Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[O:31][CH2:30][CH2:29][O:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH3:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.Cl>C(O)C>[O:28]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH:15]([CH3:16])[CH2:14][NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:18][CH2:19]3)[C:32]=2[O:31][CH2:30][CH2:29]1
Reactant: CC(CN(C(=O)OC(C)(C)C)c1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Agent: Cl
Solvent: CCO
Product: CC(CNc1ccccn1)N1CCN(c2cccc3c2OCCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
Compound VII as a crude oil (49.0 g, 0.106 mol) is dissolved in ethanol (150 mL) and to this solution is added 1N HCl solution in ethanol (212 mL). The resulting solution is refluxed for 18 h, then concentrated in vacuum to a small volume (˜100 mL) until product starts to crystallize. Ether (100 mL) is added slowly to resulting slurry, in portions, and the mixture is stirred at ambient temperature for 2 h. Slightly gray crystals are filtered and washed with ethanol/ether (50:50) mixture to afford 22.2 g of compound VIII (49% over 3 steps). The purity is determined to be 97.9% by LC-MS. This batch is then recrystallized from methanol (150 mL) and ether (200 mL) to produce 19.3 g of VIII with 99% purity. 1H NMR (CD3OD) δ8.01 (m, 2H), 7.30 (d, J=9 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 6.82 (t, J=8.1 Hz, 1H), 6.63 (m, 2H), 4.30 (m, 4H), 4.10 (m, 1H), 3.80-2.90 (m, 9H), 1.55 (d, J=6.2 Hz, 3H). MP=245-248° C.
Reaction SMILES: Br[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:4]=2[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:3][C:4]=2[CH:10]=1
Reactant: Brc1ccc2[nH]c(Br)nc2c1
Reactant: C1CCNC1
Solvent: CC#N
Product: Brc1ccc2[nH]c(N3CCCC3)nc2c1
Temperature: 150 °C

Procedure:
A suspension of 1 g (3.6 mmol) of 2,5-dibromo-1H-benzimidazole and 0.85 mL (10.18 mmol) of pyrrolidine in 45 mL of acetonitrile is heated for 2 hours at 150° C. in the microwave. The reaction mixture is poured onto water and extracted with EtOAc. The organic phase is washed three times with water and dried over sodium sulfate. The solvent is distilled off, and the residue is stirred with DIPE and the solid is filtered off. Yield: 0.43 g (45% of theoretical); C11H12BrN3 (M=266.13); calc.: molpeak (M−H)—: 264/266; found: molpeak (M−H)−: 264/266; Rf value: 0.5 (silica gel, DCM/MeOH 10:1).
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2+:11][CH2:12][C:13]#[CH:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:2][C@@H:3]([NH:11][CH2:12][C:13]#[CH:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CC[NH2+][C@H](C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C#CCN[C@H](C)Cc1ccccc1

Procedure:
840 mg (4 mmol) ((R)-1-methyl-2-phenyl-ethyl)-prop-2-ynyl-ammonium hydrochloride (Sigma) is dissolved in 10 ml dichloromethane and 1M aqueous sodium carbonate. The organic phase is separated. The aqueous phase is extracted three times with 10 ml dichloromathane. The combined organic phases are washed with brine and dried with magnesium sulfate. The crude product 6a is used without further purification.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.Cl[CH2:13][CH:14](Cl)[CH2:15][CH3:16].C(O)CCC>>[CH2:13]([P:6]1(=[O:5])[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)[CH2:14][CH2:15][CH3:16]
Reactant: CC1=CCP(OCCCCl)C1
Reactant: CCC(Cl)CCl
Solvent: CCCCO
Product: CCCCP1(=O)CC=C(C)C1
Yield: 65.3 %

Procedure:
To a solution of 26.4 g. (0.137 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene in 57 ml. of 1,2-dichlorobutane was added 30.4 g. (0.411 mole) of n-butanol. The mixture was heated under reflux for 4 hours and then the solvent was removed by evaporation. The residue was distilled under reduced pressure to obtain 15.4 g. (65.3% yield) of 1-butyl-3-methyl-3-phospholene-1-oxide in the form of a liquid having a boiling point of 106° - 116° C at 0.2 mm. of mercury.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]([OH:17])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]>CC(C)=O.CN(C=O)C>[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:17][C:12]2[CH:13]=[C:14]([I:16])[CH:15]=[C:10]([C:9](=[O:18])[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=2)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]
Reactant: O=C(NCc1ccccc1)c1cc(O)cc(I)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(C(=O)NCc3ccccc3)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 48 h
Yield: 100.8 %

