Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH3:16])[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[NH:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O.CO>[O:27]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:2]([CH3:16])[C@@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC([C@H](C)NC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 0.72 g of benzyl [(2S)-3-hydroxybutan-2-yl]carbamate (Example 133A, 3.3 mmol, 1 equivalent), 0.57 g of 1H-isoindole-1,3(2H)-dione (3.9 mmol, 1.2 equivalents) and 1.3 g of triphenylphosphine (4.9 mmol, 1.5 equivalents) were dissolved in 15 ml of THF, and 1.1 g of di-tert-butyl(E)-diazene-1,2-dicarboxylate (DIAD, 4.9 mmol, 1.5 equivalents) were added at RT. The mixture was stirred at RT overnight, 2 drops of water and Extrelut® were added and the mixture was concentrated. The residue was purified on a silica gel cartridge (Biotage SNAP Cartridge KP-Sil 25 g) (gradient cyclohexane/ethyl acetate from 5% to 100%). The crude product obtained was left in a mixture of 5 ml of methanol and 1 ml of water overnight. The solid obtained was filtered off, washed with a little methanol/water mixture and dried under reduced pressure. The filtrate was purified by preparative HPLC (Method 9). This gave a total of 692 mg (53% of theory, purity 87%) of the title compound (diastereomer mixture in a ratio of about 4:1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:13][CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])(=[O:12])[CH3:11].C(N(CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.O1CCOCC1>[C:10]([O:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17][C:6]([C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:7])(=[O:12])[CH3:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(=O)COC(C)=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a round bottom flask containing 4-bromobenzaldehyde (1.4 g, 7.80 mmol), 2-oxobut-3-enyl acetate (1 g, 7.80 mmol) and 3-benzyl-5-(2-hydroxyethyl)-4-methyl-thiazolium chloride (0.21 g, 0.78 mmol) was added dioxane (20 ml). The mixture was stirred at room temperature and triethylamine (0.65 ml, 0.60 mmol) was added. The reaction mixture was heated to 80 C for overnight. Afterward, the reaction was cooled down to room temperature, quenched with a solution of saturated ammonium chloride and concentrated. The residue was taken up in MTBE and washed with saturated ammonium chloride solution twice, then once with brine. The organic portion was dried over sodium sulfate, filtered and concentrated. The resulting crude material was purified by column chromatography to afford the title compound as a light orange solid after drying (1.63 g, 67% yield). MS (ESI) m/z 315.0 (M+1). Retention time 1.14 min. (Condition X).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)C(=O)N2C
Yield: 65.8 %

Procedure:
A mixture of 0.030 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.017 g (0.0001 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.028 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-1) as an off-white solid.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([F:26])[C:12]([NH2:25])=[C:13]2[C:18]=1[O:17][CH2:16][CH:15]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[NH:14]2.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.O>[Br:8][C:9]1[C:18]2[O:17][CH2:16][CH:15]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:14]3[C:28](=[O:30])[NH:25][C:12]([C:13]=23)=[C:11]([F:26])[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Br)c2c1NC(c1cccnc1)CO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cc(Br)c3c2n1C(c1cccnc1)CO3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (140 μL, 1.0 mmol) was added to a solution of 8-bromo-6-fluoro-3-pyridin-3-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (160 mg, 0.50 mmol)) in THF (6.0 mL), followed by addition of triphosgene (60 mg, 0.2 mmol), and the mixture was subsequently stirred at room temperature for 10 min. The mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine and concentrated. Purification on silica gel eluting ethyl acetate in hexanes afforded the title compound. LCMS calc. for C14H10BrFN3O2 (M+H)+: m/z=350.0. found: 350.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([Cl:25])([Cl:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH3:2].[OH:27]O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([Cl:25])([Cl:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCSc1ccc(Cl)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cl)(Cl)CCCCCCCCCCS(=O)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
2.0 g (4.55 mmol) 104 and 6 ml 30% hydrogen peroxide in 20 ml glacial acetic acid were oxidized to form 2.08 g (99%) 106 as a colourless oil analogously to 78 (example 26).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36]O)=[CH:33][CH:32]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:33][CH:32]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: OCCc1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc3[nH]ccc3c2)cc1
