Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
To an ice cold solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1 g, 4.04 mmol) and cesium carbonate (1.45 g, 4.45 mmol) in DMF (10 ml) under an argon atmosphere was added bromo-acetic acid ethyl ester (490 μl, 4.45 mmol). The mixture was naturally warmed to room temperature, stirred for 14 h, poured onto 1 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 1.2 g (3.6 mmol, 89%) of the title compound as yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)C.[CH2:18]([O:24][C:25]1[CH:26]=[C:27]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:40]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:39]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl.[Fe](Cl)Cl>[OH:4][C:5]1[C:6]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][C:8]2[C:43]3[C:38](=[CH:39][C:40]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:42]=3)[C:27]3[C:28](=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:25]([O:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:26]=3)[C:9]=2[CH:10]=1
Reactant: CCCCCCOc1ccccc1OC(C)=O
Reactant: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Agent: Cl[Fe]Cl
Solvent: ClCCl
Product: CCCCCCOc1cc2c(cc1O)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Reaction time: 5 h
Yield: 66.9 %

Procedure:
Anhydrous iron chloride (4.7 g, 28.9 mmol) was added to a stirred mixture of 2-acetoxy-1-hexyloxybenzene (3.4 g, 14.4 mmol) and 3,3′,4,4′-tetrahexyloxybiphenyl (4.0 g, 7.2 mmol) in dichloromethane. The mixture was stirred for 5 h and poured onto methanol (300 ml). The resultant precipitate was filtered off and saponified with potassium carbonate in ethanol (5% water) under reflux for over night. After cooling, water (50 ml) was added and the product was extracted with dichloromethane, dried (MgSO4), concentrated and purified by column chromatography on silica gel using dichloromethane and petroleum spirit (1:1) as eluent and then recrystallised from ethanol to yield a white solid (3.59 g, 67%). Found: C, 77.30; H, 9.85. C48H72O6 requires C, 77.38; H, 9.74. δH (CHCl3) 7.96 (s, 1H, ArH), 7.83-7.82 (m, 4H, ArH), 7.77 (s, 1H, ArH), 5.92 (1H, s, OH), 4.31-4.18 (m, 10H, OCH2), 1.99-1.92 (m, 10H, CH2), 1.58-1.55 (m, 10H, CH2), 1.46-1.38 (m, 20H, CH2), 0.97-0.83 (15H, m, CH3).
Reaction SMILES: Br[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.S[C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Br
Reactant: Sc1nc2ccccc2o1
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1-c1nc2ccccc2o1

Procedure:
The title compound was prepared from 2-bromo-6,7-dichloro-3-trifluoromethylquinoxaline and 2-mercaptobenzoxazole in analogy with the method outlined in example 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>CCOC(C)=O>[ClH:22].[CH3:21][C:17]1[CH:16]=[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(C2(O)CCNCC2)c1

Procedure:
To a solution of N-t-butoxycarbonyl-4-(3-methylphenyl)-4-hydroxy piperidine (0.546 mg, 1.87 mmol) in EtOAc (30 ml) at 0° C. was bubbled gasseous HCl until saturated. After 10 min the solvent was evaporated in vacuo to afford the title compound of sufficient purity to be used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][C:15](=[O:16])[CH2:14][O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:16]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(N)cc(C(=O)O)c1
Solvent: c1ccncc1
Product: COCC(=O)Nc1cc(NC(=O)COC)cc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a solution of 3,5-diaminobenzoic acid (6.1 g) in pyridine (80 ml) is added dropwise methoxyacetyl chloride (8.0 ml) at room temperature, and the mixture is stirred for 2 hours as it stands. From the reaction mixture, pyridine is distilled off under reduced pressure. To the residue is added 1N hydrochloric acid, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (8.0 g) having the following physical properties.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[C:31]2[CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[N:25]([CH3:33])[N:24]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[C:31]2[CH:30]3[CH2:32][CH:27]([CH2:28][CH2:29]3)[C:26]=2[N:25]([CH3:33])[N:24]=1)=[O:19]
Reactant: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c2c1C1CCC2C1
Agent: [Pd]
Solvent: CO
Product: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)c2c1C1CCC2C1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N-[(1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-ylmethoxy]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 150 (0.34 g, 0.75 mmol) and Pd/C (0.12 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to give 151 (0.27 g, quantitative yield) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH:37]5[CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: NC1CC1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (40 mg, 17%).
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[N:12]=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:8]=2[CH2:7][C:6]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:5]1)[CH:2]=[CH2:3].[H][H]>CCO.[Pd]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]2[CH2:7][C:6]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[C:13]=2[N:12]=1
Reactant: [H][H]
Reactant: C=CCC1CC2(Cc3ccc(OC)nc31)OCCO2
Agent: [Pd]
Solvent: CCO
Product: CCCC1CC2(Cc3ccc(OC)nc31)OCCO2
Yield: 97.8 %

