Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:25][O:26][CH3:27])[C:9]([NH:11][CH:12]2[C:23](=[O:24])[N:14]3[C:15]([C:20]([OH:22])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.[Na].[C:29]([O:36][CH2:37]I)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(OCC)(=O)C>O.CN(C)C=O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:25][O:26][CH3:27])[C:9]([NH:11][CH:12]2[C:23](=[O:24])[N:14]3[C:15]([C:20]([O:22][CH2:37][O:36][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CCCCCC(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCC(=O)OCOC(=O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Yield: 55.5 %

Procedure:
7-[2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid hydrochloride (syn-isomer: 1.5 g.) and sodium bicarbonte (0.56 g.) were dissolved in water (50 ml.) at room temperature with stirring and lyophilized. A solution of iodomethyl hexanoate (0.93 g.) in dimethylformamide (5 ml.) was added dropwise to a solution of the product obtained above in dimethylformamide (15 ml.) at -5° C. and stirred at the same temperature for 30 minutes. Ethyl acetate (50 ml.) and water (100 ml.) were added to the resultant solution and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml.) twice. The extracts were combined with the ethyl acetate layer, washed with a saturated aqueous solution of sodium bicarbonate three times and a saturated aqueous solution of sodium chloride three times in turn, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. After washing the concentrate with n-hexane (50 ml.), n-hexane (50 ml.) and diethylether (25 ml.) were added to the residue and allowed to stand in a refrigerator overnight. The precipitating powder was collected by filtration, washed with n-hexane and dried to give a mixture (1.0 g.) of n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn-isomer) and n-hexanoyloxymethyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloro-2-cephem-4-carboxylate (syn-isomer.)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[NH2:75])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68](=[O:76])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[NH:75][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]1)=[O:30])[CH3:66]
Reactant: CCOC(=O)c1ccccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 2-amino benzoic acid ethyl ester (Aldrich, 43 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 13 mg.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:13]=[CH:12][N:11]=2)=[O:8])=[CH:5][N:6]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)CCC>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:17]([NH:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:7]([C:4]2[S:3][C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:6][CH:5]=2)=[O:8])[CH:15]=1)=[O:26]
Reactant: C1COCCN1
Reactant: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cnc(Br)s1
Solvent: CCCCO
Product: O=C(Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1)c1cnc(N2CCOCC2)s1
Temperature: 50 °C
Yield: 69.7 %

Procedure:
To a suspension of 2-bromo-N-(4-(2,6-dichlorobenzamido)pyridin-2-yl)thiazole-5-carboxamide (Example 7) (24.0 mg, 0.051 mmol) in 1-butanol (1 mL) was added morpholine (44.4 mg, 0.51 mmol). The mixture was heated at 50° C. for 6 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC (Gemini, 3×10 cm, gradient: 5-85% CH3CN/H2O with 0.1% NH4OH over 10 min) to afford the desired product (17 mg, 69.4% yield). 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.68 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.27 (d, J=5.5, 1H), 7.63-7.57 (m, 2H), 7.56-7.51 (m, 2H), 3.73-3.68 (m, 4H), 3.52-3.46 (m, 4H). LCMS (ESI) m/z: 478.2 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)=O.CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccc(-c2ccnc(Cl)n2)s1
Reactant: Nc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Clc1nccc(-c2ccc(CNc3ccccc3)s2)n1
Reaction time: 18 h
Yield: 59.4 %

Procedure:
[5-(2-Chloro-pyrimidin-4-yl)-thiophene-2-carbaldehyde (100 mg, 0.446 mmol) was dissolved in 25% HOAc in DMA (4 mL) and was treated with aniline (61 uL, 0.669 mmol) for 2 h. MP-CNBH3 resin was added the reaction was shaken for 18 h. The reaction was filtered and rinsed with DMA and the solution was concentrated in vacuo. The crude material was purified by SiO2 chromatography using a gradient 0-100% hexanes/EtOAc to afford title compound (80 mg, 59%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([O:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:10])[CH2:2]2.Cl[CH2:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30]>CCOC(C)=O>[Cl-:19].[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:11][C:9]([CH:3]2[CH:4]3[CH2:5][CH2:6][N+:1]([CH2:28][C:29](=[O:30])[C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)([CH2:8][CH2:7]3)[CH2:2]2)=[O:10])=[CH:25][CH:24]=1
