Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([CH2:14][CH:15]=[CH2:16])[CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:22][CH2:21]C1>ClCCl.[CH-]=O.[CH-]=O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Co].[Co+2]>[C:1]([O:5][C:6]([N:7]1[CH2:14][CH:15]2[CH2:16][C:21](=[O:22])[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]2[CH2:8]1)=[O:17])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(CC#CCCC)C(=O)OC(C)(C)C
Agent: [Co+2]
Agent: [Co]
Agent: [C-]#[O+]
Solvent: ClCCl
Product: CCCC1=C2CN(C(=O)OC(C)(C)C)CC2CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
A solution of allyl-hex-2-ynyl-carbamic acid tert-butyl ester (741 mg, 3.12 mmol) in dichloromethane (50 mL) was added to dicobalt octacarbonyl (1.12 g, 3.28 mmol) under an argon atmosphere. The resulting solution was stirred at room temperature for 1.5 h. After this time, N-methylmorpholine N-oxide (2.56 g, 21.9 mmol) was added in portions during a 60 min period. Upon completion of addition, the reaction mixture was stirred for an additional 2.5 h. At the conclusion of this period, the mixture was filtered through silica gel, and the solid was washed with a 1:1 ethyl acetate-hexane solution (200 mL). The filtrate was concentrated under vacuum to yield a residue. The residue was purified by flash column chromatography to provide a light brown oil (321 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 5.3-3.9 (m, 3H), 3.17 (m, 1H), 2.80 (m, 1H), 2.67 (m, 1H), 2.29 (m, 1H), 2.13 (m, 2H), 1.51 (m+2s, 11H), 0.91 (m, 3H). MS (ES+) m/z 266.19 (M+H+).
Reaction SMILES: [N:1]([C@@H:4]([C@H:40]([C:48]1[CH:56]=[CH:55][C:51]2[O:52][CH2:53][O:54][C:50]=2[CH:49]=1)[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].CP(C)C>CCOC(C)=O.O>[NH2:1][C@@H:4]([C@H:40]([C:48]1[CH:56]=[CH:55][C:51]2[O:52][CH2:53][O:54][C:50]=2[CH:49]=1)[C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@@H:19]([CH2:22][O:23][C:24](=[O:31])[NH:25][CH2:26][C:27]([F:28])([F:30])[F:29])[N:18]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:17]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(Cl)cc2)c2ccc3c(c2)OCO3)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from step 2 (80 mg, 0.102 mmol) in EtOAc (8 mL) and water (2 mL), was added trimethylphosphine (0.5 mL, 1M solution in THF, 0.5 mmol). The reaction mixture was stirred at ambient temperature for 2 h, then diluted with water (20 mL) and extracted with EtOAc (25 mL×3). The combined organic extracts were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound as colorless oil. This material was used in the next step without any additional purification. (M+H-Boc)+=682.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)Cl.C(Cl)Cl.C[OH:26]>>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:26])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 72 h

