Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.S(=O)(=O)(O)O.O[CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23].[OH-].[K+]>C(O)(=O)C>[Cl:23][CH2:22][C:21]([NH:20][CH2:19][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][C:6]=1[OH:10])=[O:24]
Reactant: O=C(CCl)NCO
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(CCl)NCc1ccc(OC(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
3-(Trifluoromethoxy)phenol (4.827 g, 27 mmol) was dissolved in glacial acetic acid (20 mL). The mixture was cooled in an ice bath between 14–17° C. and concentrated sulfuric acid (2 mL) was slowly added keeping the temperature below 20° C. The mixture was cooled below 10° C. and N-hydroxymethyl-2-chloroacetamide (3.52 g, 28.5 mmol) was added. The mixture was warmed slowly to room temperature and stirred overnight. The mixture was then poured slowly into ice (200 mL) and the pH was adjusted to ˜4–5 with KOH pellets, keeping the temperature below 5° C. The reaction mixture was warmed to room temperature and extracted twice with ethyl acetate (150 mL). The organic layer was collected and washed with NaHCO3 (sat., 30 mL). The organic layer was dried over MgSO4, filtered and the solvent removed to dryness. The mixture was purified by column chromatography (SiO2, 700 mL) using an eluent of hexane/ethyl acetate (10/2). Recovery: 2.42 g (33.8% yield). 1H NMR (DMSO) δ=10.23 (1H, s), 8.56 (1H, st), 7.16–7.14 (1H, sd), 6.71–6.70 (2H, br), 4.18–4.17 (2H, d), 4.08 (2H, s).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]([CH2:30][CH2:31][OH:32])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:33]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][N:15]([CH2:30][CH2:31][OH:32])[C:16]=1[C:26]([F:27])([F:29])[F:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2O)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2OCc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.5 %

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole (111 mg) in N,N-dimethylformamide (0.5 mL) were added benzyl bromide (49 mg) and potassium carbonate (43 mg), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1–5/1) to give the title compound (108 mg).
Reaction SMILES: C1C2C(C[O:15][C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=3)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[F:56][C:57]1[CH:82]=[CH:81][C:60]([CH2:61][O:62][C:63]2[CH:64]=[C:65]([CH:69]=[CH:70][C:71]=2[O:72][CH2:73][C:74]2[CH:79]=[CH:78][C:77]([F:80])=[CH:76][CH:75]=2)C(O)=O)=[CH:59][CH:58]=1>>[F:56][C:57]1[CH:82]=[CH:81][C:60]([CH2:61][O:62][C:63]2[CH:64]=[C:65]([CH:69]=[CH:70][C:71]=2[O:72][CH2:73][C:74]2[CH:79]=[CH:78][C:77]([F:80])=[CH:76][CH:75]=2)[C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=2)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:59][CH:58]=1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)c(OCc2ccc(F)cc2)c1
Reactant: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Product: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2ccc(OCc3ccc(F)cc3)c(OCc3ccc(F)cc3)c2)cc1O

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-3-hydroxy-4-methoxyaniline (642 mg, 0.9 mmol, example 109, step A) as described for example 109 (step B) using 3,4-di-(4-fluorobenzyloxy)benzoic acid (485 mg, 1.3 mmol) instead of N-(4-fluorobenzyl)indole-2-carboxylic acid. The crude material was purified by flash chromatography using successively 5%, 10% and 30% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as white crystals (260 mg, 34%).
Reaction SMILES: CO[CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[O:12]=[C:13]1[C:22]2[CH2:21][CH:20]([C:23]([CH3:25])=[O:24])[O:19][CH2:18][C:17]=2[C:16](=[O:26])[CH:15]=[CH:14]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[OH:7][C:5]1[CH:6]=[C:14]2[C:15](=[CH:3][CH:4]=1)[C:16](=[O:26])[C:17]1[CH2:18][O:19][CH:20]([C:23]([CH3:25])=[O:24])[CH2:21][C:22]=1[C:13]2=[O:12]
Reactant: C=C(C=COC)O[Si](C)(C)C
Reactant: CC(=O)C1CC2=C(CO1)C(=O)C=CC2=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)C1CC2=C(CO1)C(=O)c1ccc(O)cc1C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
A mixture of 1-methoxy-3-trimethylsilyloxy butadiene (776 mg, 4.51 mmol) and methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (309 mg, 1.50 mmol) in 6 mL of dry toluene was stirred for 90 minutes at room temperature under argon atmosphere. The solvent was then removed in vacuo and the dried residue was dissolved in 10 mL of THF. To this solution was added 2 mL of a 4% aq. HCl solution. The combined organic layers were then washed with water and dried over MgSO4. Flash chromatography (toluene:ethyl acetate; 95%:5%) of the residue gave 180 mg (65% yield) of the titled compound (MP: 169°-170° C.).
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[CH2:36]([NH2:46])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:46][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[N:6]=1
Reactant: CCCCCCCCCCN
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCCCNc1nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)n1

