Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14](B(O)O)=[CH:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:13]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccccc1-c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2cc(-c3ccccc3-c3ccccc3)ccc2c1
Yield: 57.8 %

Procedure:
15 g of 2,6-dibromonaphthalene on the market, 12.5 g of 2-biphenylboronic acid and 1.8 g of tetrakis(triphenylphosphine)palladium were mixed, followed by argon displacement. After adding 250 ml of toluene and 90 ml of 2M sodium carbonate aqueous solution thereto, it was refluxed on heating for 7 hours. After standing to cool, the organic layer was extracted by toluene, and then it was washed by water and saturated salt water. Subsequently the organic layer was dried by using sodium sulfate anhydride, and then the solvent was removed by distillation. The product was refined through a silica gel chromatography and then 10.9 g of 2-(biphenyl-2-yl)-6-bromonaphthalene of white crystal was obtained (yield: 58%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[O:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:7][CH:8]=2)[O:3]1
Reactant: CC1(C)CC(C)(C)c2ccc(Br)cc2O1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2ccc(C#C[Si](C)(C)C)cc2O1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of 2 g (7.4 mmol) of 2,2,4,4 tetramethyl-7-bromochroman (Compound 42) and 3.63 g (37.0 mmol) of trimethylsilylacetylene in 5 ml of triethylamine was placed in a heavy walled glass tube and degassed under nitrogen. The mixture was then treated, under nitrogen, with 130 mg (0.6826 mmol) of cuprous iodide and 260 mg (0.3704 mmol) of bis (triphenyl phosphine) palladium (II) chloride. The reaction mixture was degassed again and placed under nitrogen and the tube was sealed. The mixture was heated to 60 degrees C. for 24 hours and then cooled to room temperature and filtered through celite. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica; 2% ethyl acetate/hexane) to give the title compound as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:22]=[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]2[N:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]3=[N:36][CH:35]=2)=[O:33])[CH:30]=1)[NH2:24]>CN1C(=O)CCC1>[F:1][CH:2]1[CH2:3][CH:4]([C:6]2[O:8][N:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([CH3:43])=[C:29]([NH:31][C:32]([C:34]4[N:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]5=[N:36][CH:35]=4)=[O:33])[CH:30]=3)[N:24]=2)[CH2:5]1
Reactant: O=C(O)C1CC(F)C1
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 3-fluorocyclobutanecarboxylic acid (76 mg, 0.647 mmol) in anhydrous NMP (1.5 mL) was added 1,1′-carbonyldiimidazole (105 mg, 0.647 mmol). The reaction was stirred for 5 minutes. 5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) (100 mg, 0.323 mmol) was added and the reaction was stirred for 25 minutes, then heated in the microwave at 120° C. for 10 minutes. The crude product was purified by reverse phase preparative HPLC to give N-(5-(5-(3-fluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F36). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.53-9.50 (m, 1H), 8.69 (s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.89-7.86 (m, 1H), 7.84 (dd, J=1.6, 8.0 Hz, 1H), 7.70-7.65 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.32-7.29 (m, 1H), 5.48-5.28 (m, 1H), 3.99-3.91 (m, 1H), 2.81-2.73 (m, 4H), 2.37 (s, 3H). MS m/z 392.14 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (331.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R, 3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (320.1 mg; yield: 95.8%). HPLC analysis revealed that the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 8.5:1. The results of elementary analysis were as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])(=[O:10])=[O:9]
Reactant: NCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Product: O=S(=O)(NCCCCO)c1ccc(Br)cc1F

