Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:22]=1)O)C1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C>[CH2:30]([S:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:19][C:10]2[CH:11]=[C:12]([C:15]([F:17])([F:16])[F:18])[CH:13]=[CH:14][C:9]=2[OH:8])=[CH:26][CH:25]=1)(=[O:28])=[O:29])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(C(O)c2cc(C(F)(F)F)ccc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1ccc(Cc2cc(C(F)(F)F)ccc2O)cc1
Reaction time: 2 h

Procedure:
A mixture of the product from example 3 step (iii) (0.225 g), 10% palladium on carbon (0.05 g) and acetic acid (2 drops) in ethanol (20 ml) was hydrogenated at 3 Bar for 2 h then SBar for 5 h. After filtration the solvent was evaporated under reduced pressure. Yield 0.16 g
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[NH:6][C:5](=O)[CH:4]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:5]1[CH:4]=[C:3]([CH2:2][Cl:1])[N:8]=[C:7]([S:9][CH3:10])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(CCl)cc(=O)[nH]1
Product: CSc1nc(Cl)cc(CCl)n1

Procedure:
A mixture of 35 g (0.18 mole) of the known compound 6-chloromethyl-2-methylthiopyrimidin-4-one and 300 ml of phosphorous oxychloride was heated at reflux for 3.5 hours, cooled and evaporated. The mixture was poured into 600 ml of an ice-water mixture and the mixture was extracted with four 200 ml portions of chloroform. The combined extracts were washed sequentially with two 200 ml portions of water, 20 ml of saturated aqueous sodium bicarbonate solution and 200 ml of saturated aqueous sodium chloride solution, and were then dried over magnesium sulfate and evaporated. The residue was distilled at reduced pressure to provide 4-chloro-6-chloromethyl-2-methylthiopyrimidine as a yellow liquid, b.p. 90°-95° C./0.15 mm Hg. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([CH2:3][CH2:2][NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[N:5]=1
Reactant: CCOC(=O)Cl
Reactant: NCCc1cc2ccccc2cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To an ice-bath cooled solution of 3-(2-aminoethyl)isoquinoline (Description 113; 2.70 g, 15.7 mmol) and triethylarnine (2.84 ml, 20.41 mmol) in anhydrous dichloromethane (75 ml) was added slowly ethyl chloroformate (1.65 ml, 17.27 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water, sat NaCl, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica elution with a gradient rising from DCM to 2% MeOH in DCM+0.5% NH4OH to give the title compound (2.27 g, 59%).
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.C(=O)(O)[O-].[Na+].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].CN(C=O)C>O>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([Br:1])=[CH:3][C:4]=1/[CH:18]=[CH:17]/[C:16]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Nc1cc(F)c(Br)cc1I
Reactant: C=CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cc(Br)c(F)cc1N
Temperature: 100 °C
Yield: 77.3 %