Procedure:
To a solution of N-benzyl-3-hydroxy-5-iodo-benzamide (4.1 g) in a mixture of acetone and DMF (2:1, 100 mL) were added potassium carbonate (16.0 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (6.0 g). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 8.7 g of yellow oil (100% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1ccccc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccccc1

Procedure:
The compound prepared in Example 3 was reacted with benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound.
Reaction SMILES: Br[C:2]1[C:26](=[O:27])[N:25]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH:21]([CH3:23])[O:20][CH:19]([CH3:24])[CH2:18]4)=[CH:13][N:12]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:33].C([Sn](CCCC)(CCCC)[C:39]([O:41][CH2:42][CH3:43])=[CH2:40])CCC>C1(C)C=CC=CC=1.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>[CH:28]1([N:25]2[C:5]3[N:6]=[C:7]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:18][CH:19]([CH3:24])[O:20][CH:21]([CH3:23])[CH2:22]5)=[CH:13][N:12]=4)[N:8]=[CH:9][C:4]=3[C:3]([CH3:33])=[C:2]([C:39]([O:41][CH2:42][CH3:43])=[CH2:40])[C:26]2=[O:27])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)OC(C)C4)cn3)ncc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CC(C)OC(C)C4)cn3)nc2n(C2CCCC2)c1=O

Procedure:
6-Bromo-8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.062 g, 0.121 mmol), tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (0.068 mg, 0.188 mmol) were dissolved in toluene (2 mL) and slowly brought to reflux for 12 hours. Additional tetrakis(triphenylphosphine)palladium (0.010 g) was added and the reaction brought to reflux for 16 hours. The reaction mixture was cooled and purified by silica gel chromatography to 8-cyclopentyl-2-[5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamino]-6-(1-ethoxy-vinyl)-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.055 g, 90.2%). 1H NMR δ(400 MHz, CDCl3) 8.72 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.83 (s, 1H), 7.29 (dd, J=2.9, 9.0 Hz, 1H), 5.89 (m, 1H), 4.51 (d, J=2.5 Hz, 1H), 4.17 (d, J=2.4 Hz, 1H), 3.93 (q, J=7.1 Hz, 2H), 3.83 (m, 2H), 3.37 (d, J=10.3 Hz, 2H), 2.44 (dd, J=10.5, 10.5, 2H), 2.41 (s, 3H), 2.34 (m, 2H), 2.06 (m, 2H), 1.84 (m, 2H), 1.65 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.26 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[C:25]1[CH:26]=[C:27]([CH3:32])[C:28]([CH3:31])=[CH:29][CH:30]=1.C1(CNCC2CCCCC2)CCCCC1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[CH3:32][C:27]1[CH:26]=[C:25](/[CH:21]=[CH:20]/[C:18]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:7]([NH:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[CH:19]=2)[CH:30]=[CH:29][C:28]=1[CH3:31]
Reactant: Cc1ccc(Br)cc1C
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1C
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g were added 4-bromo-o-xylene 0.19 mL, N,N-dicyclohexylmethylamine 0.41 mL and palladium acetate 5.4 mg at room temperature, and it was stirred at 130° C. for 4 hours. 4-bromo-o-xylene 0.063 mL, N,N-dicyclohexylmethylamine 0.10 mL and (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 5.4 mg were added to it, and it was stirred at 130° C. for 2 hours. (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 11 mg and tri-tert-butylphosphine tetrafluoroborate 6.9 mg were added to it, and it was stirred at 130° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, and the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-((E)-2-(3,4-dimethylphenyl)vinyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([NH:10][C@@H:11]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:20](OC)=[O:21])[CH2:16][CH2:15]1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:3]([NH:10][C@@H:11]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17]([CH2:20][OH:21])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1(c2ccccc2)CCN(C(=O)[C@H](COCc2ccc(Cl)c(Cl)c2)NCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C([C@H](COCc1ccc(Cl)c(Cl)c1)NCc1ccccc1)N1CCC(CO)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
Lithium borohydride (5.0 mg) was added to a stirred solution of (S)-methyl 1-[2-benzylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-phenylpiperidin-4-carboxylate (100 mg) in toluene (5.0 mL) and tetrahydrofuran (5.0 mL). The resulting solution was warmed to reflux for 3 h., cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonium chloride (saturated) and the organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1) to give the title compound as a colorless solid (26 mg), δH (CDCl3) 1.69-1.82 (5H, m), 2.41-2.61 (4H, m), 3.15-3.21 (2H m), 3.44 (2H, s), 3.53-3.68 (4H, m), 4.34 (1H br s), 6.98-7.46 (12H, m). m/e (ES+) 527 (MH+).
Reaction SMILES: [OH-].[K+:2].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([C:17]#[C:18][C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]4)[CH2:20]2)[CH2:26]3)[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)=[O:6]>C(O)CCC>[K+:2].[K+:2].[C:19]12([C:18]#[C:17][C:9]3[CH:10]=[C:11]([C:13]([O-:15])=[O:14])[CH:12]=[C:7]([CH:8]=3)[C:5]([O-:6])=[O:4])[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][CH:25]([CH2:27]3)[CH2:26]1)[CH2:28]2
Reactant: COC(=O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C([O-])c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)[O-])c1
Yield: 97 %