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (3.0 g) and n-decylamine (1.5 g) were dissolved in dioxane (70 ml), followed by addition of potassium carbonate (1.0 g). The mixture was refluxed for 5 hours with stirring. After completion of the reaction, dioxane was distilled off and the resulting residue was recrystallized from ligroin to give the desired product as white crystals melting at 106°-107° C.
Reaction SMILES: [OH-].[Na+].[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([O-:6])([O-:5])=[O:4].[Ba+2].[N+]([O-])(O)=O>O>[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([OH:5])([OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [Ba+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)COP(=O)(O)O
Reaction time: 504 h

Procedure:
The pH of an 11.3-ml aqueous solution of 0.67 M cis-[Pt(NH3)2 (H2O)2 ](NO3)2 was adjusted with sodium hydroxide to 4. Then, 3.0 grams of barium D-galactose-6-phosphate dissolved in 30 ml water were added. The pH of the resulting solution was adjusted to 5.0 with 2 M nitric acid. After stoppering the solution with a porous plug and stirring for 21 days, the above-identified complex which had formed during that time period was recovered as a water-insoluble blue precipitate by the method described in Example 5.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:11]=1)=[N:8][S:9][N:10]=2.C(O)C.[C-:15]#[N:16].[K+]>O>[N:10]1[S:9][N:8]=[C:7]2[CH:11]=[C:3]([CH2:2][C:15]#[N:16])[CH:4]=[CH:5][C:6]=12
Reactant: [C-]#N
Reactant: BrCc1ccc2nsnc2c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc2nsnc2c1
Yield: 53.3 %

Procedure:
A mixture of 5-bromomethyl-benzo[1,2,5]thiadiazole [RN65858-50-6](7.0 g, 30 mmol), ethanol (50 ml)and a solution of potassium cyanide (2.3 g, 36 mmol) in water (25 ml) was stirred at 50° C. for 15 hours. The alcoholic solution was concentrated and the residue suspended in water. The solid was collected by filtration, washed with water and dried in vacuo to give benzo[1,2,5]thiadiazol-5-yl-acetonitrile (2.8 g, 47%)
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:22]=1)[O:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15](Cl)=[O:16].N.C(O)C.C[N:36](C)C=O>O>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:22]=1)[O:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15]([NH2:36])=[O:16]
Reactant: O=C(Cl)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: N
Solvent: O
Solvent: CCO
Product: NC(=O)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A mixture of {o-[5-(2,4-dichlorophenoxy)-2nitrophenoxy]phenoxy}acetyl chloride (1.11 g, 2.38 mmol), ammonia solution (5 mL of a 35% solution), ethanol (5 mL) and N,N-dimethylformamide (10 mL) is stirred for one hour, poured into water and extracted with an ether/ethyl acetate (1:1) solution. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow oil (1.0 g) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3[S:15][CH2:16][CH2:17][S:18][C:11]=3[C:10]2=[O:19])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O1CCCC1>[OH:14][CH:13]1[C:12]2[S:15][CH2:16][CH2:17][S:18][C:11]=2[C:10](=[O:19])[N:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(N2C(=O)C3=C(SCCS3)C2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)C3=C(SCCS3)C2O)cc1
Temperature: 0 °C
Yield: 98.1 %

Procedure:
2,3,6,7-Tetrahydro-6-(4-methoxyphenyl)-5H-1,4-dithiino[2,3-C]pyrrole-5,7-dione (8.50 g) was suspended in methanol-tetrahydrofuran (1:1, 80 ml) and, under ice-cooling and stirring, sodium borohydride (0.88 g) was added. The mixture was stirred for about 3 hours and then poured into ice water. After extraction with ethyl acetate, the extract was washed with water, dried (over Na2SO4) and evaporated to give 2,3,6,7-tetrahydro-7-hydroxy-6-(4-methoxyphenyl)-5H-1,4-dithiino[2,3-C]pyrrol-5-one (8.40 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH:16][C:17]([CH:19]3[N:24]4[C:25]([CH3:32])=[N:26][C:27]([C:28]([F:31])([F:30])[F:29])=[C:23]4[CH:22]=[CH:21][CH2:20]3)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>Cl.O=[Pt]=O.CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH:16][C:17]([CH:19]3[N:24]4[C:25]([CH3:32])=[N:26][C:27]([C:28]([F:31])([F:29])[F:30])=[C:23]4[CH2:22][CH2:21][CH2:20]3)=[O:18])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)c2n1C(C(=O)Nc1cnn(-c3ccc(Cl)cc3)c1C(C)C)CC=C2
Agent: O=[Pt]=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1nc(C(F)(F)F)c2n1C(C(=O)Nc1cnn(-c3ccc(Cl)cc3)c1C(C)C)CCC2
Reaction time: 0.42 h
Yield: 26.9 %

