Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:18][C:19]2[CH:20]=[C:21]([NH:26][C:27]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[N:35]=[CH:34][CH:33]=[CH:32]4)=[O:28])[CH:22]=[CH:23][C:24]=2[CH3:25])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1N
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1ccc(OCc2ccccc2)cc1
Yield: 50 %

Procedure:
Using analogous procedures to those described in the last two paragraphs of the portion of Example 7 which is concerned with the preparation of starting materials, 4-benzyloxybenzoic acid was reacted with N-(3-amino-4-methylphenyl)quinoline-6-carboxamide to give N-[3-(4-benzyloxybenzamido)-4-methylphenyl]quinoline-6-carboxamide in 50% yield, m.p. 227-228° C.; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 5.2 (s, 2H), 7.12 (d, 2H), 7.25 (d, 1H), 7.39 (m, 5H), 7.61 (m, 2H), 7.86 (d, 1H), 8.52 (d, 1H), 8.62 (d, 1H), 8.99 (m, 1H), 9.76 (s, 1H), 10.47 (s, 1H); and that compound was hydrogenolysed to give the required starting material in 93% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 6.83 (d, 2H), 7.23 (d, 1H), 7.61 (m, 2H), 7.85 (m, 3H), 8.12 (d, 1H), 8.25 (d, 1H), 8.52 (d, 1H), 8.62 (s, 1H), 8.99 (d, 1H), 9.61 (s, 1H), 10.46 (s, 1H); Mass Spectrum: M−H− 396.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:14][N:15]=[C:16]=[S:17]>ClCCl>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:16]([NH:15][CH3:14])=[S:17])[CH2:9][CH2:10]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)Nc1ccccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 4-(2-aminophenyl)morpholine (5.3 g) in dichloromethane (25 ml) was treated with methyl isothiocyanate (3.2 g) and the mixture stirred at room temperature for 36 hours to yield 1-(2-morpholino phenyl)-3-methylthiourea (m.p. 115°-116° C.) which was recrystallised from a 4:1 mixture of ethyl acetate and hexane.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([CH3:6])([OH:5])[CH3:4].[C:9](=O)([O:17]C1C=CC=CN=1)[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[F:1][C:2]([F:8])([F:7])[C:3]([O:5][C:9](=[O:17])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:6])[CH3:4]
Reactant: CC(C)(O)C(F)(F)F
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Solvent: C1CCOC1
Product: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of KH (1.03 g, 25.8 mmol) in THF (70 mL) was added 1,1,1-trifluoro-2-methylpropan-2-ol (3 g, 23.42 mmol). The reaction was stirred at 0° C. for 20 min. A solution of dipyridin-2-yl carbonate (5.06 g, 23.42 mmol) in THF (30 mL) was then added to the mixture. The mixture was stirred at rt for overnight. A lot of solid came out from the solution. The solid was filtered and washed with EtOAc (30 mL). The combined THF/EtOAc solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The obtained white solid (1.24 g, 21%) was directly used for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:26]=[CH2:27])=[C:4]([CH:9]=[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.O.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[C:3]([CH:26]=[CH2:27])=[C:4]([CH:9]=[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Temperature: 20 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of methyl 3-chloro-2-ethenyl-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.10 g) in THF (3.00 mL)-water (3.00 mL) and methanol (0.50 mL) was added lithium hydroxide monohydrate (0.10 g), and the mixture was stirred at 20° C. for 16 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.08 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][C:21]=2[CH2:22][CH3:23])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:30][C:31]([F:45])([F:44])[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:43])[CH2:39][C:40](=O)[CH3:41])=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.COC(OC)OC.C(Cl)Cl>[CH2:22]([C:21]1[O:20][C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:18][C:17]=1[CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:2]([NH:1]/[C:40](/[CH3:41])=[CH:39]\[C:38](=[O:43])[C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:30])([F:44])[F:45])=[CH:33][CH:34]=2)[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)[CH3:23]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CCc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N/C(C)=C\C(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 57 mg (0.14 mmol) of Intermediate 60, 33 mg (0.14 mmol) of Intermediate 24, and 0.042 mL triethylamine in MeOH (1.5 mL) and trimethylorthoformate (0.5 mL) to yield 24 mg (28% yield) of Example 67 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH, 4/1): Rf=0.62; 1H NMR (DMSO-d6, 300 MHz) δ11.53 (d,1H, J=9.0), 7.97 (d, 2H, J=8.4), 7.89 (d, 2H, J=7.8), 7.73 (d, 2H, J=8.4), 7.46 (m, 3H), 7.97 (d, 2H, J=8.1), 6.79 (d, 2H, J=8.4), 5.62 (s, 1H), 4.25-4.19 (m, 1H), 3.90 (t, 2H, J=6.0), 3.21-3.15 (m, 1H), 2.58-2.83 (m, 5H), 1.98 (t, 2H, J=5.7), 1.72 (s, 3H), 1.11 (t, 3H, J=7.5); low resolution MS (ES+)m/e 607.18 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Preparation Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[F:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17]C(O)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:1]([O:5][CH2:4][CH2:3][OH:2])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C1OCCO1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: OCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
6.8 g of ethylene carbonate and 2.3 g of tetrabutylammonium bromide are added to a solution of 13.8 g of p-(p-fluorophenoxy)phenol in 35 ml of dimethylformamide. After 4 hours at reflux there are added an additional 1.2 g of ethylene carbonate, and the mixture is heated at reflux for an additional 2 hours. The cooled mixture is poured into 150 ml of ice/water and extracted three times with 100 ml of ethyl acetate each time. The extracts are washed twice with 100 ml of saturated sodium chloride solution each time, dried and evaporated. The residue is purified by recrystallization from n-hexane/ethyl acetate to yield pure 2-[p-(p-fluorophenoxy)-phenoxy]-ethanol, m.p. 74°-76° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][C:21]([CH2:24][OH:25])([OH:23])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C)C=O>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][C:21]([CH2:24][OH:25])([OH:23])[CH2:22]3)=[N:17][C:18]=2[I:1])[CH:13]=[CH:14][N:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OCC1(O)CC(c2ncc3c(Cl)nccn23)C1
Solvent: CN(C)C=O
Product: OCC1(O)CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C