Procedure:
A solution of 4a (1.04 g, 4 mmol) in 100 mL of EtOH was hydrogenated at 60 psi hydrogen pressure (Parr shaker) over 200 mg of 5% Pd/C for 5 h. Filtration, concentration, and flash chromatography of the residue (30% ethyl acetate in hexanes) gave 1.03 g (98%) of 4d: IR (neat) 2955, 1599, 1477, 1084, 1031 cm-1 ; 1H NMR δ7.20 (d, 1H, J=8.3 Hz), 6.50 (d, 1H, J=8.3 Hz), 4.01 (m, 4H), 3.89 (s, 3H), 2.98 (m, 2H), 2.78 (dd, 1H, J=16.0, 2.4 Hz), 2.01 (m, 2H), 1.67 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H, J=7.2 Hz); 13C NMR δ162.0, 155.7, 139.6, 121.3, 107.9, 107.7, 64.4, 53.0, 39.5, 38.0, 37.2, 35.9, 19.9, 14.3; MS m/z 263 (M+).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([NH:10][C:11]([NH:13][C:14]2[N:15]=[C:16]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]3=[N:18][CH:19]=2)=[O:12])[CH2:4]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([NH:10][C:11]([NH:13][C:14]2[N:15]=[C:16]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]3=[N:18][CH:19]=2)=[O:12])[CH2:4]1)(=[O:34])=[O:33]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCNC3)cnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCN(S(C)(=O)=O)C3)cnc21

Procedure:
Racemic 1-(1-methanesulfonyl-azepan-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from racemic 1-azepan-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and methanesulfonyl chloride.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:44]([O:46][C:47](=[O:61])[C@H:48]([OH:60])[CH2:49][C@H:50]([NH2:59])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][CH:53]=1)[CH3:45]>CN(C=O)C>[CH2:44]([O:46][C:47](=[O:61])[C@H:48]([OH:60])[CH2:49][C@H:50]([NH:59][C:7]([C:5]1[N:4]=[N:3][N:2]([OH:1])[CH:6]=1)=[O:9])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([Br:58])=[CH:56][CH:57]=1)[CH3:45]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(Br)cc1
Reactant: O=C(O)c1cn(O)nn1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
1-Hydroxy-1H-1,2,3-triazole-4-carboxylic acid (163 mg, 1.3 mmol),), HCTU (523 mg, 1.3 mmol), and DMF were combined and stirred for 5 minutes at room temperature. DIPEA (661 μL, 3.8 mmol) and (2R,4R)-4-amino-5-(4-bromophenyl)-2-hydroxypentanoic acid ethyl ester (4 mg, 1.3 mmol) were added and the resulting mixture was stirred for 10 minutes. The reaction mixture was evaporated under reduced pressure and purified (C18 column; 20-70% MeCN in water with 0.05% TFA) to yield the title compound (330 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[Na].ClCCl.C1(C)C=CC=CC=1>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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:14]([O:13][C:11]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:21]3[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]3)=[CH:3][CH:4]=2)[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)OC(C)(C)C)CC3)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg, 0.001000 mol), tert-butyl piperazine-1-carboxylate (186.2 mg, 0.001000 mol), sodium text-pentoxide (110.1 mg, 0.001000 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (24.5 mg, 0.0000300 mol) and 1,1′bis(diphenylphosphino)ferrocene (16.6 mg, 0.0000300 mol) was deaerated and then charged with nitrogen. To the mixture was added toluene (3.0 mL, 0.028 mol), and the resulting mixture was heated at 100° C. overnight. The mixture was poured into ice-water and was extracted with ethyl acetate (4×10 mL). The combined organic layer was washed with water and brine successively, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash with ethyl acetate/hexane.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:25])[CH2:6][C:7]1[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([C:13](=[O:18])[NH:14][CH2:15][CH2:16][CH3:17])[CH:12]=1.CO.O>O>[CH2:15]([NH:14][C:13]([C:11]1[CH:12]=[C:7]([CH2:6][C:5]([OH:25])=[O:4])[CH:8]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1)=[O:18])[CH2:16][CH3:17]
Reactant: CCCNC(=O)c1cc(CC(=O)OC)cc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCNC(=O)c1cc(CC(=O)O)cc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of LiOH (800 μL of a 2 M solution in H2O) was added to a solution of 68G (50 mg, 0.16 mmol) in 4 mL of a 3:1 mixture MeOH/H2O. After 1 hour, the reaction was complete as shown by TLC. The reaction mixture was then concentrated and the residue was dissolved in water and HCl 10% was then added. As no product precipitated, the aqueous solution was extracted 3 times with AcOEt. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. A white foamy solid was obtained and used in the next step without further purification (47 mg, quantitative). NMR 1H (ppm, DMSO-d6): 7.86 (s, 1H), 7.61-7.60 (m, 3H), 7.57 (s, 1H), 7.46-7.33 (m, 3H), 6.16 (br, s, 1H), 3.72 (s, 2H), 3.70 (s, 3H), 3.46-3.39 (m, 2H), 1.64 (sext., J3=7.43 Hz, 2H), 0.98 (t., J3=7.50 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH2:3]1.[C:15]([SiH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.CO>CN(C)C=O>[Si:19]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH2:3]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1coc(N2CC(O)C2)n1
Reactant: CC(C)(C)[SiH](c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1coc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-hydroxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (2.64 g, 13.4 mmol) (obtained as described in Reference Example 70(7)) in dimethylformamide (80 ml) were added t-butyldiphenylsilane (6.97 ml, 26.8 mmol) and imidazole (1.82 g, 26.8 mmol) in an ice bath and the mixture was stirred in an ice bath overnight. After checking the completion of the reaction, methanol was added to the reaction mixture and the mixture was stirred for 30 minutes. The resulting mixture was partitioned between ethyl acetate and 1 0% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:3→3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-methoxycarbonyl-1,3-oxazol-2-yl)azetidine (4.95 g, yield 85%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[C:14]2=[O:39])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>FC(F)(F)C(O)=O.ClCCl>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:31][C:32]([OH:34])=[O:33])[C:14]2=[O:39])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate (300 mg) was dissolved in a 20% trifluoroacetic acid/dichloromethane solution (2 mL), and the solution was stirred at room temperature overnight. After a 1N aqueous hydrogen chloride solution was added, the solution was extracted three times using chloroform (50 mL). The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further, recrystallization from IPE afforded 231 mg of white crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:28]([NH:30][C:31]1[S:32][C:33]([Br:43])=[C:34]([C:36](=[N:40][O:41][CH3:42])[C:37](O)=[O:38])[N:35]=1)=[O:29]>C(OCC)(=O)C.CN(C)C=O>[CH:28]([NH:30][C:31]1[S:32][C:33]([Br:43])=[C:34]([C:36](=[N:40][O:41][CH3:42])[C:37]([NH:1][CH:2]2[C:13](=[O:14])[N:4]3[C:5]([C:10]([OH:12])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]23)=[O:38])[N:35]=1)=[O:29]
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1nc(NC=O)sc1Br
Yield: 78.6 %

