1.55 (m, 1H), 1.80-1.84 (m, 1H), 2.19-2.22 (m, 1H), 2.25-2.57 (m, 1H), 239-2.84 (m, 1H); 3.70 (s, 3H); m/z (M+1): 214. Step II: To a solution of (1R,3S)-3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentanecarboxylic acid (4.1 g, 19.2 mmol) in 18 mL of DCM and oxalyl chloride (2.1 mL, 24.9 mmol), 2 drops of DMF were added. The solution was stirred for 5 hours at −15° C. All the volatiles were removed by passing nitrogen gas. The residue was dissolved in THF and the solution added dropwise to 80 mL of anhydrous acetonitrile saturated with NH3 gas maintained at −30° C. The reaction mixture was stirred for another 15 minutes and the volatiles were removed under reduced pressure. The residue was taken in hot ethyl acetate and the solution was filtered; the crude product obtained after evaporation of the solvent was purified by column chromatography to furnish methyl (1S,3R)-3-carbamoyl-2,2,3-trimethyl cyclopentanecarboxylate (3.45 g) in 84% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.85 (s, 3H), 1.22 (s, 3H), 1.30 (s, 3H), 1.45-1.48 (m, 1H), 1.80-1.91 (m, 1H), 2.20-2.27 (m, 1H), 2.35-2.43 (m, 1H), 2.79-2.84 (m, 1H), 3.69 (s, 3H), 5.60 (d, J=37.96, 2H); m/z (M+1): 213. Step III: To a stirred solution of methyl (1S,3R)-3-carbamoyl-2,2,3-trimethyl cyclopentanecarboxylate (2.6 g; 12.2 mmol) in 12 mL of t-butanol, 0.2 mL of stannic chloride was added followed by lead tetraacetate (7.02 g, 15.86 mmol). The reaction mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure; the residue was taken up in diethyl ether, washed with 10% K2CO3 solution. The ether extract was concentrated and the crude product was purified by column chromatography to obtain methyl (1S,3R)-3-[(t-butoxycarbonyl)amino]-2,2,3-trimethylcyclopentanecarboxylate (2.58 g) in 74% yield. 1H NMR (400 MHz, CDCl3) δ ppm 0.86 (s, 3H), 1.18 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.8-1.9 (m, 1H), 1.98-2.05 (m, 3H), 2.72-2.76 (m, 1H), 3.71 (s, 3H), 4.73 (bs, 1H); m/z (M+1): 285.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:9])[CH2:7][F:8])[CH3:4].[C:10](OCC)(=O)[C:11](OCC)=O.[Cl:20][C:21]1[CH:22]=[C:23]([C@@H:28]2[CH2:30][C@H:29]2[CH:31]=O)[CH:24]=[CH:25][C:26]=1[Cl:27]>O.C1COCC1>[CH2:3]([O:5][C:6](=[O:9])/[C:7](/[F:8])=[C:31](/[C@@H:29]1[CH2:30][C@H:28]1[C:23]1[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=1)\[CH2:10][CH3:11])[CH3:4]
Reactant: CCOC(=O)CF
Reactant: O=C[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(\CC)[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h

Procedure:
Sodium hydride (0.74 g of a 60% dispersion in mineral oil) (ex BDH)in THF (30 ml) was treated with Ethylfluoroacetate (2.7 ml) (ex Lancaster) and diethyl oxalate (ex BDH) (3.8 ml). After 4 hours at 80° C., (±)-trans-2-(3,4-dichlorophenyl)cyclopropylmethanal (6 g) (example 2(i) and example 1(ii) to (iv)) was added. After 18 hours at 25°, water was added and the mixture worked up in the usual manner. Purification by chromotography (silica, hexane/ether) gave (±)-Ethyl-(2Z)-3-[trans-2-(3,4-dichlorophenyl)cyclopropyl]-2-fluoropent-2-enoate (4 g). NMR 1H 7.30(1H,d), 7.15(1H,d), 6.90(1H,dd), 5.70(1H,dd), 4.30(2H,q), 2.08(2H,m), 1.35(2H,m), 1.30(3H,t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[CH3:17][C:18]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=1C=C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:19]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]=1[CH3:17])[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: C=Cc1ccc(C)cc1C
Reactant: CCC(=O)C(=O)[O-]
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2CC(C(=O)O)Nc3cc(Cl)cc(Cl)c32)c(C)c1