Procedure:
To a vial was added, 4-bromo-5-fluoro-2-iodoaniline (5.67 g, 17.95 mmol), PdOAc2 (0.201 g, 0.897 mmol), sodium bicarbonate (3.77 g, 44.9 mmol), ethyl acrylate (2.049 ml, 18.85 mmol) and DMF (12.0 ml). The reaction was heated for 3 hour at 100° C. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was triturated with heptane overnight and then filtered to afford (E)-ethyl 3-(2-amino-5-bromo-4-fluorophenyl)acrylate (4.00 g, 13.88 mmol, 77% yield) as a light yellow solid. m/z (ESI) 288.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[CH:13]=[C:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:28]=1.C(N(CC)CC)C>CS(C)=O>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([N:17]2[CH2:16][CH2:15][C:14](=[CH:13][C:12]3[CH:20]=[CH:21][CH:22]=[C:10]([O:9][C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:25])[F:26])=[CH:24][CH:23]=4)[CH:11]=3)[CH2:19][CH2:18]2)=[O:35])[N:28]=1
Reactant: FC(F)(F)COc1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(3-(4-(2,2,2-trifluoroethoxy)phenoxy)benzylidene)piperidine (40 mg, 0.110 mmol; Example 99, Step 5), phenyl pyridazin-3-ylcarbamate (24 mg, 0.110 mmol), and triethyl amine (55 mg, 0.55 mmol) in DMSO (2.5 mL) was stirred at room temperature for overnight. The reaction was quenched with water, extracted with EtOAc, dried over sodium sulfate, concentrated, and purified by column chromatography (50% acetone/hexane) to yield the title compound. (45 mg, 80%). 1H NMR (500 MHz, CDCl3): δ ppm 8.76 (s, 1H), 7.52 (s, 1H), 7.02 (m, 2H), 6.95 (m, 2H), 6.83 (m, 2H), 6.78 (s, 1H), 6.37 (s, 1H), 4.37 (m, 2H), 3.72 (s, 2H), 3.63 (s, 2H), 2.63 (s, 2H), 2.58 (s, 2H), m/z (485.1 MH+); HPLC: 98.33%.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ccc(C=C(Br)Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C#CBr)cn1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
A mixture of 5-(2,2-dibromovinyl)-2-methylpyridine (0.10.9 g, 0.00393 mol), potassium tertbutoxide (0.88 g, 0.00787 mol) and toluene (13 mL) were heated at 80° C. for 4 h. After completion of reaction, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.25 g, 32.4%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(I)c1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(I)c1
Reaction time: 0.05 h
Yield: 86 %

Procedure:
40% Methanolic Triton B (0.07 mL, 0.15 mM) was added to a solution of the 9-[(3-iodophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (60 mg, 0.13 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (30 mg, 0.19 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 60 mg (86%) of the {9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.6-7.0 (m, 11H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3500, 3350, 1727, 1642, 1291, 1236, and 772. MS (ES) m/e 515.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]1[S:24][CH:23]=[C:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])[CH:21]=1.[F:33][C:34]([Si](C)(C)C)([F:36])[F:35].Cl>C1COCC1>[F:33][C:34]([F:36])([F:35])[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[C:22]1[CH:21]=[C:20]([CH3:19])[S:24][CH:23]=1)[OH:28]
Reactant: Cc1cc(-c2ccccc2C=O)cs1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2C(O)C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 185.1 %

Procedure:
Tetrabutylammonium fluoride (0.028 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 2-(5-methylthiophen-3-yl)-benzaldehyde (550 mg, 1.29 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (483 μl, 3.27 mmol) in 10 ml of THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 10 ml of 1N HCl and stirred at room temperature overnight. The product was extracted with ethyl acetate (3×50 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 650 mg of 2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethanol, yield: 87%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([OH:26])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:37](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](=[O:26])[NH2:37])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(N)=O)CC1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxynitrobenzene (0.9 g) in dichloromethane (20 ml) were added isobutyl chloroformate (0.3 ml) and triethylamine (0.4 ml) in an ice bath and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia (0.2 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (0.9 g, yield 98%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH2:25])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH:25][C:27](=[O:34])[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(N)c45)[nH]c3c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(NC(=O)c6ccccc6)c45)[nH]c3c2)CC1
Reaction time: 8 h

Procedure:
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine is dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OC)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: CCCCN
Solvent: CO
Product: CCCCNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Yield: 66.8 %