Procedure:
A solution of 7-amino-2-methyl-3-cephem-4-carboxylic acid (1.0 g.) and trimethylsilylacetamide (3.7 g.) in dry ethyl acetate (30 ml.) and a solution of dimethylformamide (0.47 ml.), phosphoryl chloride (0.56 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.6 g.) in dry ethyl acetate (11.6 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer, 1.85 g.).
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[O:8][CH3:9].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[CH2:10][N:7]([O:8][CH3:9])[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(Cl)c(Cl)c1)OC
Agent: C=O
Agent: CN
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 49 %

Procedure:
3-[(3,4-Dichlorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 47-C) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12, yielding the title compound as a white solid (49% yield); mp 149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.82 (2H, s, NCH2), 7.18 (1H, dd, J=2.0 Hz, J=8.2 Hz, aromatic), 7.42 (1H, d, J=8.2 Hz, aromatic), 7.43 (1H, d, J=2.0 Hz, aromatic). Anal. calcd for C14H14Cl2N2O4: C, 48.72; H, 4.09; N, 8.12. Found: C, 48.81; H, 4.04; N, 7.99.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:23]([C:26]2[S:27][C:28](Br)=[CH:29][CH:30]=2)(=[O:25])=[O:24])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].C(O)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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:23]([C:26]2[S:27][C:28]([C:36]3[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=3)=[CH:29][CH:30]=2)(=[O:25])=[O:24])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C1(NS(=O)(=O)c2ccc(Br)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)C1(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Temperature: 60 °C

Procedure:
A solution of the bromo intermediate D6 (0.2 g, 0.00037 moles), 4-chlorophenylboronic acid (0.070 g, 0.00045 moles), K2CO3 (2M solution, 1 ml), ethanol (1 ml) and toluene (2 ml) at room temperature was degassed by bubbling argon through the solution for 10 minutes. Pd(PPh3)4 (0.1 g, 0.000086 moles) was added and the mixture heated at 60° C. under argon for 24 hours. Upon cooling the mixture was partitioned between water and ethyl acetate. The aqueous phase was re-extracted with ethyl acetate (×3) and the combined organic phase washed with water, brine then dried over anhydrous MgSO4. The solution was evaporated to dryness then purified by chromatography over silica eluting, with hexane up to 50% EtOAc/hexane, affording the title compound D8 as a off white foam, which was used directly in the next step. M-H 563.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1F
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 9.45 g (50 mmol) of 5-bromo-2-fluorotoluene in 30 ml of carbon tetrachloride were added 9.08 g (50 mmol) of N-bromosuccinimide and 0.26 g (1 mmol) of 1,1′-azobis(cyclohexane-1-carbonitrile) and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to obtain 13.54 g of crude 5-bromo-2-fluorobenzylbromide as liquid.