Procedure:
Under inert atmosphere N-iodosuccinimide (3.6 g, 0.016 mol) and 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol (3.16 g, 0.012 mol) were dissolved in N,N-dimethylformamide (30 mL) and heated at 60° C. for 3.0 h. The reaction mixture was then concentrated in vacuo to a dark oil and purified by HPFC Jones 20 g silica gel column, eluting with 5% MeOH: CH2Cl2 to yield a light brown fluffy solid which was triturated with diethyl ether and hexanes to afford the title compound; MS (ES+): m/z 379.85 and 381.80 [MH+]; HPLC: tR=2.30 min. (OpenLynx, polar—5 min).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[C:19]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:20]=1)[CH3:10]
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCCCC(=O)c1cc(CCC(=O)OCC)ccc1OC
Temperature: 50 °C

Procedure:
98 ml (0.7 mol) of hexanoyl chloride are added dropwise to a solution of 70 g (0.336 mol) of ethyl3-(4-methoxyphenyl)propanoate in 280 ml of dichloromethane. 89 g (0.67 mol) of aluminium chloride are then added in small amounts, and the mixture is heated for one hour at 50° C. The mixture is poured into cold water and extracted with ether. The organic phase is washed with sodium bicarbonate solution. After drying (Na2SO4) and evaporating off the solvents, a yellow liquid is obtained, and then distilled: Bp0.4 mmHg=160° C. (74 g; 72%);
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][NH:25]C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O-])(O)=O.[Na+]>ClCCl.FC(F)(F)C(O)=O>[C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][NH2:25])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C
Yield: 93.7 %

