Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Cl[CH2:42][C:43]1[C:44]([C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[C:57]([F:60])([F:59])[F:58])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>C1COCC1.O>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C@@H:51]3[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]3[C:57]([F:59])([F:60])[F:58])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:50][CH2:49]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: FC(F)(F)[C@@H]1CCCC[C@H]1c1noc(C2CC2)c1CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c([C@@H]3CCCC[C@H]3C(F)(F)F)noc1C1CC1)C2
Reaction time: 0.17 h

Procedure:
A solution of N-Boc-nortropine (579 mg, 2.55 mmol) and 18-crown-6 (808 mg, 3.06 mmol) in THF (8.5 mL) was treated with potassium tert-butoxide (343 mg, 3.06 mmol) and stirred for 10 minutes. A solution of 4-(chloromethyl)-5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazole (784 mg, 2.55 mmol) in THF was added. The resulting mixture was stirred at rt for 2 hours and then poured into water and extracted with EtOAc. Organics were collected, dried (MgSO4), filtered, concentrated and chromatographed (SiO2, linear gradient, 0-60% EtOAc in Hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3) δ 4.28 (m, 2H), 4.19 (m, 1H), 4.11 (m, 1H), 3.66 (dd, J=4.8, 4.7 Hz, 1H), 3.47 (dd, J=7.6, 3.7 Hz, 1H), 2.42 (m, 1H), 2.19 (ddd, J=25.2, 12.5, 3.4 Hz, 1H), 2.00-1.77 (m, 13H), 1.69 (m, 1H), 1.52 (m, 1H), 1.46 (s, 9H), 1.35 (m, 1H), 1.12 (m, 2H), 1.03 (m, 2H)4; MS m/z 443.2 (M-tBu+1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])#[CH:9].O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:5]([NH:13][C:12]1[CH:11]=[C:10]([C:8]#[CH:9])[CH:16]=[CH:15][CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Acetic anhydride (13.8 mL, 144 mmol) was added dropwise to a solution of 3-ethynylaniline (14.0 g, 120 mmol) and 4-(Dimethylamino-)pyridine (DMAP) (1.5 g, 12 mmol) in tetrahydrofuran (300 mL). The mixture was stirred at room temperature for 2 hours, water (100 mL) was added to the mixture and the whole was extracted with dichloromethane (2×250 mL). The combined organics was washed with 10% citric acid (100 mL) followed by saturated sodium bicarbonate solution (100 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 3-(acetylamino)phenylacetylene as a yellow solid (18.3 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:4]2[C:9]([C:10]=1[C:11](O)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([CH:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:2]=2[CH3:1])=[O:12])=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C(C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccccc3)c3ccccc23)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylic acid (150 mg, 0.54 mmol) in anhydrous dichloromethane (10 mL) was added N-hydroxybenzotriazole (87 mg, 0.64 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (124 mg, 0.64 mmol) and trimethylamine (163 mg, 1.61 mmol). The mixture was stirred at room temperature for 0.5 hours, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (98 mg, 0.64 mmol) was added. The mixture was stirred at room temperature for 12 hours. To the reaction mixture was added water (20 mL), extracted with dichloromethane (20 mL×2). The organic layers were combined and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give compound N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxamide as an off-white solid (130 mg, 59%). LRMS (M+H+) m/z: calcd 413.21. found 413. 1H NMR (300 MHz, d6-DMSO) δ: 11.59 (s, 1H), 7.73-7.66 (m, 2H), 7.34-7.29 (m, 3H), 7.23 (d, J=7.5 Hz, 1H), 7.16-6.89 (m, 4H), 5.94 (q, J=7.2 Hz, 1H), 5.88 (s, 1H), 4.32 (d, J=5.4 Hz, 2H), 2.60 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H), 1.88 (d, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:11][CH:10]=2)[C:5](=[O:30])[N:4]([CH3:31])[CH:3]=1.[C:32]([C:36]1[S:43][C:42]2[C:41](=[O:44])[N:40]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47](B4OC(C)(C)C(C)(C)O4)[C:46]=3[CH3:60])[CH2:39][C:38]=2[CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:32]([C:36]1[S:43][C:42]2[C:41](=[O:44])[N:40]([C:45]3[C:46]([CH3:60])=[C:47]([C:2]4[N:7]=[C:6]([NH:8][C:9]5[CH:10]=[CH:11][C:12]([CH:15]6[C:20](=[O:21])[N:19]([CH3:22])[CH2:18][CH2:17][N:16]6[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:13][CH:14]=5)[C:5](=[O:30])[N:4]([CH3:31])[CH:3]=4)[CH:48]=[CH:49][CH:50]=3)[CH2:39][C:38]=2[CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CN1CCN(C(=O)OC(C)(C)C)C(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1=O
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2cn(C)c(=O)c(Nc3ccc(C4C(=O)N(C)CCN4C(=O)OC(C)(C)C)cc3)n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A 25-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with of 102k (200 mg, 0.486 mmol), 102g (217 mg, 0.442 mmol), sodium carbonate (115 mg, 1.08 mmol), water (1.5 mL), 1,4-dioxane (5 mL), and DMF (2 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.07 mmol) was added and the reaction mixture was heated at reflux for 16 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (40 mL) and water (5 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gave an 88% yield (272 mg) of 102l as a brown foam: mp 120-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.33 (s, 1H), 7.79 (d, 2H, J=6.9 Hz), 7.71-7.28 (m, 5H), 6.92 (s, 1H), 6.75 (s, 1H), 5.30 (s, 3H), 4.63 (s, 2H), 4.61 9s, 1H), 3.62 (s, 3H), 3.50 (m, 2H), 3.42-3.22 (m, 2H), 3.04 (m, 4H), 1.46 (s, 18H); MS (APCI+) m/z 697.5 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:13]3([CH2:18][CH3:19])[O:17][CH2:16][CH2:15][O:14]3)=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[N:5]2[N:4]=1)[CH3:2].[CH3:21][Mg]Br.C1COCC1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([C:3]1[CH:20]=[C:6]2[C:7]([C:13]3([CH2:18][CH3:19])[O:14][CH2:15][CH2:16][O:17]3)=[CH:8][CH:9]=[C:10]([CH:11]([OH:12])[CH3:21])[N:5]2[N:4]=1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1cc2c(C3(CC)OCCO3)ccc(C=O)n2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc2c(C3(CC)OCCO3)ccc(C(C)O)n2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The compound of Example 152 (321 mg) was dissolved in THF (12.0 mL) in an argon atmosphere. While the solution was kept at −78° C., 0.90 mol/L methyl magnesium bromide/THF solution (1.70 mL) was added dropwise and the mixture was stirred for 3.5 hours as it was allowed to gradually warm to room temperature. Subsequently, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a yellow oil (340 mg).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:5][CH:4]=1)#[CH:2].FC(F)(F)C([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[CH:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([C:1]3[NH:22][C:23]4[C:28]([CH:2]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:4][CH:5]=1)[CH2:9]2
Reactant: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Reactant: O=C(Nc1ccccc1I)C(F)(F)F
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(-c3ccc(OC4CN5CCC4CC5)cc3)cc2c1