Procedure:
(2-tert-Butoxycarbonylamino-ethyl-2-{[tert-butoxycarbonyl-(2-tert-butoxycarbonylaminoethylamino]-methyl}-8-hydroxyoctyl)-carbonic acid tert-butyl ester (2.52 g, 3.82 mmol), p-toluenesulfonyl chloride (1.0 g, 5.2 mmol), triethylamine (1.3 g, 12.8 mmol) and CH2Cl2 (30 ml) were stirred at room temperature with the slow evaporation of solvent. The reaction was monitored by carbon NMR and after 3 days little starting material remained. The reaction volume was made up to 30 ml with CH2Cl2, extracted with water (50 ml×3), dried (MgSO4), filtered and the solvent evaporated to leave a brown residue. This residue was subjected to chromatography on silica gel using CH2Cl2/MeOH (100:5) as eluent. The first compound to elute was unreacted tosyl chloride with an rf=0.95. The title compound eluted with an rf=0.2 and was isolated as a pale yellow viscous oil. Yield (1.20 g, 39%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH:28]([C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccccc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]5[N:40]=[CH:39][CH:38]=[CH:37][C:26]=5[C:27]([NH:29][C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)=[O:28])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][CH:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]2[N:40]=[CH:39][CH:38]=[CH:37][C:26]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:28])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([NH:42][CH:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(Nc5ncccc5C(=O)Nc5ccc(F)cc5)cc4F)c23)CC1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(4-(1-(4-methoxybenzyl)-3-(1-methylpiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(4-fluorophenyl)nicotinamide (0.023 g, 0.0333 mmol) and TFA (3 mL). The reaction mixture was heated to 70° C. for 1 hour. The reaction was concentrated and the residue was purified by preparative TLC [0.5 mm thickness eluting with 15% MeOH(NH3)/CHCl3] to provide the product (9 mg, 46%). LRMS M−1 (571.1) observed. 1H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 10.12 (br s, 1H), 8.43 (m, 1H), 8.18 (m, 1H), 8.06 (m, 2H), 7.91 (m, 1H), 7.53 (m, 2H), 7.31 (m, 1H), 7.13 (m, 3H), 6.86 (m, 1H), 6.11 (m, 1H), 4.58 (d, J=7 Hz, 1H), 3.74 (br s, 1H), 2.92 (br s, 2H), 2.37 (s, 3H), 2.27 (br s, 2H), 1.72 (br s, 2H), 1.59 (br s, 1H). 19F NMR (376 MHz, CDCl3) δ −76.0 (3F), −117.0 (1F), −127.6 (1F).
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:45])([F:44])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][N:29]=[C:28]([S:41][CH3:42])[N:27]=3)[C@H:20]2[CH3:43])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Br[C:47]1[C:48]([O:54][CH3:55])=[N:49][CH:50]=[C:51]([Cl:53])[CH:52]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:47]4[C:48]([O:54][CH3:55])=[N:49][CH:50]=[C:51]([Cl:53])[CH:52]=4)=[CH:30][N:29]=[C:28]([S:41][CH3:42])[N:27]=3)[C@H:20]2[CH3:43])[CH:10]=[C:9]([C:8]([F:7])([F:44])[F:45])[CH:14]=1
Reactant: COc1ncc(Cl)cc1Br
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 170 °C
Reaction time: 0.17 h

Procedure:
A dioxane (17.3 mL) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 mmol), 3-bromo-5-chloro-2-methoxypyridine (0.925 g, 4.16 mmol) and 2M potassium phosphate tribasic (3.5 mL, 7.00 mmol) in a microwave vial was evacuated and charged three times with nitrogen. Then Pd(Ph3P)4 (0.400 g, 0.346 mmol) was added and the reaction vial was capped. The reaction was stirred for 10 minutes at 170° C. in a microwave reactor. LCMS showed complete conversion to the product. The reaction was diluted with acetonitrile (5 mL) and filtered through a 2 g plug of RP C18 silica, rinsing with 10 mL acetonitrile. The filtrate was concentrated and the crude was purified by silica gel chromatography, eluting with a gradient of 0-50% ethyl acetate/hexanes to give the title compound as a pale yellow foam. LCMS (M+H)+: 593.3
Reaction SMILES: [NH2:1][C@@H:2]([C:15]([NH:17][C@@H:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C:20](=[O:23])[O:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14].[N:31]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][CH2:53][C@H:32]1[C:33]([NH:35][C@@H:36]([C:42]([NH:44][C@H:45]([C:50](O)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[C:37]([S:40][CH3:41])([CH3:39])[CH3:38])=[O:34].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[N:31]1([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[CH2:55][CH2:54][CH2:53][C@H:32]1[C:33]([NH:35][C@@H:36]([C:42]([NH:44][C@H:45]([C:50]([NH:1][C@@H:2]([C:15]([NH:17][C@@H:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C:20](=[O:23])[O:21][CH3:22])=[O:16])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]#[N:14])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[C:37]([S:40][CH3:41])([CH3:39])[CH3:38])=[O:34]
Reactant: COC(=O)C[C@@H](NC(=O)[C@H](N)Cc1c(C#N)[nH]c2ccccc12)C(=O)OC(C)(C)C
Reactant: CSC(C)(C)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C[C@@H](NC(=O)[C@@H](Cc1c(C#N)[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(C)(C)SC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a mixture of H-DTrp(2-CN)-DAsp(OMe)-OtBu (26 mg, prepared in Example (9-b)) and Boc-Pro-DPen(Me)-Leu-OH (33 mg, prepared in Example (9-f)) in DMF (3 mL) were added HOBT·H2O (12 mg) and EDCI·HCl (15 mg) under ice-cooling. The mixture was stirred under ice-cooling for 1 h and at room temperature for 1.5 h. The mixture was diluted with ethyl acetate (30 mL), washed with sat. aq. NaHCO3 (15 mL), 10% aq. citric acid (15 mL) and brine (15 mL) successively, dried over MgSO4 and evaporated under reduced pressure. The residue was purified by preparative TLC (Merck, Kieselgel 60 F254) with chloroform/methanol=30/1 for development to give the product (42 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH3:8])[CH:7]=1>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)c(N)cc1N
Yield: 50 %

