Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O.C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH2:16][CH2:17][OH:18])[C:8]=1[F:19]>[Fe].C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH2:16][CH2:17][OH:18])[C:8]=1[F:19]
Reactant: O=[N+]([O-])c1ccc(Cl)c(F)c1CCO
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(F)c1CCO
Yield: 79.6 %

Procedure:
4.8 g of iron powder and 0.45 ml of concentrated hydrochloric acid were added to a mixture solvent of 50 ml of water and 10 ml of ethanol, and the solution was heated at 80°-90° C. 6.69 g (31 mmol) of 4-chloro-3-fluoro-2-(2-hydroxyethyl)nitrobenzene was added to the solution through 10 minutes, and the solution was heated for 1 hour as was. After air-cooling, 100 ml of ethyl acetate was added to the solution, and insoluble matter was filtered. The organic layer was separated and was washed with aqueous 10% sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solvent was removed by distillation to obtain 4.68 g of the subject compound (126) in a 80% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([F:20])=[C:16]([CH2:18][OH:19])[CH:17]=1>>[F:20][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:7](=[O:8])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[CH:17][C:16]=1[CH:18]=[O:19]
Reactant: Cc1cncc(C(=O)Cl)c1
Reactant: Nc1ccc(F)c(CO)c1
Product: Cc1cncc(C(=O)Nc2ccc(F)c(C=O)c2)c1

Procedure:
The title compound is prepared according to the reaction sequence described above using 5-methylnicotinoyl chloride and (5-amino-2-fluorophenyl)methanol followed by oxidation of the crude alcohol: LC-MS A: tR=0.60 min; [M+H]+=258.88.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][N:35]1[C:39](=[O:40])[C:38]2[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Benzyl(2-hydroxyethyl)carbamate (5.857 g, 30.0 mmol) was stirred under an argon atmosphere at room temperature with dehydrated tetrahydrofuran (150 mL). Then, triphenylphosphine (7.90 g) and N-hydroxyphthalimide (Pht-OH, 4.89 g) were added. After the reaction mixture was under ice cooling, 2.2M diethyl azodicarboxylate toluene solution (13.7 mL) was added dropwise gradually, followed by stirring overnight at room temperature. After completion of the reaction, the residue resulting from distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=1/1) to afford 9.36 g of the title compound (yield 92%).
Reaction SMILES: [NH:1]([C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:17])[CH2:2][C:3](N[C@H](C(O)=O)CC1N=CNC=1)=[O:4].C(N(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=[O:38].[Na+].[Na+].[Na+].[Na+]>>[NH:1]([C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:17])[CH2:2][C:3]([OH:4])=[O:38]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Na+]
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
N-palmitoyl-Gly-His obtained in the above-described synthesis example was added in a screw bottle (manufactured by Maruemu Corporation) such that the concentration of N-palmitoyl-Gly-His was 1.0 wt % (w/w) and the concentration of an additive (sodium ethylenediaminediacetate, sodium ethylenediaminetetraacetate) was 1.0 wt % (w/w), and a stirring bar (manufactured by As One Corporation, 4 mm×10 mm) was put thereinto. The additives (each having a pH that is outside the range of 6.5 to 9.3 or 1.8 to 2.5) are outside the scope of the present invention. Next, heating and stirring were performed, with a cap of the screw bottle being open, in a water bath (NWB-180N, manufactured by Nissinrika K. K.) for 60 minutes at a maximum until a transparent dispersion state was confirmed at 80° C. After heating and stirring, there were no undissolved residues in the solution with sodium ethylenediaminetetraacetate, whereas undissolved residues were observed by visual inspection in the other.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[F:21][C:22]1[CH:27]=[CH:26][C:25](/[C:28](=[N:36]/[S@@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])/[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:23]=1[O:43][CH3:44].[Al](C)(C)C.FC1C=C([Li])C=C(OC(F)(F)C(F)F)C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@:28]([NH:36][S@@:37]([C:39]([CH3:40])([CH3:42])[CH3:41])=[O:38])([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[C:4]([F:15])[CH:3]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][C:23]=1[O:43][CH3:44]