Procedure:
A solution of 8.7 g (19.22 mmol) of (13.10) in 180 ml of trifluoroacetic acid dichloromethane=1/1 is added, after 1 min, to 1.5 ml of an ice-cold solution of NaHCO3. The solution is extracted 3 times with dichloromethane and the dichloromethane phase is then dried over sodium sulfate. 6.35 g (94%) of (13.11) are obtained as a colorless solid after filtering and removing the solvent in vacuo.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.Cl.[CH3:10][O:11][C:12](=[O:21])[CH:13]([N:18]=[N+]=[N-])[CH2:14][CH2:15][CH2:16][CH3:17]>C(OCC)(=O)C.[Re]([O-])(=O)(=O)=O.[Na+]>[CH3:10][O:11][C:12](=[O:21])[C:13]([N:18]=[C:2]=[O:1])=[CH:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC(N=[N+]=[N-])C(=O)OC
Agent: O=[Re](=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC=C(N=C=O)C(=O)OC
Reaction time: 1 h

Procedure:
27.3 mg (0.1 mmole) of sodium perrhenate and 1.04 grams (5.25 mmoles) of diphosgene were present at 80° C. in 1 ml of ethyl acetate saturated with hydrogen chloride. Then there were added within 20 minutes with vigorous stirring 1.71 grams (10 mmoles) of 2-azidohexanoic acid methyl ester dissolved in 5 ml of ethyl acetate. The reaction was ended after 1 hour uniform development of gas. The reaction mixture was then filtered with suction over a vacuum frit and the ethyl acetate distilled off under reduced pressure. The crude product thus obtained was distilled in a high vacuum (0.0013 mbar) at 50° to 55° C. apparatus temperature in a bulbed tube. There resulted 1.35 grams (79.8% of theory) of analytically pure 2-isocyanato-2-hexenoic acid methyl ester as a colorless, readily mobile liquid:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1.[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.C(O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:17]([NH2:18])=[O:16])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:5]=2[CH:6]=1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 80 °C
Yield: 80.2 %

Procedure:
30 g iminostilbene are heated to 60° C. in 360 ml acetic acid and 50 ml ethanol, and 20 g 98% sodium cyanate is added within 1.5 hours at this temperature. After a short heating to 80° C., the mixture is further stirred at 60° C., and then cooled to 15° C., sucked off, washed with 20 l acetic acid and dried to yield 29.4 g (80.3% of theoretical) of carbamazepine, having a melting point of 189° C. to 192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:6](C=O)=[CH:5][C:4]=1[CH3:14].[OH:15]O>CO.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([OH:15])=[CH:5][C:4]=1[CH3:14]
Reactant: COc1c(C)cc(C=O)c2c1CCC2
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CO
Product: COc1c(C)cc(O)c2c1CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
The stirred solution of 7-methoxy-6-methyl-indan-4-carbaldehyde (1.0 gm, 0.0060 mole) in Methanol (20 ml), Sulphuric acid (0.6 ml) was added at room temperature. To the reaction mixture, 30% Hydrogen peroxide (1.6 ml) was added and stirred for 1 hour at 0° C. Methanol was distilled under vacuum and the residue was dissolved in Ethylacetate (50 ml), further ethyl acetate layer was washed with water and evaporated to give a crude product, which upon triturating with Hexane give 600 mg title compound as a solid.
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F.CCOCC>C(Cl)Cl>[S:30]1[CH2:29][CH2:28][CH2:27][S:31][CH:1]1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C1SCCCS1
Yield: 72.1 %