Procedure:
To N-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-3-methyl-1-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyridine-5-carboxamide (30 mg, 0.064 mmol) was added EtOH (10 mL), 12 N HCl (4 drops), and PtO2 (30 mg). The resulting suspension was evacuated with hydrogen gas twice and stirred under hydrogen gas (55 psi) on Parr shaker for 25 min. the reaction mixture was then filtered through a syringe filter, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give N-[1-(4-chlorophenyl)-5-isopropyl-pyrazol-4-yl]-3-methyl-1-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-carboxamide (10 mg, 0.0172 mmol, 27% yield) as a TFA salt. 1H NMR (400 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.57 (d, J=11.76 Hz, 2H), 7.42 (d, J=11.76 Hz, 2H), 5.20-5.22 (m, 1H), 3.0-3.18 (m, 2H), 2.8-2.95 (m, 1H), 2.40 (s, 3H), 2.32-2.55 (m, 2H), 1.80-2.05 (m, 2H), 1.27 (d, J=23.4 Hz, 3H), 1.24 (d, J=23.4 Hz, 3H); MS: (ES) m/z calculated for C22H23ClF3N5O [M+H]+ 466.9, found 466.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccc(F)cc2F)n1
Yield: 79 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2,4-difluorophenyl)-5-fluoropicolinic acid in 79% yield. LC/MS=254.1 (M+H), Rt=0.75 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22]>>[CH2:21]([O:23]/[CH:24]=[C:11]1\[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[C:10]\1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[CH3:22]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Product: CCO/C=C1\C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one [(Example 107, Step 1), 85 mg, 0.31 mmol] and triethylorthoformate (0.057 mL, 0.34 mmol, 1.1 equiv) were combined and placed into a preheated oil bath at 100° C. for 1 hour. The mixture was cooled to ambient temperature and concentrated in vacuo, providing the titled compound.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([C:10]1[N:11]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[C:14](OC3C=CC=CC=3)[C:13]=2[N:27]=1)[CH2:7][CH2:8][CH3:9]>C(OCC)(=O)C>[CH2:6]([C:10]1[N:11]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[C:14]([NH2:5])[C:13]=2[N:27]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCOc1ccccc1
Temperature: 150 °C

Procedure:
A sealed tube containing ammonium acetate (7.5 g) and 2-butyl-6,7-dimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (0.75 g) from Part C was heated in an oil bath to 150° C. for 48 hours. The reaction reached 70% completion and was allowed to cool to room temperature. The reaction mixture was then dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The product was passed through a silica gel column using 10/90 methanol/ethyl acetate as the eluant. To remove impurities, the product was recrystallized twice from acetonitrile with charcoal. The resulting white crystals were crushed and dried to yield 2-butyl-6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 130.0–132.0° C.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]2=[N:4][C:3]=1[CH2:12][CH2:13][CH3:14].[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]([OH:35])[C:2]3[N:6]4[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]4=[N:4][C:3]=3[CH2:12][CH2:13][CH3:14])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: CCCc1nc2c(C)nccn2c1I
Product: CCCc1nc2c(C)nccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 108.9 %

Procedure:
[step 3] Using 3-iodo-8-methyl-2-propylimidazo[1,2-a]pyrazine (0.5 g, 1.7 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (0.3 g, 1.0 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 14A, step 3, (E)-2-{3-fluoro-8-[hydroxy(8-methyl-2-propylimidazo[1,2-a]pyrazin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (0.51 g, quantitative) was obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:20]([N:6]2[C:7](=[O:15])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: O=c1[nH]c2ccccc2c2ccccc12
Reactant: O=C(Cl)C1CCC1
Product: O=C(C1CCC1)n1c(=O)c2ccccc2c2ccccc21