Procedure:
2 g (0.01 ml) of 5-fluoro-2,4-dinitrotoluene from Step 1 are hydrated with catalytic amounts of palladium/carbon (10% Pd) in 50 ml absolute ethanol. After the catalyst is removed by filtration, the solvent is distilled off completely and the obtained product is recrystallized from toluene. 0.7 g (50 % of theory) of 5-fluoro-2,4-diaminotoluene is obtained which melts at 112° Celsius accompanied by decomposition.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)(=O)=O)=CC=1.[NH:40]1[CH:44]=[N:43][N:42]=[N:41]1.C(N(CC)CC)C>CN(C=O)C>[N:40]1[N:41]([CH2:12][C@@H:13]2[C@@H:18]([OH:19])[C@H:17]([OH:20])[C@@H:16]([OH:21])[C@H:15]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][C:30]4[S:31][C:32]([C:35]5[O:36][CH:37]=[CH:38][CH:39]=5)=[CH:33][N:34]=4)[CH:23]=3)[O:14]2)[N:42]=[N:43][CH:44]=1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@@H]1[C@@H](O)[C@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)O[C@H](Cn2ncnn2)[C@H]1O
Yield: 23.8 %

Procedure:
The solution of toluenesulfonate 90 (612 mg, 1.03 mmol), tetrazole (0.45 M in acetonitrile) (11.5 mL 5.17 mmol) and triethyl amine (0.72 mL 5.17 mmol) in DMF (2.0 mL) was stirred at 80° C. for 3 d. Reaction mixture was evaporated under reduced pressure. The residue was purified by prep HPLC (C18) to afford the titled compound 98 (120 mg, 24%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:25]([CH:28]=[CH2:29])[CH2:26][S:27][C@H:22]12)[C:9](=[O:20])[CH:10]([C:12]1[N:13]=[C:14]([NH:17]C=O)[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH:21]1[C:46](=[O:47])[N:23]2[C:24]([C:30]([O:32][CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:31])=[C:25]([CH:28]=[CH2:29])[CH2:26][S:27][C@H:22]12)[C:9](=[O:20])[CH:10]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 7.5 %

Procedure:
A mixture of benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-formamidothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (5.6 g) and conc. hydrochloric acid (2.6 ml) in methanol (60 ml) and tetrahydrofuran (15 ml) was stirred at ambient temperature for 2.5 hours. The precipitated substance in the reaction mixture was collected by filtration, and washed with a mixture of methanol and water (1:2 by volume) and then water, followed by drying to give benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (0.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[C:24]([O:33][CH2:34][CH3:35])=[N:25][C:26]([C:29]([F:31])([F:30])[F:32])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1nc(C(F)(F)F)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(C(F)(F)F)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 5) was reacted with 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H32N6O4SF3Cl2 [(M+H)+] 699.1530, observed 699.1533.
Reaction SMILES: Cl.BrC1SC2=NC(N)=CN2C=1.C(OC(NCC(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C.[C:31]([O:35][C:36](=[O:64])[NH:37][C@@H:38](C1C=CC=CC=1)[C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1[C:46](=[O:57])[NH:47][C:48]1[N:49]=[C:50]2[N:54]([CH:55]=1)[CH:53]=[C:52]([Br:56])[S:51]2)=[O:40])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:64])[NH:37][CH2:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1[C:46](=[O:57])[NH:47][C:48]1[N:49]=[C:50]2[N:54]([CH:55]=1)[CH:53]=[C:52]([Br:56])[S:51]2)=[O:40])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1
Yield: 46 %