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)C1CN2CCC1CC2
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)C(C(=O)OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a solution of bis(4-chlorophenyl)methyl quinuclidine-3-carboxylate (45 mg, 0.11 mmol, prepared as in example 6) in EtOAc (1.6 ml), 2-chloro-1-(thiophen-2-yl)ethanone (20.0 mg, 0.13 mmol) was added. The reaction was stirred at room temperature for 16 hours. Solvent was removed, and the crude was purified by preparative HPLC to afford 3-((bis(4-chlorophenyl)methoxy)-carbonyl)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (16 mg, racemic mixture).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.OC1[C:41]2[N:40]=NN[C:37]=2[CH:36]=[CH:35][CH:34]=1.C(O)(=O)C(O)=O.[CH2:48]1C2(CCNCC2)[CH2:50][O:49]1.C1C2(CCNCC2)CO1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][C:28]([N:40]4[CH2:34][CH2:35][C:36]5([CH2:50][O:49][CH2:48]5)[CH2:37][CH2:41]4)=[O:29])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: Oc1cccc2[nH]nnc12
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCC(=O)O
Reactant: C1CC2(CCN1)COC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCC(=O)N1CCC2(CC1)COC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a solution of Compound 8 (9.8 g, crude, containing lithium chloride) in N,N-dimethylformamide (100 mL) was added hydroxybenzotriazole (6.22 g, 46.07 mmol), 2-oxa-7-azaspiro[3.5]nonan hemioxalate (4.39 g, 34.56 mmol), N,N-diisopropylethylamine (8.93 g, 69.11 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.83 g, 46.07 mmol) sequentially. The reaction mixture was stirred overnight at room temperature and then poured into water (800 mL). Gray solid formed was collected by filtration. This solid was purified by flash chromatography (gradient from dichloromethane to dichloromethane:methanol 10:1) to give Compound 9 (5.20 g) as an off-white solid. m/z 535.3 (M+H, 100%) (positive ionization mode). 1H-NMR (CDCl3, 400 MHz): δ 1.83 (4H, m); 2.27 (2H, m); 2.30 (3H, s); 2.46 (2H, t); 3.41 (2H, t); 3.42 (2H, t); 4.05 (3H, s); 4.27 (2H, t); 4.46 (4H, q); 6.34 (1H, q); 7.0 (1H, dd); 7.10 (1H, d); 7.34 (1H, s); 7.63 (1H, s); 8.17 (1H, s); 8.60 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[O:19]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][N:22]([C:30]([C:32]2[N:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[S:35][CH:36]=2)=[O:31])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(#N)C>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:27]1[CH2:28][CH2:29][C:24]2([O:19][CH2:20][CH2:21][N:22]([C:30]([C:32]3[N:33]=[C:34]([C:37]([F:38])([F:39])[F:40])[S:35][CH:36]=3)=[O:31])[CH2:23]2)[CH2:25][CH2:26]1
Reactant: O=C(c1csc(C(F)(F)F)n1)N1CCOC2(CCNCC2)C1
Reactant: OCCc1cccc(CBr)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(c1csc(C(F)(F)F)n1)N1CCOC2(CCN(Cc3cccc(CCO)c3)CC2)C1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.354 g) was added to a solution of 1-oxa-4,9-diazaspiro[5.5]undecan-4-yl(2-(trifluoromethyl)thiazol-4-yl)methanone trifluoroacetate (example 25, step a) (0.74 g) and triethylamine (0.689 mL) in acetonitrile (15 mL) and the mixture stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 3% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.640 g.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:16]([O:20][C:21]([N:23](C1C=CC=CC=1)[CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.N1(OC(N(C)C)=[N+](C)C)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:4][C:5](=[O:15])[C@@H:6]([NH:7][C:25](=[O:26])[CH:24]([NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-phenylalanine ethyl ester hydrochloride (5.09 g, 22.2 mmol) and tert-butyloxycarbonylphenylglycine (5.06 g, 20.1 mmol) in N,N-dimethylformamide (100 mL) was added diisopropylethylamine (4.2 mL, 24.1 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexaflurorophosphate (9.16 g, 24.2 mmol) and the mixture stirred at ambient temperature overnight. The reaction mixture was poured into ethyl acetate (750 mL), washed with 1:1 1M aqueous hydrochloric acid/brine (2×75 mL), 1:1 saturated aqueous sodium bicarbonate solution/brine (2×75 mL), brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give 2-(S)-(2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-phenyl-propionic acid ethyl ester as a pale yellow solid which still contained some N,N-dimethylformamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].C[Si](C)(C)[O:33][CH:34]=[C:35]([CH3:37])[CH3:36].