Procedure:
In 20 ml of anhydrous methylene chloride was dissolved 1.0 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 300 mg of 1,3-propanedithiol and 0.8 ml of boron trifluoride ethyl etherate were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 900 mg of the titled compound as a colorless crystal.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8]2[C:9]([OH:15])=[N:10][CH:11]=[N:12][C:13]=2[CH:14]=1.[C:17]([O:23][CH2:24]Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C=O>[C:17]([O:23][CH2:24][N:10]1[C:9](=[O:15])[C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][C:7]=2[OH:16])[N:12]=[CH:11]1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(O)c2c(O)ncnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
Sodium hydride (60 mg, 1.49 mmol) was added portionwise over 5 minutes to 7-methoxyquinazoline-4,5-diol (260 mg, 1.35 mmol) in dimethylformamide (2 ml) at 0° C. Chloromethyl pivalate (200 μl, 1.36 mmol) was added dropwise over 15 minutes to give a clear orange solution. The reaction mixture was allowed to warm to ambient temperature and stirred for a further 18 hours. Incomplete reaction was seen by tlc, therefore the reaction was cooled to 0° C. and sodium hydride (10 mg, 0.25 mmol) was added followed by chloromethyl pivalate (26 μl, 6.18 mmol). The reaction was complete after stirring for 1 hour at ambient temperature. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel, eluting with 2-10% methanol in dichloromethane, to yield (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (170 mg, 41% yield) as a cream solid:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[CH2:20][CH2:19]4)=[C:14]([CH3:28])[CH:13]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[C:45]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)=[O:46]>>[CH3:27][O:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[O:9][C:10]4[C:2]([C:34]5[CH:33]=[CH:32][C:31]([C:45]([N:47]6[CH2:48][CH2:49][O:50][CH2:51][CH2:52]6)=[O:46])=[C:30]([CH3:29])[CH:35]=5)=[CH:3][CH:4]=[CH:5][C:6]=4[N:7]=3)=[CH:13][C:14]=2[CH3:28])[CH2:19][CH2:20]1
Reactant: COCCN1CCN(c2ccc(Nc3nc4cccc(Br)c4o3)cc2C)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)N1CCOCC1
Product: COCCN1CCN(c2ccc(Nc3nc4cccc(-c5ccc(C(=O)N6CCOCC6)c(C)c5)c4o3)cc2C)CC1

Procedure:
The title compound is prepared from (7-bromo-benzooxazol-2-yl)-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-3-methyl-phenyl}-amine and [2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-phenyl]-morpholin-4-yl-methanone using methodology described in the preparation of example 65. The title compound is obtained as an off-white foam. Rt=2.00 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 570 (M+1)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1.[Cl:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[ClH:27].[ClH:1].[N:29]1[CH:30]=[CH:31][CH:32]=[N:33][C:28]=1[NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:16][C@H:15]3[C:17]4[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[CH:21][C:22]=4[O:23][CH2:24][C@@H:14]3[CH2:13]2)[CH2:6][CH2:5]1
Reactant: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](N)CC3)C[C@H]1CO2
Reactant: Clc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4ncccn4)CC3)C[C@H]1CO2

Procedure:
A suspension of 0.715 g of the compound of Example 1 (2.2 mmol), 0.303 mg of 2-chloropyrimidine and 0.47 g of sodium carbonate in 45 ml of ethanol is heated at reflux for 72 hours. After filtering, the solvents are then evaporated off After extraction with ethyl acetate and drying (MgSO4), evaporation yields an oil which is purified by chromatography on a silica column using a mixture of dichloromethane/methanol/ammonium hydroxide (98/2/0.2) as eluant to yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: N(C[C:5]1[CH2:6][S:7][C@@H:8]2[CH:15](NC(=O)/C(/C3N=C(N)SC=3)=N\OC)[C:14](=[O:29])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+]=[N-].CO.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>[Ni].CO>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[S:7]1[C@@H:8]2[CH2:15][C:14](=[O:29])[N:9]2[C:10]([C:11]([OH:13])=[O:12])=[CH:5][CH2:6]1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(N)n1
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Yield: 45 %