Reactant: COc1cc(/C(Cc2ccccc2)=N/[S@](=O)C(C)(C)C)ccc1F
Reactant: Fc1cc(Br)cc(OC(F)(F)C(F)F)c1
Agent: C[Al](C)C
Agent: [Li]CCCC
Agent: [Li]c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc([C@@](Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
To a solution of 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene (357 mg, 1.23 mmol) in toluene (1.5 mL) at −60° C. was added n-BuLi (2.5 M in hexane, 352 mL, 0.88 mmol). The reaction mixture was stirred for 1.5 h at −20° C. to −55° C. In a separate vial, to a −78° C. solution of (R,E)-N-(1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene)-2-methylpropane-2-sulfinamide (122 mg, 0.35 mmol) in toluene (1 mL) was added Al(CH3)3 (210 mL, 0.42 mmol). The resulting solution was stirred for 10-15 min, then added to the mixture of (3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)lithium. The combined reaction mixture was stirred at −55° C. overnight and then diluted with EtOAc. The organic portion was washed with H2O and the aqueous portion was extracted with EtOAc (3×). The combined organic portions were concentrated under reduced pressure and the residue was purified by preparative HPLC (Phenomenex Luna AXIA 100A, C18, 5μ; 10%-90% ACN/H2O containing 0.1% TFA, monitoring at 220 nm) to yield (R)—N—((R)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (83 mg, 42% yield). LCMS: RT=3.49 min [M+H] 560.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ 7.21-7.12 (m, 3H), 7.08 (dd, J=11, 8 Hz, 1H), 7.00-6.94 (m, 1H), 6.91-6.81 (m, 4H), 6.72-6.62 (m, 2H), 5.99-5.70 (m, 1H), 4.36 (s, 1H), 3.96 (d, J=13 Hz, 1H), 3.77 (s, 3H), 3.55 (d, J=13 Hz, 1H), 1.21 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([N:13]([C:17]([C:19]2[C:24]([N:25]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=3)(=[O:31])=[O:30])COC)=[CH:23][C:22]([Cl:43])=[CH:21][N:20]=2)=[O:18])[CH:14]([CH3:16])[CH3:15])=[N:9]1)=O)(C)(C)C>Cl.O1CCOCC1.O>[CH:14]([N:13]([C:10]1[CH:11]=[CH:12][NH:8][N:9]=1)[C:17]([C:19]1[C:24]([NH:25][S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)(=[O:30])=[O:31])=[CH:23][C:22]([Cl:43])=[CH:21][N:20]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(c1ccn(C(=O)OC(C)(C)C)n1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)N(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cc[nH]n1
Temperature: 85 °C

Procedure:
3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-isopropyl-amino)-pyrazole-1-carboxylic acid tert-butyl ester from step 2 was dissolved in a mixture of 4 M HCl in dioxane (4 mL) and water (1 mL), heated to 85° C. for 2 h. The solvent was evaporated and the residue was purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid isopropyl-(1H-pyrazol-3-yl)-amide. MS m/z: 522 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C.[CH:22]1[C:27]([CH2:28][CH2:29]O)=[CH:26][CH:25]=[C:24]([Cl:31])[CH:23]=1.CS(Cl)(=O)=O>CN(C=O)C>[Cl:31][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:22][CH:23]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 4′-hydroxyacetophenone (4 mmol) in DMF (10 mL) at rt, solid potassium carbonate (12.0 mmol) was added. 4-chlorophenthoxy mesylate (prepwered from the 4-chlorophenethanol and methanesulfonyl chloride) (4.4 mmol) was added to the reaction mixture and heated to 80° C. until completion according to General Procedure Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was poured into EtOAc (30 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulfate, and the solvent was removed in vacuuo to afford the desired 1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated product was purified by silica gel chromatography and the pure product obtained from 10% EtOAc/hexanes (yield 70%).