Procedure:
Under N2, the mixture of product from Example 6A (114 mg, 0.5 mmol), the product from Example 6B (157 mg, 0.5 mmol), CuI (Strem Chemicals, 14 mg, 0.075 mmol), PPh3 (Aldrich, 39 mg, 0.15 mmol) and K3PO4 (212 mg, 1 mmol) in dioxane (5 mL) was stirred at 80° C. for 20 h. After the reaction was complete, it was diluted with EtOAc (30 mL) and washed with brine (2×5 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as solid (70 mg, yield, 44%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.59 (m, 1H), 1.65-1.91 (m, 2H), 2.00-2.14 (m, 1H), 2.17-2.24 (m, 1H), 2.75-3.01 (m, 5H), 3.31-3.42 (m, 1H), 4.54-4.62 (m, 1H), 6.66 (d, J=0.7 Hz, 1H), 6.93-7.00 (m, 3H), 7.01-7.08 (m, 1H), 7.35 (dq, J=8.2, 1.0 Hz, 1H), 7.48 (dq, J=7.8, 0.7 Hz, 1H), 7.71 (dt, J=8.8, 2.6 Hz, 2H) ppm. MS (DCI/NH3): m/z 319 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(N2[C:23]([C:24]3[CH:29]=[C:28](F)[CH:27]=[C:26]([Cl:31])[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=N2)C=CC=1F>>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=3)=[CH:22][C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Br)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 3A and 3-bromophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 2.50 g of the title compound with 70% purity (67% of theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:19])=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:19])[C:12]3[S:18][CH:17]=[CH:16][C:13]=3[N:14]([CH2:29][CH3:30])[CH:15]=2)=[O:9])=[CH:20][CH:21]=1
Reactant: CCI
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccsc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sccc21
Temperature: 100 °C

Procedure:
N-(4-chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (Example 1, 885 mg)was dissolved in DMF (20 mL) and to the solution was added potassium carbonate (1.92 g) and iodoethane (1.1 mL). The mixture was heated to 100° C. for 16 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×25 mL) followed by brine (25 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (EtOAc/heptane, 1/1; CH2Cl2/methanol, 100/1) and the resulting solid was recrystallized from ethanol to afford 590 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:23]([Cl:24])=[C:22]([CH2:25][CH3:26])[N:21]=[CH:20][N:19]=1>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[C:23]([Cl:24])=[C:22]([CH2:25][CH3:26])[N:21]=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ncnc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.4 g (10 mmol) of sodium hydride (80% dispersion in oil) was added to a solution of 2.0 g (10 mmol) of 1-(tert-butoxycarbonylpiperidin-4-ol and 1.8 g (10 mmol) of 4,5-dichloro-6-ethylpyrimidine in 25 ml of tetrahydrofuran, and the mixture was stirred for 2 hours at room temperature for 1 hour at reflux. After cooling, the mixture was concentrated, the residue was taken up in water/toluene, and the organic phase was dried and concentrated. For purification, the product was chromatographed on silica gel (petroleum ether/ethyl acetate 7:3). This gave 2.5 g (73.5% of theory) of a yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([OH:10])=O.C(N(CC)CC)C.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([N:32]=[N+:33]=[N-:34])=[O:10]
Reactant: O=C(O)/C=C/c1ccco1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)/C=C/c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a mixture of (2E)-3-(2-furyl)acrylic acid (660 g, 4.78 mol) and triethylamine (800 mL, 5.74 mol) in tetrahydrofuran (960 mL) was added diphenylphosphoryl azide (1.13 L, 5.26 mol) under ice-cooling. After stirring at room temperature for 4 hr, the reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with methanol to give the title compound (580 g, yield 74%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(Cl)Cl>[CH3:17][S:18]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccnc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccnc1F
Reaction time: 0.5 h