Procedure:
Compound 28 was synthesized from compound 11 (0.471 mmol) and compound 27 (0.707 mmol), following the procedure as described for compound 23, as an off-white solid in 46% yield. MS (ESI, EI+) m/z=471.99-474.01 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9]([N:11]2[C@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (4.24 g, 16.0 mmol) in dry THF (80 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (17.6 mL, 17.6 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (5.0 mL, 80.0 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (48 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (200 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 2.59 g (9.28 mmol, 58%) of (4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.34–7.31 (m, 2H), 7.02–6.96 (m, 2H), 5.13 (q, 1H, J=7.7 Hz), 4.38–4.33 (m, 1H), 4.18–4.13 (m, 2H), 2.48–2.37 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 280.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[S:15]1[CH:19]=[C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH2:25])[N:17]=[CH:16]1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:25][C:24]3[CH:23]=[CH:22][S:21][C:20]=3[C:18]3[N:17]=[CH:16][S:15][CH:19]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccsc1-c1cscn1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1cscn1

Procedure:
2-(Isoquinolin-5-yl)-N-(2-(thiazol-4-yl)thiophen-3-yl)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (120 mg, 0.641 mmol) and 2-(thiazol-4-yl)thiophen-3-amine (117 mg, 0.641 mmol) according to protocol A. Retention time (min)=2.147, method [7], MS (ESI) 352.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.99 (s, 1H), 9.63 (s, 1H), 8.59 (d, J=5.9 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.23-8.42 (m, 2H), 8.04-8.08 (m, 2H), 7.90 (dd, J=8.1, 7.2 Hz, 1H), 7.18-7.23 (m, 2H), 4.31 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.FC1C=CC(C2C(COC3N=[N:42][C:41]([C:44](O)=[O:45])=CC=3)=C(C)ON=2)=NC=1.C(CN)O>>[OH:45][CH2:44][CH2:41][NH:42][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23]
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)nn1
Reactant: Cc1onc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Solvent: NCCO
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NCCO)nn1
Yield: 42 %

Procedure:
As described for example 112b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (38 mg, 0.12 mmol) was converted, instead of 6-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid, using ethanolamine instead of 2-amino-2-methyl-1-propanol, to the title compound (18 mg, 42%) which was obtained as a light yellow foam. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:22][S:23](Cl)(=[O:25])=[O:24].O.CCOCC>N1C=CC=CC=1>[CH3:22][S:23]([O:21][CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:25])=[O:24]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(C)(=O)=O
Reaction time: 5 h
Yield: 59 %

Procedure:
Arachidonyl alcohol (0.34 mmol, 100 mg) in dry pyridine (5 ml) was cooled to 0° C. Methane sulfonyl chloride (0.52 mmol; 40 mg) was added to the above solution under a nitrogen atmosphere. The reaction mixture was slowly brought to room temperature at which the reaction was continued for 5 hours. Water (20 ml) and ether (20 ml) were then added to the reaction mixture after which the organic phase was separated, washed with 2N sulfuric acid, then with water and then with a 10% solution of potassium carbonate. The reaction mixture was dried by evaporation of the solvents to obtain an the oily product arachidonyl methane sulfonate, (75 mg; yield 59%) exhibiting the following: 1H HMR (CDCl3) δ 5.34-5.41 (m, 8H), 4.23 (t, J=6.6 Hz, 2H), 3.00 (s, 3H), 2.75-2.84 (m, 6H), 2.04-2.12 (m, 4H), 1.65-1.74 (m, 2H), 1.33-1.50 (m, 2H), 1.25-.130 (m, 6H), 0.89 (t, J=7.2 Hz, 3H). IR (cm−1): 2900, 2850, 1350, 1170, 940.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=1)=[CH2:11]>C(O)C>[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([N:20]=[CH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH3:19])=[CH:14][CH:13]=1)=[CH2:11]
Reactant: Cc1cccc(C=O)n1
Reactant: C=Cc1ccc([C@@H](C)N)cc1
Solvent: CCO
Product: C=Cc1ccc([C@@H](C)N=Cc2cccc(C)n2)cc1

Procedure:
A solution of 1.69 g (13.9 mmol) of 6-methylpyridine-2-carbaldehyde, 2.05 g (13.9 mmol) of (R)-1-(4-vinylphenyl)-ethylamine and 25 ml of ethanol is heated under reflux for 1 hour. The solvent is then distilled off under about 3 kPa, and the residue is distilled in a bulb tube furnace at 170° C. and under 0.11 Pa. 3.3 g (88% of theory) of an oil are obtained, which crystallises at room temperature. Melting point: about 25° C., [α]D20 =21.6° (c=1.036, chloroform). Elemental analysis: Found: C 81.71; H 7.25; N 11.02%; Calculated for C17H18N2 (250.35): C 81.56; H 7.25; N 11.19%.