Procedure:
7.05 g (0.025 mole) of 4-bromo-1-methoxy-2-nitronaphthalene is dissolved in 300 cc of methanol by heating the mixture at reflux temperature, then 5 cc (0.05 mole) of butylamine is gradually dripped into the obtained solution and when the addition is terminated the reaction mixture is still refluxed for 30 minutes with stirring. Upon cooling to 0°-5° C. a precipitate forms which is separated by filtration and dried, yielding 5.4 g of 4-bromo-N-butyl-2-nitro-1-naphthylamine. An additional 0.92 g is recovered from the mother liquor and the two crops are combined together and recrystallized from methanol. M.p. 65°-66.5° C. A mixture of 17.6 g (0.0544 mole) of this compound and 7.84 cc (0.0816 mole) of 3-chloropropionyl chloride is stirred at 60° C. for four hours. When the reaction is completed the mixture is poured in a separatory funnel and vigorously shaken with methylene chloride and a 5% aqueous NaHCO3 solution. The organic layer is separated, washed with water and dried. The residue which is obtained by evaporating off the methylene chloride is dissolved in 180 cc of EtOH and 22 cc of glacial acetic acid. 10.4 g of powdered iron is added to the obtained solution and the resulting mixture is refluxed with stirring for 20 minutes; then it is poured into 720 cc of water and extracted with methylene chloride. The methylene chloride is evaporated off, the residue is dissolved in a mixture of 125 cc of 95% EtOH and 50 cc of 10% HCl and heated at reflux temperature for 11/2 hour. The solvent is boiled off and the solid residue is triturated with ether, filtered and dried. The yield in 5-bromo-1-butyl-2-(2-chloroethyl)-1H-naphth[1,2-d]imidazole, m.p. 172° C. (dec.), is 19.4 (90.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[CH2:23]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 213 mg, 0.7 mmol), tetrabutylammonium iodide (271 mg, 0.7 mmol) and benzyl bromide (0.45 mL, 3.7 mmol) in dimethylformamide (1.4 mL) was heated at 100° C. in a sealed tube for 24 h and then left at room temperature for a further 24 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 10% aqueous sodium thiosulfate and brine, dried (sodium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc. Burlington, Wis.) with a RS-12G silica gel column, eluting with 10-100% ethyl acetate/hexanes, to give a light brown foam. This was dissolved in ethanol and the solution was treated with activated carbon (15 mg) and heated at 50° C. for 1 h. The mixture was filtered through Celite and the Celite was washed with ethanol. The combined filtrates were evaporated and the resulting foam was dried under high vacuum to give (4R,7S)-1-benzyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg, 80%) as an off-white solid. ES(+)-MS (M+H) 395.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCCC2)cn1
Yield: 75 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using piperidine instead of 3-methoxypropylamine, to the title compound (91 mg, 75%) which was obtained as a yellow gum. MS: m/e=378.5 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:27].[Cl-].[NH4+]>C1COCC1>[Br:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.82 mL) in THF (30 mL) was added n-butyllithium (2.5M in hexanes, 16.4 mL) at 0° C. and the mixture was stirred for 30 min at this temperature before being cooled to −78° C. Ethyl isobutyrate (5 mL) was added dropwise and the resultant mixture was stirred at −78° C. for 1 h before addition of 1,5-dibromopentane (5.61 mL). The reaction mixture was stirred at −78° C. for 1 h then at RT for 2.5 h before being poured into saturated ammonium chloride solution. The solution was extracted with ethyl acetate (×2), then the combined organics were washed with water and dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the subtitled compound as a yellow liquid. Yield 4.45 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1.C(=O)(O)[O-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:18]2[N:17]=[N:16][C:15]([NH2:14])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)nn1
Yield: 82.2 %

Procedure:
48.9 g (278 mmol) of 1-benzylpiperazine and 12.0 g (92.6 mmol) of 3-amino-6-chloropyridazine are heated at 160° C. for 1 hour. The brown oil obtained is poured into 500 ml of an aqueous solution of sodium bicarbonate and the product is extracted with dichloromethane. The organic phase is dried and then concentrated under reduced pressure. The oil obtained is triturated in diethyl ether and 20.5 g of a solid are isolated after filtration and drying.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([NH:12][CH:13]1[C:25](=[O:26])[N:15]2[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH3:21])[CH2:18][S:19](=[O:20])[C@H:14]12)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[C:4]([NH:12][CH:13]1[C:25](=[O:26])[N:15]2[C:16]([C:22]([O:24][CH3:3])=[O:23])=[C:17]([CH3:21])[CH2:18][S:19](=[O:20])[C@H:14]12)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=[N+]=[N-]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Solvent: ClCCl
Product: COC(=O)C1=C(C)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 0 °C
Yield: 86.6 %