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a solution of 1.06 g (8 mmol) 5-hydroxyindole and 2.09 g (8 mmol) triphenylphosphine in 40 ml anhydrous THF, cooled to 0° C. in ice, was added 1.0 mL (8 mmol) 4-fluorophenethylalcohol and 1.6 ml (8 mmol) diisopropylazodicarboxylate. The solution was allowed to gradually come to room temperature overnight. The solution was concentrated and the residue was chromatographed on silica using 20-25% EtOAc-hexane to afford 0.525 g 5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[NH:19][C:18]([CH2:20][O:21][CH3:22])=[N:17][N:16]=3)=[CH:10][C:5]=2[C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[NH:19][C:18]([CH2:20][O:21][CH3:22])=[N:17][N:16]=3)=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COCc1nnc(-c2cc(C(=O)OC)c(C3CC3)cc2C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nnc(-c2cc(C(=O)O)c(C3CC3)cc2C)[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a round-bottom flask was added a solution of methyl 2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate (compound 190.7, 200 mg, 0.600 mmol, 1.00 equiv, 90%) in methanol (4 mL). A solution of sodium hydroxide (106 mg, 2.65 mmol, 4.00 equiv) in water (2 mL) was added to the reaction mixture. The resulting solution was stirred for 2 h at 60° C. After cooling to ambient temperature, the organic solvent was removed under reduced pressure and the pH the remaining aqueous layer was adjusted to 2-3 with hydrogen chloride (aq, 6 M). The resulting solids were collected by filtration and dried to yield 170 mg (89%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: C1CCNCC1
Product: N#Cc1ccc(N2CCCCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-bromo-3-(trifluoromethyl)-benzonitrile and piperidine (Fluka, Buchs, Switzerland), with a reaction temperature of 95° C.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([F:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(F)cccc2c1=O
Product: CCCC(=O)c1cnc2c(F)cccc2c1Cl

Procedure:
3-Butyryl-8-fluoro-4(1H)-quinolone (2.7 g, 12 mmol) and phosphoryl chloride (40 ml) were heated at reflux for 3 hours. Excess phosphoryl chloride was evaporated in vacuo. the residue poured onto ice and neutralised with aqueous ammonia. Filtration and washing with water gave 3-butyryl-4-chloro-8-fluoroquinoline ((1.75 g), m.p. 57°-60°.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[CH3:24])=O)(C)(C)C>ClCCl>[CH3:23][O:22][C:18]1[C:17]([CH3:24])=[C:16]([CH:21]=[CH:20][CH:19]=1)[NH2:15]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(N)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (40.7 mL, 548 mmol) was added to a solution of N-(tert-butyloxycarbonyl)-3-methoxy-2-methylaniline, in dichloromethane (500 mL). After 2 h at room temperature, TFA (40.7 mL, 548 mmol) was added and the resulting mixture was stirred at room temperature overnight. Then, volatiles were evaporated. The residue was triturated with toluene (100 mL) and diisopropylether (250 mL), filtered off and washed with diisopropyl ether (100 mL) to give 56.3 g of the title product as a TFA salt: m/z=138 (M+H)+. The TFA salt was transformed to the free aniline by treatment with NaHCO3.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:16]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]3[N:29]=[C:28]4[CH2:30][N:31]([C:47]([N:46]([CH3:50])[CH3:45])=[O:48])[CH2:32][CH2:33][C:27]4=[N:26][C:25]=3[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]2)=[C:9]([F:8])[CH:10]=1)#[N:13].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(C(=O)N(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (20.7 mg, 0.039 mmol) and triethylamine (0.017 mL, 0.118 mmol) in DCM (0.5 mL) was added dimethylcarbamoyl chloride (7.3 μL, 0.079 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using a 30% to 70% ACN gradient to give the title compound as a TFA salt (11.6 mg, 49.4%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.26 (m, 6H), 1.87-1.96 (m, 2H), 2.08-2.16 (m, 2H), 2.81-2.99 (m, 6H), 3.25-3.42 (m, 3H), 3.65-3.71 (m, 1H), 4.12-4.19 (m, 2H), 4.25-4.31 (m, 1H), 4.82-4.88 (m, 1H), 5.89 (d, J=8.3 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.66-7.71 (m, 1H), 7.87 (dd, J=11.4, 2.0 Hz, 1H), 9.96 (br s, 1H); ESI-MS m/z [M+H]+ 482.5.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[CH3:30]I>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:12]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH3:30])[CH2:9][C@H:8]1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(C)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (0.97 g) in N,N-dimethylformamide (5.0 ml) was added sodium hydride (0.099 g) at 0° C. After stirring at ambient temperature for 1 hour, the mixture was cooled to 0° C. To the mixture was added methyl iodide (0.31 ml) and the resulting mixture was stirred for additional 4 hours at 0° C. The reaction mixture was diluted with water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give (2S,4S)-1-allyloxycarbonyl-4-(N-allyloxycarbonyl-N-methylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (1.01 g). IR (Neat): 1700 cm-1
Reaction SMILES: [C:1]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[CH3:28])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC(C)([O-])C.[K+]>CCN(C1C=CC=CC=1)CC>[CH2:2]([C:1]1[NH:18][C:19]2[C:20]([CH:28]=1)=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1ccc(C(=O)O)cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)c1ccccc1
Product: CCCCCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A stirred mixture of 4-(n-hexadecanamido)-3-methylbenzoic acid (4 g), potassium tert-butoxide (4 g) and diethylaniline (10 ml) was refluxed for 3.5 hours. The fraction boiling at less than 200° C. during the reaction was collected. The reaction mixture was left to cool to room temperature and was then acidified with 10% w/v hydrochloric acid. The solid was filtered off, dried and recrystallized from toluene to give 2-(n-pentadecyl)indole-5-carboxylic acid (2.7 g), m.p. 108°-110° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]2[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][CH:21]12.C(O)(=O)C.C([BH3-])#N.C[NH+](C)C>CO>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:25]3[CH2:24][CH2:23][N:22]4[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][CH:21]4[CH2:20]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1CCCC2CNCCN12