Procedure:
Compound 22 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 2,4-dimethylstyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: C([Mg]Br)(C)C.[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:11][N:12]([CH3:29])[C:13](=[O:28])[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:18][C:17](I)=[N:16][CH:15]=1.[CH:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:11][N:12]([CH3:29])[C:13](=[O:28])[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:18][C:17]([CH:39]([OH:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(C(O)c2ccccc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To 1.8 ml of a 1 M solution of isopropyl magnesium bromide in tetrahydrofuran (1.8 mmol) a solution of 500 mg (0.865 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide (Example 4) in 10 ml tetrahydrofuran was added dropwise at 40° C. After 2 h 0.116 ml (I1.15 mmol) benzaldehyde were added. The reaction mixture was allowed to warm to room temperature over night. Addition of water and saturated aqueous ammonium chloride solution was followed by extraction with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 274 mg (57%) of the title compound as an off-white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23](O)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23]([NH:9][NH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)NNc1ccc(F)cn1
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (143 mg, 1.13 mmol) in DCM (10.0 mL) was added (R)-morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (260 mg, 1.13 mmol), EDC (238 mg, 1.24 mmol) and HOBt.H2O (15.0 mg, 0.11 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (375 mg, 98%). LCMS (Method 1): Rt 2.69, m/z 341.2 [MH+].
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[N:12]([CH3:19])[NH:13][C:14](=[O:18])[C:15](=[O:17])[N:16]=3)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH:30]1([O:33][N:34]=[C:35]([C:39]2[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=2)[C:36](O)=[O:37])[CH2:32][CH2:31]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH:30]1([O:33][N:34]=[C:35]([C:39]2[N:40]=[C:41]([NH:44][CH:45]=[O:46])[S:42][CH:43]=2)[C:36]([NH:1][C@@H:2]2[C:23](=[O:24])[N:4]3[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]4[N:12]([CH3:19])[NH:13][C:14](=[O:18])[C:15](=[O:17])[N:16]=4)[CH2:7][S:8][C@H:3]23)=[O:37])[CH2:32][CH2:31]1
Reactant: Cn1[nH]c(=O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1[nH]c(=O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Yield: 57.5 %

Procedure:
To a solution of 7β-amino-3-(5,6-dioxo-2-methyl-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (966 mg) and sodium bicarbonate (437 mg) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) was dropwise added the activated acid solution, prepared from 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (500 mg) according to a similar manner to that described in Example 1, with stirring and keeping pH 7.0 to 8.0 with saturated aqueous solution of sodium bicarbonate at 0° to 5° C. The mixture was stirred for 20 minutes at the same temperature. To the mixture was added ethyl acetate (40 ml) and the mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The resulting insoluble material was filtered off. The organic layer was separated from the filtrate, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β-[2-cyclopropyloxyimino-2 -(2-formamidothiazol-4-yl)acetamido]-3-(5,6-dioxo-2-methyl-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (685 mg).
Reaction SMILES: [I:1]Cl.[F:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:11])[C:4]=1[F:3]
Reactant: Cc1c(N)cccc1F
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(N)ccc(I)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Iodine monochloride (0.5 ml) was added to a solution of 3-fluoro-2-methylaniline (1.25 g) in glacial acetic acid (15 ml). The mixture was stirred for two hours at 70° C. The mixture was allowed to cool to ambient temperature and saturated sodium sulphite solution (50 ml) was added. The solution was extracted with EtOAc (2×100 ml), and the extracts were combined, washed with saturated sodium bicarbonate solution (100 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography on silica gel, eluted with 0-10% EtOAc in hexane to give the title compound (1.53 g) as a solid. NMR: 1.98 (s, 3H), 5.32 (s, 2H), 6.30 (d, 1H), 7.20 (t, 1H); m/z: 250.
Reaction SMILES: [CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([C:16](OC)=[O:17])([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)[O:6][CH2:5][CH2:4][O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH3:1][C:2]1([C:7]23[CH2:14][CH:13]4[CH2:15][C:9]([CH2:16][OH:17])([CH2:10][CH:11]2[CH2:12]4)[CH2:8]3)[O:3][CH2:4][CH2:5][O:6]1
Reactant: COC(=O)C12CC3CC(C1)C(C1(C)OCCO1)(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C23CC4CC2CC(CO)(C4)C3)OCCO1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Methyl 3-(2-methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]nonane-1-carboxylate (2.3 g, 8.64 mmol) obtained in step III, in THF (15 mL) was added slowly under N2 atmosphere through a dropping funnel to a suspension of LiAlH4 (0.32 g, 8.64 mmol) in ether (15 mL) at ice bath temperature. The reaction mixture was stirred for 30 minutes before being quenched by addition of sat. aq. NH4Cl solution (9 mL), followed by 1N NaOH solution (9 mL) and the reaction mixture was stirred at room temperature for 15 minutes before it was filtered through a pad of celite. The organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure to obtain [3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methanol (1.9 g) in 94% yield as viscous liquid. m/z (M+1) 269; IR cm−1 3436, 2936, 1634, 1459, 1373, 1309, 1047, 757. 1H NMR (CDCl3) 300 MHz δ 4.15-3.80 (m, 4H), 3.53 (s 3H), 2.50-2.30 (m 2H), 1.90-1.30 (m, 10H), 1.29 (s, 3H).