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[F:12][B-:13]([F:16])([F:15])[F:14].[H+].[N:18]([O-])=O.[Na+]>O>[F:12][B-:13]([F:16])([F:15])[F:14].[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([N+:8]#[N:18])=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-(Difluoromethoxy)aniline (796 mg, 5 mmol) was dissolved in tetrafluoroboric acid (2.38 g, 1.7 ml, 13.0 mmol) and water (2 ml). After cooling to 0° C., a solution of sodium nitrite (345 mg, 5.0 mmol) in water (0.75 ml) was slowly added. The mixture was stirred for 30 min and the thick precipitate was collected by filtration and washed with diethylether (about 3 ml). The light red solid was dissolved in 1.5 ml of acetone and 5 ml of diethylether was added. After stirring for 15 min with cooling, the white solid was filtered, washed with diethylether and dried at HV for 15 min to yield 4-difluoromethoxy-benzenediazonium tetrafluoroborate.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[N:60]1([C:65]([NH:67][C:68]2[S:69][C:70]3[CH:75]=[CH:74][N:73]=[CH:72][C:71]=3[N:76]=2)=[O:66])[CH2:64][CH2:63][CH2:62][CH2:61]1.C(O)(C(F)(F)F)=O>CS(C)=O.C1(OC)C=CC=CC=1>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:73]4[CH:74]=[CH:75][C:70]5[S:69][C:68]([NH:67][C:65]([N:60]6[CH2:64][CH2:63][CH2:62][CH2:61]6)=[O:66])=[N:76][C:71]=5[CH:72]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(Nc1nc2cnccc2s1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CS(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(NC(=O)N5CCCC5)nc4c3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
A solution of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) and 2-(pyrrolidin-1-yl-carbonylamino)thiazolo[4,5-c]pyridine (124 mg, 0.5 mmoles) in 2 ml DMSO was allowed to stand at room temperature for 1.5 hours and then triturated with ether to give 606 mg of crude quaternary salt as a powder. The powder was added to a mixture of 5 ml of TFA and 3 drops of anisole and stirred 30 minutes at room temperature. The mixture then was evaporated under reduced pressure and triturated with ether to give 375 mg of crude It, which was purified on a column of HP-20 resin (40 ml) using 50% aqueous CH3OH as an eluant to give 165 mg (51%) of the desired product It. Mp. 184°~198° C. (dec.). Estimated purity by HPLC: 65%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15](Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
1-(4-Methoxyphenyl)cyclopropanecarboxylic acid (0.970 g, 5.05 mmol) in dichloromethane (DCM; 5 mL) was mixed with oxalyl chloride (1.28 mL, 15.1 mmol) followed by addition of a drop of N,N-dimethylformamide (DMF; 20 μL). The mixture was stirred at room temperature (RT) for 2 h. The solvent was evaporated. The residue was co-evaporated with toluene (2×), and dissolved in DCM (10 mL). The solution was cooled at −10° C., and then methanol (3 mL) was carefully added to the solution. The resulting mixture was allowed to warm to RT. The volatiles were evaporated under reduced pressure to afford the desired product (1.03 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1H-indole (2 g, 10.2 mmol) in THF (20 mL) at 0° C. was added 0.46 g of sodium hydride (12 mmol) in 3 portions. The mixture was stirred 30 min followed by addition of chlorotriisopropylsilane (2 g, 10.4 mmol). The reaction was allowed to warm to room temperature and stirring was continued overnight. The mixture was then poured into sat. aq. sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrate under vacuum to afford the crude product as an orange oil that was purified by flash chromatography on silica gel using a 4:1 ethyl acetate/heptane mixture as the eluent. The purified product (2.8 g) was a light orange oil.