Procedure:
In a 5 L four-neck flask provided with a thermometer, a Dimroth condenser and an agitator, 3 L of n-butanol and 226 g of potassium hydroxide (85%) (2.72 mol) were charged. The mixture was heated and refluxed to be dissolved. After adding 120 g of the obtained 1-(3,5-bis(methoxycarbonyl)phenyl)-2-(1-adamantyl)ethyne (0.341 mol) therein, the mixture was heated and refluxed for 30 minutes. Next, it was cooled in an ice bath and filtered to obtain precipitated crystal. The crystal was washed with 1 L of ethanol two times followed by drying under pressure at 60° C., thus obtaining 132.49 g of 5-(2-(1-adamantyl)ethynyl) isophthalic acid dipotassium salt (the yield was 97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([CH3:19])=[N:10][N:11]2[C:15](Br)=[C:14]([S:17][CH3:18])[S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([CH2:36][O:37][CH3:38])[CH:33]=[C:32]([O:39][CH3:40])[C:31]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.O.C(O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([CH3:19])=[N:10][N:11]2[C:15]([C:31]3[C:32]([O:39][CH3:40])=[CH:33][C:34]([CH2:36][O:37][CH3:38])=[CH:35][C:30]=3[O:29][CH3:28])=[C:14]([S:17][CH3:18])[S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reactant: CSc1sc2c(NC(=O)OC(C)(C)C)c(C)nn2c1Br
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: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1cc(OC)c(-c2c(SC)sc3c(NC(=O)OC(C)(C)C)c(C)nn23)c(OC)c1
Temperature: 110 °C
Yield: 91.3 %

Procedure:
To a mixture of tert-butyl[3-bromo-6-methyl-2-(methylthio)pyrazolo[5,1-b][1,3]thiazol-7-yl]carbamate (397 mg, 1.03 mmol), toluene (6.8 mL) and ethanol (3.4 mL) were added 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (349 mg, 1.55 mmol) synthesized by the method described in WO2004/037822, a 1M aqueous solution of sodium carbonate (2.06 mL, 2.06 mmol) and tetrakis(triphenylphosphine)palladium (119 mg, 0.10 mmol) in this order, and the mixture was heated to reflux at 110° C. for three hours. Water was added to the reaction mixture and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was stirred at 75° C. for five hours. Chloroform was added to the reaction mixture, insoluble matters were filtered off, and then the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 33% then 66%) to obtain 450.9 mg (0.94 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([C:12]2[C:21]3[C:16](=[C:17]([CH3:25])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2[C:26]#[N:27])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:28]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.S(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:28][CH2:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[C:21]2[C:16]=1[N:15]=[CH:14][C:13]([C:26]#[N:27])=[C:12]2[N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9](=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(C)cc([N+](=O)[O-])cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N(c1cccc(Br)c1)c1c(C#N)cnc2c(CBr)cc([N+](=O)[O-])cc12
Yield: 119 %

Procedure:
A stirred mixture of 4-[(3-bromophenyl)-N-acetylamino]-8-methyl-6-nitro-quinoline-3-carbonitrile (10.6 g, 25 mmol), N-bromosuccinimide (6.68 g, 37.5 mmol), 0.30 g of dibenzoyl peroxide, and 200 ml of carbon tetrachloride was refluxed for 2 h, treated with an additional 0.30 g of dibenzoyl peroxide, and refluxed an additional 2.5 h, cooled, diluted with methylene chloride, and stirred with aqueous sodium bisulfite. The organic layer was separated and washed successively with water, sodium bicarbonate solution, and water. The solution was dried and evaporated to give 15 g of a white foam, NMR (CDCl3) d 5.19 (dd, CH2Br).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15](/[CH:18]=[CH:19]\[C:20]4[N:21]=[N:22][S:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:36][CH2:37][CH2:38]Br)(=[O:35])[CH3:34]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH:37]([O:36][C:33](=[O:35])[CH3:34])[CH3:38])=[O:26])=[C:15](/[CH:18]=[CH:19]\[C:20]4[N:21]=[N:22][S:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OCCBr
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C\c4csnn4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(=O)OC(C)OC(=O)C1=C(/C=C\c2csnn2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 23.1 %