[BH4-].[Na+]>CN(C=O)C.F[Zn]F>[OH:33][CH2:34][C:35]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([C:27]4[CH:26]=[N:25][N:24]([CH3:28])[C:23]=4[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30])([CH3:37])[CH3:36]
Reactant: CC(C)=CO[Si](C)(C)C
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Agent: F[Zn]F
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1C(C)(C)CO
Reaction time: 0.17 h

Procedure:
To a microwave vial was added difluorozinc (16 mg, 0.15 mmol) and Pd(tBu3P)2 (7.6 mg, 0.015 mmol). The vial was capped and purged with nitrogen for 10 minutes. DMF (1 mL) was added and the reaction mixture was allowed to stir for 10 minutes. (4-Bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (140 mg, 0.30 mmol) dissolved in DMF (0.5 mL) was added followed by trimethyl(2-methylprop-1-enoxy)silane (83 μL, 0.45 mmol). The reaction vessel was placed in an oil bath held at 80° C. for 16 hours. The reaction mixture was filtered, quenched with brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in MeOH (2 mL). NaBH4 (34 mg, 0.90 mmol) was added and the reaction mixture immediately turned from yellow to brown. The mixture was filtered and purified by HPLC (1-99%) MeOH:H2O to provide [4-(2-hydroxy-1,1-dimethyl-ethyl)-3-methoxy-phenyl]-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 461.5. found 462.2 (M+1)+. Retention time: 2.73 minutes (4 min run).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]2[CH:10]([C:11](=[O:23])[N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]=1)[CH2:9]2)(=O)=O.[C:26]1([C:32]2[O:33][C:34]3[CH2:35][NH:36][CH2:37][CH2:38][C:39]=3[N:40]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)Cl>CS(C)=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]2[N:13]=[C:7]([N:36]3[CH2:37][CH2:38][C:39]4[N:40]=[C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:33][C:34]=4[CH2:35]3)[CH:8]3[CH:10]([CH2:9]3)[C:11]2=[O:23])=[CH:16][CH:17]=1
Reactant: COc1ccc(CN2N=C(OS(=O)(=O)C(F)(F)F)C3CC3C2=O)cc1
Reactant: c1ccc(-c2nc3c(o2)CNCC3)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(CN2N=C(N3CCc4nc(-c5ccccc5)oc4C3)C3CC3C2=O)cc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
322 mg (0.85 mmol) 4-(4-methoxy-benzyl)-5-oxo-3,4-diaza-bicyclo[4.1.0]hept-2-en-2-yl trifluoro-methanesulphonate dissolved in 4 ml DMSO and some molecular sieve are added to 400 mg (1.69 mmol) 2-phenyl-4,5,6,7-tetrahydro-oxazolo[5,4-C]pyridine. The mixture is stirred for 5 h at 40° C. and then combined with DCM. It is extracted 1× each with sat. sodium carbonate solution and sat. saline solution, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V., the residue is purified through silica gel (eluant: DCM/methanol).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Br:14][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 142.3 %

Procedure:
To a solution of 10 g of methyl 4-hydroxymethylbenzoate and 80 g of carbon tetrabromide in 300 ml of diethyl ether was added 63.2 g of triphenylphosphine. The reaction was warmed to room temperature overnight, filtered through Celite® and concentrated to 87.2 g of a yellow oil. Chromatography on silica gel (95:5, hexane:ethyl acetate) afforded 19.62 g of a white solid, m.p. 52° to 55° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][C@H:23]([CH3:26])[CH2:24][OH:25].O>C(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: C[C@@H](N)CO
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](CO)Nc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 4-chloro-3-nitro[1,5]naphthyridine (6.30 g, 30.1 mmol) dissolved in 150 mL of CH2Cl2 was treated with triethylamine (8.35 mL, 60.0 mmol) and (R)-2-aminopropanol (2.76 mL, 35.5 mmol) and the mixture was stirred under N2. After 18 hours, the reaction mixture was concentrated to give a yellow solid. The yellow solid was combined with 150 mL of H2O and the suspension was heated to reflux, with stirring, for 20 minutes. The mixture was cooled in an ice bath and the resulting yellow solid was isolated by filtration. The solid washed with cold H2O and two 50 mL-portions of Et2O and then dried with suction to give (2R)-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]propan-1-ol (7.10 g) as a yellow powder.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[BH4-].[Na+].CO.[H][H]>C(O)(C)(C)C.C1(C)C=CC=CC=1>[OH:2][CH2:3][C@H:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CC[C@@H](CO)N1Cc1ccccc1