Procedure:
An excess of an ethereal diazomethane solution was added to an ice-cooled suspension of 5 gm of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 150 ml of dichloromethane and the mixture was stirred for half an hour. Then, excess diazomethane was destroyed with acetic acid and methanol was added. The mixture was evaporated to dryness in vacuo and the residue was crystallized from methanol to obtain 4.5 gm (86.6% yield) of methyl 7-benzamido-3-methyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[O:4]=[C:5]([C@H:7]([CH2:9][C:10]1[CH:17]=[C:15]([OH:16])[C:13]([OH:14])=[CH:12][CH:11]=1)[NH2:8])O.Cl>>[CH3:2][CH2:1][O:3][C:5]([C@@H:7]([NH2:8])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:14])=[C:15]([OH:16])[CH:17]=1)=[O:4]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Absolute ethanol (395 g, 500 ml, 8.58 moles, 17 eq.) and L-DOPA (100 g, 0.507 moles, 1 eq.) are introduced into 1 L reactor. The batch is cooled to 15° C. and HCl(g) (37.01 g, 1.014 mole, 2 eq.) is bubbled into the reaction mixture at 15-30° C. The reaction is heated to reflux (79° C.) and kept at reflux for 3 hours. The batch is then cooled to 40° C. and 350-400 ml of solvent is distilled out under vacuum during 1.5-2 hours (50 mbar, jacket temperature 60° C.). Deionized water (220 ml) is introduced, the pH of the solution is adjusted to 2-3 with 5N NaOH solution (65 ml) and 170 ml of the reaction mixture is distilled out during 1.5-2 hours (50 mbar, jacket temperature 50° C.). Toluene (20 ml) is added to the resulting solution, the pH of the solution is adjusted to pH 4-5 with 5N NaOH solution and sodium metabisulfite (2 g, 2% w/w) is added. The operations from this stage on are done at nitrogen atmosphere. The temperature of the reaction is adjusted to 25-30° C., the pH is adjusted to 6.5-6.7 with 5N NaOH and the solution is seeded with L-DOPA ethyl ester (1 g). The precipitation is continued by controlled addition of 5N NaOH solution (70 ml/hr.) until pH 7.6-7.8, the reaction mixture cooled to 5° C. and kept at this temperature for one hour. The precipitate is collected by filtration and washed with (2×40 ml) cold water. The crude wet precipitate is dried by azeotropic distillation of the water with toluene (500 ml) under vacuum (50 mbar, jacket temperature 25-45° C.) until no more water is distilled out. The mixture is cooled to ambient temperature, L-DOPA ethyl ester (crude) is collected by filtration, washed with toluene and dried in a vacuum oven at 30-35° C. until constant weight. The yield of crude material is 85%.
Reaction SMILES: [Li]CCCC.[Br-].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:12]=[CH:11]2.[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][C@@H:48]([S:57][CH2:58][C:59]1([CH2:62][C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:60]1)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=O)[CH:50]=1>CCCCCC.C1COCC1>[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][C@@H:48]([S:57][CH2:58][C:59]1([CH2:62][C:63]([O:65][CH3:66])=[O:64])[CH2:60][CH2:61]1)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:19][C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][C:17]([F:18])=[C:8]([F:7])[CH:9]=3)[N:14]=2)[CH:50]=1
Reactant: Fc1cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2cc1F
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=O)c2)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=Cc3ccc4cc(F)c(F)cc4n3)c2)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
At -78° C., 1.6M BuLi in hexane (700 μL) was added to a suspension of the phosphonium salt of Step 9 (646 mg, 1.1 equiv.) in 6 mL of anh. THF and the mixture was stirred at -10° C. for 10 min. At -78° C., a solution of the aldehyde of Step 8 (515 mg, 1.12 mmol) in 4 mL of THF was then added dropwise. The mixture was stirred at -78° C. for 30 min. and at -10° C. for 30 min. and was quenched with 25% aq. NH4OAc. The product was extracted in EtOAc, dried over Na2SO4, is and purified by flash chromotography on silica with EtOAc:toluene 2.5:97.5 and 5:95.