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-2-fluorophenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([OH:22])[C@H:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].CS(Cl)(=O)=O.CCOC(C)=O.S([O-])(=O)(=O)C>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:9]1([C:8]2[O:22][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])[C@H:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1OC(c2ccccc2)=N[C@H]1c1ccccc1
Reaction time: 1.5 h

Procedure:
In a 100 ml flask containing a solution of (2R,3S)-N-benzoyl-3-phenylisoserine ethyl ester (2.00 g, 6.38 mmol) in pyridine (20 ml) at 0° C. was added methanesulfonyl chloride (0.52 ml, 6.70 mmol) dropwise over a 2 minute period. The solution was stirred at 0° to 4° C. for 90 minutes and then at 65°-70° C. for 18 hours. (The reaction was monitored by TLC using 1:2 EtOAc:Toluene as eluent, Rf for the starting material=0.42, Rf for the mesylate=0.48 and Rf for the cis-oxazoline title product=0.78, UV visualization.)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.C(N(CC)CC)C.[Cl-].[NH4+].C[OH:27]>ClCCl>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: C=CCC1(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(CC=O)CC1
Temperature: -72 °C
Yield: 56 %

Procedure:
6.9 g (36.34 mmol, 1 eq., 96% a % by GC) 1-allyl-cyclopropanecarboxylic acid tert-butyl ester were dissolved in 40 ml dichloromethane and 40 ml methanol. The solution was cooled to −72° C. and the ozone was bubbled through the reaction mixture until a blue color was obtained. Then nitrogen was bubbled to remove excess ozone until a colorless solution was obtained. 10 ml (3.68 eq.) dimethyl sulfide and 14 ml (2.76 eq.) triethylamine were added. The reaction mixture was warmed to room temperature and stirred overnight at that temperature (peroxide test negative, pH 7-8). The yellowish reaction mixture was added to 100 ml sat. aq. ammonium chloride solution (exothermic) and extracted 3 times with 70 ml dichloromethane. The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude aldehyde, which was purified by filtration over SiO2 (dichloromethane; TLC: ethyl acetate/heptane 1:2) to provide 3.90 g (96% GC, 56% yield) of the title compound as an oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:24]=2)[C:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>FC(F)(F)S(O)(=O)=O>[CH2:1]([C:8]1[CH:9]=[C:10]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=2)[C:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccccc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(Cc3ccccc3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
A mixture of 4-(5-benzyl-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 0.172 mmol) in TFA (265 μL, 3.44 mmol) was treated with a couple of drops of trifluoromethanesulfonic acid (15.27 μL, 0.172 mmol) and the mixture was heated at 80° C. overnight. After cooling, the mixture was concentrated and the residue was dissolved in 5% MeOH/DCM and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (pure DCM to 3% MeOH in DCM w/NH3) to give 4-(5-benzyl-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (15 mg, 0.038 mmol, 21.84% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.68 (s, 1H); 8.61 (d, J=2.15 Hz, 1H); 8.53 (d, J=2.54 Hz, 1H); 8.23 (d, J=2.15 Hz, 1H); 8.16 (dd, J=8.80, 2.74 Hz, 1H); 7.83 (br. s., 1H); 7.69 (br. s., 1H); 7.11-7.45 (m, 5H); 6.81 (d, J=8.80 Hz, 1H); 3.94 (s, 2H); 3.84 (s, 3H). m/z (ESI, +ve ion) 400.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:33]1[CH:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[CH:30]=[CH:29][C:28]=1[O:27][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
A stirred suspension of (4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one (63 mg, 0.137 mmol), 2-methoxy-5-isopropylphenyl boronic acid (52 mg, 0.274 mmol), K2CO3 (47 mg, 0.34 mmol) and Pd(OAc)2 (9.2 mg, 0.0137 mmol) in acetone:H2O (5:1) (6 mL) was heated at reflux for 1 h. The reaction mixture was concentrated in vacuo, diluted with H2O (15 mL) and extracted with EtOAC (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by silica-gel flash chromatography (0-20% EtOAc in hexanes gradient) to (4S)-4-benzyl-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. Rf=0.35 (15% EtOAc/hexanes). LCMS 484 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present; doubling of some peaks observed in 1H NMR) δ 7.72 (br s 1H), 7.65 (br s, 1H), 7.42 (m, 1H), 7.32-7.22 (m, 3H), 7.08 (d, J=2.3 Hz, 1H), 6.90-6.84 (m, 3H), 4.80 (d, J=15.8 Hz, 1H), 4.35 (d, J=15.8 Hz), 4.28 (t, J=8.7 Hz, 1H), 3.96-3.92 (m, 3H), 3.78 (s, 3H), 3.62-3.52 (m, 1H), 2.94-2.86 (m, 1H), 2.82 (dd, J=9.4, 3.9 Hz, 1H), 2.42 (dd, J=9.6, 3.9 Hz), 1.26 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>O>[C:22]([NH:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 60 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