Reaction SMILES: C([O-])(=O)CC[C@H](NC(C1C=CC(NC[C:17]2[CH2:18][NH:19][C:20]3[N:21]=[C:22]([NH:24][C:25]([C:27]=3[N:28]=2)=[O:26])[NH2:23])=CC=1)=O)C(O)=O.CN(C1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)CC1C=NC2N=C(N)N=C(N)C=2N=1.C1C(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=C(NCC2C=NC3N=C(N)N=C(N)C=3N=2)C=1.NC1N=C(N)C(C2C=CC(Cl)=C(Cl)C=2)=C(C)N=1.CC1C2C(N)=NC(N)=NC=2C=CC=1CNC1C=C(OC)C(OC)=C(OC)C=1.CCC1N=C(N)N=C(N)C=1C1C=CC(Cl)=CC=1.C1C2C(N=C(N)NC=2NCC1CCC1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)=O>>[N:21]1[C:20]2[C:27](=[N:28][CH:17]=[CH:18][N:19]=2)[C:25](=[O:26])[NH:24][C:22]=1[NH2:23]
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Agent: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Agent: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Product: Nc1nc2nccnc2c(=O)[nH]1

Procedure:
When in the above examples, other dihydrofolate reductase inhibitors replace methotrexate, e.g. aminopterin or 10-propargyl-5,8-dideazafolate or 2,4-diamino,5-(3',4'-dichlorophenyl),6-methylpyrimidine trimetrexate, or pyrimethamine or trimethorprim or pyritrexim 5,10-dideazatetrahydrofolate or 10-ethyl,10-deaza-aminopterin, similar results of pterin salvage pathway blocking are obtained.
Reaction SMILES: N#N.[Mg].II.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[CH:23](N1CCCCC1)=[O:24]>C1COCC1.BrC1C=CC(C#CC2C=CC(CC)=CC=2)=CC=1>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([CH:23]=[O:24])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1)[CH3:22]
Reactant: O=CN1CCCCC1
Reactant: CCc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: II
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.6 %

Procedure:
To a dry 100 mL three-necked flask under a flow of N2 containing magnesium turnings (0.782 g; 32.17 mmol) in dry THF (10 mL) at reflux, an activating, small amount of 1-bromo-4-[(4-ethylphenyl) ethynyl] benzene (VIIc) (0.500 g; 1.75 mmol) was added in one portion. N2 flow and stirring were stopped. Reaction mixture was heated at reflux for 5 minutes then iodine crystal was added keeping vigorous reflux to start the reaction. The reaction mixture went colourless after 5minutes and reaction mixture turned black-green after an additional minute. A solution of the remaining amount of 1-bromo-4-[(4-ethylphenyl) ethynyl] benzene (VIIc) (7.84 g; 27.49 mmol) in dry ThF (30 mL) was added drop wise into the reaction mixture while keeping gentle reflux. Reflux was maintained for 15 minutes then temperature was allowed to cool to RT under stirring for 1 h. The reaction mixture was cooled to 3° C. and a solution of dry 1-formyl-piperidine (4.12 mL; 43.87 mmol) in dry THF (25 mL) was added drop wise maintaining temperature at 5° C. The reaction mixture was then allowed to warm to room temperature (RT) and it was stirred overnight. Protocol and work-up was then similar with those described above. The title compound (m=5.77 g) was obtained as a cream solid in a 84% yield. Melting point: 89° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:27]2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=[C:23]([NH2:30])[C:22]=2[N:21]=[C:20]1[CH3:31]>>[NH2:30][C:23]1[C:22]2[N:21]=[C:20]([CH3:31])[N:19]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:27]=2[C:26]([CH3:28])=[C:25]([CH3:29])[N:24]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)[C@@H]3C[C@H]3c3ccccc3)c2c1C

Procedure:
Using the method of Examples 17–32, trans-2-phenylcyclopropylcarbonyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method B. The observed accurate mass was 408.2392.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CS(C)=O.[CH3:15][N:16]([CH3:23])[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O>[CH3:15][N:16]([CH3:23])[CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A 100 ml flask was charged with 1-fluoro-4-nitrobenzene (2.122 ml, 20 mmol), dimethylsulfoxide (30 ml), N,N-dimethylpiperidin-4-amine (2.82 g, 22.00 mmol) and triethylamine (5.58 ml, 40.0 mmol). The resulting solution was stirred at 100° C. under nitrogen for 24 hours. The reaction mixture was allowed to cool, and was poured in stirring cold water (1000 ml) and the solid collected by filtration and washed with water. The precipitate was vacuum dried to provide the title compound. MS (ESI(+)) m/e 249.9 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:11](Br)[CH:12]=[CH2:13].C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:1]([C:3]([CH:8]([CH3:10])[CH3:9])([CH2:13][CH:12]=[CH2:11])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCC(C(=O)OC)C(C)C
Reactant: C=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC(CC)(C(=O)OC)C(C)C
Yield: 81.7 %

Procedure:
The reaction of methyl 2-ethyl-3-methylbutyrate (23.76 g, 165 mmol), prepared as in Lion C, Dubois J E (1981) supra., with allyl bromide (31.34 g, 259 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (25.05 g, 248 mmol) with butyllithium in hexanes (2.5 M, 94.4 mL, 236 mmol)) in THF (330 mL) and HMPA (24.7 mL, 142 mmol), as described above in the preparation of Example 7, followed by the vacuum distillation of crude product afforded the pure olefinic ester (24.85 g, 82%) as a colorless liquid: bp 92-94° C. (20 mmHg).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+].[N+:14]([C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)([O-:16])=[O:15]>CN(C)C=O.C(OCC)C>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:18]1[CH:19]=[CH:20][N:21]=[C:17]1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Brom-2-methyl-2-pentene (25 g, 0.154 mol) was dissolved in dry dimethylformamide (DMF) (200 mL). To the solution was added K2CO3 (21.3 g, 0.154 mol) and 2-nitroimidazole (17.4 g, 0.154 mol). The mixture was stirred under N2 atmosphere at 75° C. for 48 hours. DMR was evaporated on a rotary evaporator. The yellow gummy residue was stirred with water (150 mL) to give yellow solid, which was dissolved in diethyl ether (150 mL), dried over Na2SO4 and evaporated on a rotary evaporator to yield the title product. Yield 27.8 g (92%). mp: 49-51° C. MS: (M+H)+=196, M+=195. 1H NMR (CDCl3) δ 1.45 and 1.68 (s, 6H, gem-diCH3), 2.52 (q, 2H, CH2CH=), 4.43 [t, 2H, CH2-(2-nitroimidazolyl) ], 5.08 (t, 1H, CH2CH=), 7.05 and 7.14 (s, 2H, 2-nitroimidazolyl-H).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([O:24][CH3:25])[CH:10]=1)(C)C)(C)(C)C.Cl[C:27]1[N:28]=[N:29][C:30]([CH2:33][CH:34]2[CH2:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]2)=[CH:31][CH:32]=1>>[CH3:25][O:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:27]1[N:28]=[N:29][C:30]([CH2:33][CH:34]2[CH2:35][C:36]([CH3:43])([CH3:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH2:39]2)=[CH:31][CH:32]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)CC(Cc2ccc(Cl)nn2)CC(C)(C)N1
Product: COc1cc(O)ccc1-c1ccc(CC2CC(C)(C)NC(C)(C)C2)nn1
Yield: 61.9 %

Procedure:
Following standard GENERAL METHOD 1-4 for Suzuki coupling using tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (408 mg, 1.12 mmol) and 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (200 mg, 0.75 mmol) affords 3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenol (165 mg) MS [M+H+]=356.1.