Procedure:
In like manner as in Example 20 sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.5 g) was reacted with DL-2-bromoethyl acetate (0.23 g) thereby DL-1-acetyloxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.13 g) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=O)[C:7]([Br:10])=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:26].O>C(O)(=O)C.O1CCOCC1>[Br:10][C:7]1[N:6]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[NH:26][C:3](=[O:2])[C:5]2=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cn3c(Br)ccc3c(=O)[nH]2)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 5-bromo-1-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (0.15 g, 0.43 mmol) and ammonium acetate (170 mg, 2.21 mmol) in glacial acetic acid (2 mL) was heated at 130° C. overnight. The reaction was stopped, and the recovered starting material was suspended in 1,4-dioxane (2 mL), treated with ammonium acetate (170 mg, 2.21 mmol) and then was heated in a sealed tube at 120° C. for 5 h. At this time, the reaction was treated with additional ammonium acetate, and the mixture continued stirring at 120° C. overnight. At this time, the reaction was treated with water. The resulting precipitate was collected by filtration, washed with water (2×) and dried in vacuo to afford 6-bromo-3-(4-methoxy-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (78 mg, 55%) as red solid. 1H NMR (DMSO-d6) δ ppm 7.54-7.63 (m, 4H), 7.03 (d, J=9.0 Hz, 2H), 6.96 (d, J=1.3 Hz, 1H), 3.80 (s, 3H). LC-MS calcd. for C14H12BrN2O2 [(M+H)+] 319, obsd. 319.0.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1COCCN1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N2CCOCC2)s1
Yield: 52 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using morpholine instead of rac-2-amino-1-butanol, to the title compound (98 mg, 52%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=376.3 [M+H]+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[C:18](C(OCC)=O)=[C:17]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[C:16]([N+:33]([O-:35])=[O:34])=[C:15]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:38]1[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=1[CH2:36][C:15]1[C:16]([N+:33]([O-:35])=[O:34])=[C:17]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:31][CH:32]=2)[C:18]2[C:6](=[O:5])[N:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]=2[N:14]=1
Reactant: CCOC(=O)c1c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Cc2ccc(F)cc2F)c([N+](=O)[O-])c1-c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2c3c(nc(Cc4ccc(F)cc4F)c2[N+](=O)[O-])[C@@H]2CCCN2C3=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the flask containing crude 4-[2-[(2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]-6-(2,4-difluorobenzyl)-3-(ethoxycarbonyl)-5-nitro-4-pyridinyl]benzoic acid (D, 22.2 g, 36.3 mmol), 200 ml premixed trifloroacetic acid and dichloromethane (10 ml/4.2 ml ratio) was added. The resulting mixture was stirred at room temperature for 20 minutes. The solvents were removed in vacuo. The resulting residue was dissolved in 150 ml mixture of triethyl amine and dichloromethane (10 ml/20 ml) and was stirred at room temperature for 2 hours.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH3:21])=[CH:15][CH:14]=1>O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:2][OH:3])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
Hydroxylamine hydrochloride (7.0 g, 100 mmol) and sodium acetate (8.2 g, 100 mmol) were added to 50 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(4-Methoxyphenyl)propan-1-one (15 g, 91.4 mmol) was added and the mixture was stirred at room temperature for 20 hours, and then refluxed for 20 hours. Water (50 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 18.3 g of the title compound. MS: (+) m/z 180.39 (M+1).
Reaction SMILES: [ClH:1].N[C@@H](CCC)[C@@H](C1C=CC=CC=1)O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23](=[O:36])[C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1>>[ClH:1].[NH2:28][C@@H:24]([CH2:25][CH2:26][CH3:27])[C@@H:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=1)[OH:36]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1cccc(OC)c1
Agent: CCC[C@H](N)[C@H](O)c1ccccc1
Agent: Cl
Product: CCC[C@H](N)[C@H](O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as 91b from (S)-tert-butyl 1-(3-methoxyphenyl)-1-oxopentan-2-ylcarbamate (213 mg, 0.693 mmol).