To a solution containing 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-diemthylformamide, 0.20 g of acetyl chloride was added and the mixture was stirred at 60° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to obtain 0.25 g of 3-acetylamino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[N:17][C:16]=2[NH:22][NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](O)=O.CC(OC(C)=O)=O>C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:24]([CH3:25])=[N:23][N:22]=3)[N:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nnc2NN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(6-Chloro-3-hydrazino-pyridazin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (5.33 g; 15.55 mmol) was treated with 20.0 ml AcOH and then with Ac2O (18.80 ml; 198.89 mmol). It was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with half saturated NaHCO3 solution and extracted with DCM. The organic layer was dried over MgSO4 and purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [O:1]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/I)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li:22])CCC>CCCCCC>[O:1]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/[Li:22])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: [Li]CCCC
Reactant: CCCCCC(/C=C/I)O[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
On the other hand, 736 mg (2 mmol) of 3-t-butyldimethylsiloxy-1-iodo-trans-1-octene was added to 2 ml. of anhydrous hexane, and 1.4 ml. (2 mmol) of a 1.4 M hexane solution of n-butyllithium was added. The mixture was stirred at -78° C for 30 minutes in an atmosphere of nitrogen to afford an anhydrous hexane solution of 3-t-butyldimethylsiloxy-1-lithio-trans-1-octene. The resulting solution was added dropwise to the anhydrous diethyl ether solution of copper pentylide obtained previously, and the mixture was stirred at -78° C for 30 minutes to afford a solution of an organic copper lithium compound of the following formula ##STR19##
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:10]([NH:12][C@@H:13]1[C:16](=[O:17])[N:15]2[C:18]([C:27]([OH:29])=[O:28])=[C:19]([CH2:22][O:23][C:24]([NH2:26])=[O:25])[CH2:20][S:21][C@H:14]12)=[O:11])/[C:5]1[O:9][CH:8]=[CH:7][CH:6]=1.[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].OS(O)(=O)=O.C(OC(C)C)(C)C>C(N)CCC.CC(N(C)C)=O.C([O-])(O)=O.[Na+].O>[CH3:35][CH:34]([O:28][C:27]([C:18]1[N:15]2[C:16]([C@@H:13]([NH:12][C:10](/[C:4](/[C:5]3[O:9][CH:8]=[CH:7][CH:6]=3)=[N:3]\[O:2][CH3:1])=[O:11])[C@H:14]2[S:21][CH2:20][C:19]=1[CH2:22][O:23][C:24]([NH2:26])=[O:25])=[O:17])=[O:29])[O:33][C:30]([CH3:31])=[O:32]
Reactant: CC(=O)OCCBr
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Solvent: CCCCN
Solvent: CC(=O)N(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.5 h

Procedure:
11.14 g of cefuroxime in the form of a salt with n-butylamine are dissolved at ca. 3° to 5° in 28 ml of dimethyl acetamide. A solution of 7.48 g of acetoxyethyl bromide in 21 ml of dimethyl acetamide is added to the solution obtained, and 1.76 g of K2CO3 are added in portions over the course of ca. 120 minutes. The resulting mixture is stirred for ca. 30 minutes, diluted with 100 ml of EtAc and aqueous 3% NaHCO3 solution is added. Two phases are formed and are separated and the organic phase is washed with 1 n HCl and 20% aqueous NaCl solution, which contains 2% NaHCO3. The organic phase obtained is mixed with 11 ml of dimethyl acetamide and 28 ml of H2O, and the pH of the mixture obtained is adjusted to ca. 4 by addition of H2SO4. The two