Agent: C[NH+](C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCC2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Temperature: 120 °C
Yield: 27.6 %

Procedure:
To a solution of 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 1.32 g, 5.6 mmol) and octahydro-6H-pyrido[1,2-a]pyrazin-6-one hydrochloride (see Bioorg. Med. Chem.; 2004; 71-86; 1.30 g, 6.8 mmol), in methanol (10 mL) was added acetic acid (1 mL). The solution was mixed with (polystyrylmethyl) trimethylammonium cyanoborohydride (4.2 mmol/g, 1.67 g, 8.8 mmol) and the mixture was heated for 5 min at 120° C. using microwave single node heating. The resin was filtered off and then the solvent was removed by evaporation. The product was purified by means of silica gel chromatography using a mixture of ammonia saturated methanol (2%) and methylene chloride. There was obtained 0.58 g (28%) of 2-[1-(diphenylmethyl)azetidin-3-yl]octahydro-6H-pyrido[1,2-a]pyrazin-6-one as an oil. 1H NMR (500 MHz, CDCl3): 1.4 (q, 1H), 1.7 (t, 2H), 1.8-2.0 (m, 3H), 2.3-2.4 (m, 1H), 2.4-2.5 (d, 1H), 2.7-2.8 (t, 3H), 3.0 (m, 3H), 3.4-3.6 (m, 3H), 4.5 (s, 1H), 4.6 (d, 1H), 7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 376 (M+1)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH:32][P:33]([O:37]C)([O:35]C)=[O:34])[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([O-:24])=[O:23])=[C:12]([CH2:15][N+:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C[Si](Br)(C)C.C(OC(C)C)(C)C>>[CH3:1][O:2][N:3]=[C:4]([C:27]1[N:28]=[C:29]([NH:32][P:33]([OH:37])([OH:35])=[O:34])[S:30][CH:31]=1)[C:5]([NH:7][CH:8]1[C:25](=[O:26])[N:10]2[C:11]([C:22]([O-:24])=[O:23])=[C:12]([CH2:15][N+:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(NP(=O)(OC)OC)n1
Agent: C[Si](C)(C)Br
Solvent: CC(C)OC(C)C
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(NP(=O)(O)O)n1
Reaction time: 2.5 h

Procedure:
To the mixture containing 7-[2-methoxyimino-2-(2-dimethoxyphosphorylaminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) was dropped trimethylsilyl bromide (14.80 g) at 3° to 8° C. under stirring, which was continued for 2.5 hours at ambient temperature. The reaction mixture was poured into diisopropyl ether (1.5 l) and the resultant resinous oil was separated by decantation. The oil was dissolved in water (300 ml), adjusted to pH 1 with 1N hydrochloric acid and subjected to column chromatography on a nonionic adsorption resin "Diaion HP-20" (320 ml). After the column was washed with water (1.4 l), the elution was carried out with 20% aqueous methanol. The fractions containing the object compound were collected, evaporated to remove methanol and lyophilized to give 7-[2-methoxyimino-2-(2-phosphonoaminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.3 g), mp. 155° to 164° C. (dec.).
Reaction SMILES: I[CH3:2].[F:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:7][NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10]>>[F:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:7][NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:2])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10]
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Reactant: CI
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3ccc(F)c(F)c3)s2)c(=O)c1
Yield: 66 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use iodomethane in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-(3,4-difluorobenzyl)-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 66% yield: mp 183-185° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=8.1 Hz, 1H), 7.18-7.05 (m, 3H), 6.20-6.15 (m, 2H), 5.97 (d, J=2.5 Hz, 1H), 4.53 (d, J=5.8 Hz, 2H), 3.82 (m, 3H), 2.68 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 162.3, 162.1, 153.6, 152.7, 135.0, 131.4, 123.7, 121.8, 117.6, 117.4, 116.9, 116.7, 104.0, 96.2, 56.0, 43.0, 17.3; MS (ES+) m/z 392.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH2:17][N:12]([C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]2)=[N:3][CH:4]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Product: CC(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
Prepared from 2,5-dibromopyridine and 1-acetylpiperazine by the method of Example 13 (b).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1)=[O:2].CO.[BH4-].[Na+].Cl>C1COCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a mixture of 4′-formyl-2′-nitrobiphenyl-2-carbonitrile (5.15 g), methanol (30 mL) and hydrofuran (30 mL) was gradually added sodium borohydride (0.40 g) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into 1 M hydrochloric acid (20 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (3.62 g, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>CC(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)=[CH:3][C:2]=1[O:1][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2ccc(OC)c(OCC=C(C)C)c2)n1
Yield: 42 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxy-4-methoxyphenylamino)thiazole-4-carboxylate (139 mg, 0.47 mmol) and K2CO3 (72 mg, 0.52 mmol) in acetone (4.7 mL) was treated with 4-bromo-2-methyl-2-butene (0.066 mL, 0.56 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 42% yield (71 mg).