Procedure:
To a stirred suspension of Raney nickel (16 g.) in MeOH (13 ml.) at 0° was added a solution of 3-azidomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid (2.96 g.) in MeOH/TFA (14 ml., 1.13 ml.). After effervescence ceased the mixture was diluted with MeOH and filtered through paper. The filtrate was evaporated, the residue purified by HPLC using water/HOAc/MeOH 79:1:20 v/v/v as eluant and the product dried over P2O5 to give 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy-imino)acetamido]ceph-3-em-4-carboxylic acid trifluoroacetate (yield 45%) having the following n.m.r. in solvent A:- 3.5-4.2 (m, 4H); 3.9 (s, 3H); 5.15 (d, 1H); 5.85 (d, 1H); 6.75 (s, 1H). 12. HPLC eluant MeOH/water/HOAc 10:89:1 v/v/v. 13. n.m.r. in solvent B: 3.46 (d,1H), 3.72 (d,1H); 3.97 (s,3H); 4.25 (s,3H); 4.11 (d,1H); 4.63 (d,1H); 5.13 (d,1H); 5.73 (d,1H); 6.97 (s,1H); 7.57 (d,1H); 7.98 (dd,1H); 8.93 (d,1H). 14. HPLC eluant MeOH/water/HOAc 15:84:1 v/v/v. 15. n.m.r. in solvent B: 3.43 (d,1H); 3.69 (d,1H); 3.97 (s,3H); 4.19 (s,3H); 4.23 (d,1H); 4.66 (d,1H); 5.12 (d,1H); 5.69 (d,1H); 7.0 (s,1H); 7.98 (d,1H); 8.2 (s,1H); 8.6 (d,1H). 16. The starting material was prepared by reaction of 3,6-difluoropyridazine and trimethyloxonium tetrafluoroborate in CH2C 12 for 15 hours at ambient temperature to give 3,6-difluoro-1-methylpyridazinium tetrafluoroborate. This compound in acetonitrile was treated with a solution of ammonia in chloroform in the presence of 1 equivalent of NaHCO3 for 0.5 hours at ambient temperature to give 3-amino-6-fluoro-2-methyl pyridazinium tetrafluoroborate. 17. HPLC eluant MeOH/water/HOAc 25:74:1 v/v/v. 18. n.m.r. in solvent B: 1.53 (s,6H); 3.5 (m,2H); 3.7 (s,3H); 3.95 (d,1H); 4.5 (d,1H); 5.15 (d,1H); 5.8 (d,1H); 7.0 (s,1H); 7.3 (s,2H). 19. The starting material was prepared by reaction of 2,5-dimethyl-3-fluoropyrazine and trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 5 hours to give 3-fluoro-1,2,5-trimethylpyrazinium tetrafluoroborate. 20. n.m.r. in solvent B: 1.53 (s,6H); 2.38 (s,3H); 2.53 (s,3H); 3.5 (m,2H); 4.1 (s,3H); 4.2 (d,1H); 4.85 (d,1H); 5.1 (d,1H); 5.85 (d,1H); 7.05 (s,1H); 7.9 (s,1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].[CH2:21](B1OC(C)(C)C(C)(C)O1)[CH:22]=[CH2:23]>C1COCC1.ClCCl.O>[CH2:23]([C:2]1[C:3](=[O:18])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[CH3:17])[CH:5]=[CH:6][CH:7]=1)[CH:22]=[CH2:21]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O

Procedure:
In a flask which had been dried by heating, 1.50 g (4.85 mmol) of the compound from Example 12A, 1.44 g (9.46 mmol) of caesium fluoride and 0.56 g (0.48 mmol) of tetrakis-(triphenylphosphine)palladium(0) are initially charged in 30 ml of degassed THF. A solution of 2.04 g (12.1 mmol) of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 5 ml of degassed THF is added dropwise, and the mixture is heated at reflux overnight. The mixture is then diluted with dichloromethane, and water is added. After phase separation, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated. The product is purified by chromatography on silica gel, giving 1.18 g (62% of theory) of the title compound.