phases formed are separated and the organic phase is mixed with activated carbon, which is filtrated off. From the filtrate obtained solvent is evaporated off and the evaporation residue obtained is mixed with seed crystals. The suspension obtained is mixed with 125 ml of diisopropyl ether and stirred at room temperature. Crystalline cefuroxime axetil is obtained, filtrated off, washed with a mixture of EtAc and diisopropyl ether and dried. Yield: 7.43 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:13][C:7]([F:12])([C:8]([F:9])([F:10])[F:11])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([N:1]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C=Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Temperature: -5 °C

Procedure:
Sixty-three and one half grams of m-amino pentafluoropropionanilide is dissolved in 150 ml of tetrahydrofuran containing 65 g. of triethylamine. This mixture is added dropwise with cooling to 37 g. of phosgene dissolved in 150 ml of tetrahydrofuran cooled to -5° C. When addition is complete the mixture is allowed to warm up to room temperature. The triethylamine hydrochloride is filtered off and the solvent is removed under vacuum. The product, 70 g., was not isolated but diluted to 140 ml with tetrahydrofuran and used in subsequent reactions.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27]>O>[CH2:1]([O:8][C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Benzyl alcohol (0.93 mL, 9 mmol) and potassium carbonate (1.24 g, 9 mmol) were added to a N,N-dimethyl formamide solution (5 mL) of 5-fluoro-N-methyl-2-nitroaniline (510 mg, 3 mmol). The mixture was stirred at 60-70° C. for 8 hours. The reaction solution was cooled, then water was added thereto, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 680 mg of orange, powdery 5-benzyloxy-N-methyl-2-nitroaniline (yield: 88%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][NH:17][CH3:18]>Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]([CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])[CH3:18])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CNCCCN(C)C
Agent: Cl
Product: CN(C)CCCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 2,5-dichloronitrobenzene (3.0 g, 16 mmol) was added N1,N1,N3-trimethylpropane-1,3-diamine (2.2 g, 19 mmol). The mixture was stirred for 2.5 days at RT, diluted with 0.01 N HCl and extracted with EtOAc. The aqueous layer was made basic with Na2CO3 and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to yield 4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine as an orange oil. MS m/z=272 [M+H]+. Calc'd for C12H18ClN3O2: 271.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:21]([OH:23])=[O:22])[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:9][N:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:6]=2[CH:30]=1.[N+](=[CH2:33])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:21]([O:23][CH3:33])=[O:22])[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:9][N:8]=[C:7]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:6]=2[CH:30]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CN1CCCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: COC(=O)C(CN1CCCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-chloro-2-[(1-carboxy-2-pyrrolidinoethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-2-pyrrolidinoethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([C:29]([OH:31])=[O:30])[NH:11][C:12]([O:14][CH2:15][CH:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])=O)(C)(C)C.[ClH:32]>C(Cl)Cl>[ClH:32].[NH2:8][CH2:9][C@@H:10]([C:29]([OH:31])=[O:30])[NH:11][C:12]([O:14][CH2:15][CH:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13]
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[(tert-butoxycarbonyl)amino]-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-alanine (1.0 g, 2.35 mmol) in CH2Cl2 (11.72 mL) was added HCl (4.0 M in dioxane, 11.72 mL, 46.9 mmol). After stirring for 16 hours, the reaction mixture was concentrated to give the title product, which was used without further purification. LC-MS Method A: m/e=327.19 [M+1]; Rt=1.73 min.