Procedure:
To a solution of (2-fluoropyridin-3-yl)methanol (200 mg, 1.57 mmol) and triethylamine (658 μL, 4.72 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (269 mg, 2.36 mmol). The reaction mixture was kept at 0° C. for 30 min., poured into water, and the mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[C:5]([CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:4]=1.[CH:27](=O)[CH:28]([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:15][CH2:16]2)=[C:5]([CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH:4]=1
Reactant: CC(C)C=O
Reactant: COc1cc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(C2CC(C)(C)CC(C)(C)C2)c(N2CCN(CC(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 1-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (10 mg, 0.028 mmol) produced in Example (87d) in tetrahydrofuran (1 mL) were added isobutyraldehyde (3.0 mg, 0.042 mmol), sodium triacetoxyborohydride (12 mg, 0.057 mmol) and acetic acid (1.7 mg, 0.028 mmol) in that order, followed by stirring for 60 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-[4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-isobutylpiperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO.[Br:17]Br>Br.O>[Br:17][CH2:13][C:12]([C:3]1[CH:4]=[C:5]([CH3:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])=[O:14]
Reactant: BrBr
Reactant: CC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Agent: Br
Solvent: O
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c(C)cc1C(=O)CBr
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(2,5-dimethyl-4-nitrophenyl)ethanone (300 mg, 1.55 mmol) in HBr (48%) (5 mL)/methanol (2.4 mL) was added bromine (250 mg, 1.55 mmol). The mixture was stirred at room temperature for 4 hrs. The mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine and concentrated. The residue was purified with silica gel column chromatography (10% ethyl acetate in hexanes) to afford 2-bromo-1-(2,5-dimethyl-4-nitrophenyl)ethanone as a white solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].CI.[C:36]([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:36][O:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate (II) (5.00 g, 10.9 mmoles), CH3I (2.04 mL, 32.8 mmoles) and K2CO3 (4.54 g, 32.8 mmoles) in dry dimethylsulfoxide (DMSO) (100 mL) was stirred at room temperature overnight and then poured into water (250 mL). The precipitate which formed was collected by filtration, washed with water and dried to give the title compound (5.15 g, quantitative yield). Mp. 115° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH3:30])[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[I-].[Na+].[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.Cl>CC(C)=O.C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH3:30])[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][N+:42]4[CH:41]=[CH:40][C:39]([C:35]5[O:34][CH:38]=[CH:37][N:36]=5)=[CH:44][CH:43]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: c1cc(-c2ncco2)ccn1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(-c4ncco4)cc3)CS[C@H]12)c1csc(N)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.75 g of sodium 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (hereinafter referred to Compound 1), 2.25 g of sodium iodide and 0.51 g of 4-(oxazol-2-yl)-pyridine were added to a mixture of 0.4 ml of 4 N hydrochloric acid and 1.2 ml of acetonitrile, followed by stirring at 80° C. for 1 hour. After allowing the mixture to cool, the reaction mixture was poured into acetone, and the precipitate formed was separated by filtration and washed with acetone. The resulting crude powder was dissolved in water, and the solution was subjected to column chromatography of Diaion HP-20 (trade name of Mitsubishi Chemical Industries, Ltd.). The column was developed with a mixture of water-tetrahydrofuran (93:7 by volume). The eluate was further subjected to reversed phase high performance liquid chromatography (column packing: Develosil, trade name of Nomura Chemical Co., Ltd.) and developed with a mixture of water-acetonitrile (89:11 by volume) to obtain the titled compound. Melting point: 160°-170° C. (decomposition).
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.O>C(O)(=O)C>[CH:7]1[CH:8]=[N+:3]([O-:1])[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=1
Reactant: N#CCc1cccnc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1ccc[n+]([O-])c1
Temperature: 95 °C
Reaction time: 72 h

Procedure:
30% Hydrogen peroxide (12 mL) was added to a solution of 3-pyridylacetonitrile (7.50 g, 63.5 mmol) in acetic acid (40 mL) and the mixture heated at 95° C. for 20 hours. The reaction mixture was then cooled and stirred at room temperature for 72 hours. Water (35 mL) was then added and the solution concentrated under reduced pressure. Water (2×100 mL) was added to the residue and solution concentrated under reduced pressure. Residual water was removed azeotropically using toluene (2×100 mL) to yield the title compound (I115) (8.3 g, 97%) as a pale yellow solid which was used without further purification.