Procedure:
5-Cyclobutanecarbonyl-5H-phenanthridin-6-one was prepared from 5H-phenanthridin-6-one and cyclobutanecarbonyl chloride according to GP 1. Yield, 2%. 1H-NMR (CD3OD): δ=1.95-2.09 (m, 1H), 2.11-2.26 (m, 1H), 2.36-2.55 (m, 4H), 3.64 (ψ-quint, J=8.5 Hz, 1H), 7.32 (“t”, J=7.5 Hz, 1H), 7.37 (“t”, J=7.7 Hz, 1H), 7.47 (“t”, J=7.5 Hz, 1H), 7.53 (“t”, J=7.5 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H); (+)-ESI-MS: m/z=278 [M+H]+, 196 [5H-phenanthridin-6-one+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[S:48][C:47]([CH2:49][NH2:50])=[CH:46][CH:45]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:50][CH2:49][C:47]2[S:48][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=3)=[CH:45][CH:46]=2)=[O:15])[CH:3]=1
Reactant: NCc1ccc(-c2ccccn2)s1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCc2ccc(-c3ccccn3)s2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of Example 104A (32.5 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL) was added, followed by the addition of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (50.4 mg, 0.16 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). Then, commercially available [5-(2-pyridinyl)-2-thienyl]methylamine (36.2 mg, 0.19 mmol) dissolved in N,N-dimethylacetamide (0.6 mL) was added followed by the addition of diisopropyl ethyl amine (57.9 uL, 0.31 mmol) dissolved in N,N-dimethylacetamide (0.8 mL). The mixture was shaken at room temperature overnight. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 dimethyl sulfoxide/methanol and purified by reverse phase HPLC (0-70% CH3CN in 10 mM aq. ammonium acetate) to give the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.08-1.28 (m, 3H) 1.29-1.37 (m, 2H) 4.25-4.53 (m, 2H) 4.54-4.69 (m, 2H) 6.95-7.06 (m, 1H) 7.09-7.12 (m, 1H) 7.16-7.32 (m, 1H) 7.49-7.64 (m, 1H) 7.68-7.91 (m, 2H) 8.31-8.52 (m, 1H); MS (ESI) positive ion 380 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(OC([NH:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)=O)(C)(C)C.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:54]4[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][NH2:50])[CH:53]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3cccc(CN)c3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
A mixture of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) and 3-(t-butyloxycarbonylaminomethyl)pyridine (516 mg, 2 mmoles) in DMSO (2 ml) was stirred at ambient temperature for 30 minutes. The mixture was poured into ethyl acetate (200 ml), and the precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg), sodium bisulfite (50 mg) in HCOOH (5 ml) was stirred at 40°-50° C. for 80 minutes and evaporated to dryness under reduced pressure. The residual solid was dissolved in water (40 ml), and the mixture was neutralized with NaHCO3. Insoluble material was filtered off, and the filtrate was chromatographed on a reverse phase column (packing of PrepPAK-500/C18 cartridge, 100 ml), eluting with water, 5%, 10%, 20% and 30% aqueous CH3OH, successively. The fractions containing the desired compound were combined, evaporated and lyophilized to provide 10 mg (1.8%) of the title compound (I-1I) (E) as a tan powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2].Cl.Cl[CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:21][C:22]3[N:23]=[CH:24][S:25][CH:26]=3)=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1coc(-c2ccc(O)cc2)n1
Reactant: ClCc1cscn1
Agent: Cl
Product: CCOC(=O)Cc1coc(-c2ccc(OCc3cscn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Intermediate 16 from [2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 64) and 4-(chloromethyl)thiazole hydrochloride except KI (2 eq.) is also added. MS (m/e): 345.2 (M+1)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14]
Reactant: [I-]
Reactant: O=c1sc2ccccc2n1CCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1sc2ccccc2n1CCCI
Yield: 96 %

Procedure:
To a solution of 3-(3-chloropropyl)benzo[d]thiazol-2(3H)-one (2.86 g, 12.56 mmol) in acetone (50 mL), was added sodium iodide (3.77 g, 25.12 mmol). After refluxing for 60 hours, the reaction mixture was filtered. The filtrate was washed with water and dried to obtain the title compound (3.85 g, 83%); 1H NMR (DMSO-d6): δ 2.13-2.16 (m, 2H), 3.28 (t, 2H, J=6.8 Hz), 4.05 (t, 2H, J=6.8 Hz), 7.18-7.22 (m, 1H), 7.38-7.39 (m, 2H), 7.66 (dt, 1H, J=7.6 and 0.8 Hz).