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester (132 g, 0.556 mol) in 600 mL of t-butanol was cooled to ca. 18° C. Sodium borohydride (41 g, 1.12 mol) was added in one portion. To the suspension was added over 45 min 425 mL of methanol. The reaction was kept at 15° C. during the addition, during which time hydrogen gas was evolved. After the addition, the mixture was kept at 20° C. until hydrogen evolution had subsided, and was allowed to stand at room temperature overnight. The solvents were removed on a rotary evaporator, and the residue was dissolved in 1 L of water and acidified to pH 7.5 with 2N HCl. The mixture was extracted with methylene chloride and the combined extracts were washed with 2N HCl and brine, and dried over Na2SO4. Evaporation of the solvent afforded 96.3 g of crude product, which was recrystallized once from toluene to give 89.5 g (77% yield) of (S)-5-(hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidinone as a white solid, mp 82°-4° C. (toluene). 1H NMR (CDCl3) δ 1.92 and 1.94 (dd, J=6.5 Hz, 1 H, OH), 1.96-2.11 (m, 2 H, CH2), 2.36-2.61 (m, 2 H, COCH2), 3.48-3.78. (m, 3 H, CH2O and CH), 4.29 and 4.81 (AB, Jgem =15 Hz, 2 H, CH2Ph), 7.26-7.35 (m, 5 H, phenyl). [α]25D =+116° (c 1.07, methanol). Anal. Calcd for C12H15NO2 : C, 70.22; H, 7.37; N, 6.75. Found: C, 70.06; H, 7.41; N 6.75.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-:19].[K+].Cl>O>[N+:16]([C:13]1[CH:14]=[CH:15][C:2]([OH:19])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([O-:18])=[O:17]
Reactant: [OH-]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
Into an autoclave, were charged 30 g of 2-chloro-5-nitrobenzophenone, 300 ml of water, and 9.70 g of potassium hydroxide. The mixture was allowed to react at 150° to 160° C. with stirring for 5 hours. Upon cooling to room temperature, there was obtained a clear liquid, reddish orange in color. The liquid was further cooled below 0° C. and strongly acidified with cold concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water, and recrystallized from ethanol to yield 15.7 g (56.1%) of 5-nitro-2-hydroxy-benzophenone having a melting point of 122°-123° C. To 150 ml of 40-% aqueous potassium hydroxide solution, was added 25.0 g of 5-nitro-2-hydroxybenzophenone followed by 50 g of hydroxylamine hydrochloride. After 5 hours, the resulting clear liquid was cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was washed with water and a small volume of 50-% aqueous methanol, then dried in air, and recrystallized from benzene and petroleum ether to yield 5-nitro-2-hydroxybenzophenone oxime.
Reaction SMILES: O[C:2]1C=CC(C(=O)C=[CH:8][C:9]2[CH:14]=[CH:13][C:12](OC)=[CH:11][CH:10]=2)=C[CH:3]=1.C(Cl)CCl.C1C=CC2N([OH:33])N=NC=2C=1.C(N(CC)CC)C.CN([CH:44]=[O:45])C>CO>[CH:9]12[CH2:8][CH:12]([CH:11]=[CH:10]1)[CH2:13][CH:14]2[C:44]([OH:45])=[O:33].[CH2:2]=[CH2:3]
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Reactant: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Solvent: ClCCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C
Product: O=C(O)C1CC2C=CC1C2
Yield: 82.5 %

Procedure:
The 5-norbornene-2-carboxylic acid/ethylene copolymer (13.2 g, 79.64 mmol) that was polymerized in (2), 4′-hydroxy-4-methoxy chalcone (Aldrich, 18.4 g, 72.4 mmol), EDC (Aldrich, 22.2 g, 115.84 mmol), and HOBT (Aldrich, 14.7 g, 108.6 mmol) were put into the 2-neck flask having the volume of 250 ml, and then dissolved in 100 ml of DMF. After the temperature was reduced to 0° C., triethylamine (Aldrich, 50 ml, 362 mmol) was slowly dropped on the reaction solution. After the temperature was increased to normal temperature and maintained for 3 hours, when the reaction was finished, the reaction solution was dropped on a large amount of methanol to precipitate the polymer, and the polymer was filtered to obtain the 5-norbornene-2-(4′-hydroxy-4-methoxy chalcone)ester/ethylene copolymer to which the 1-(3-methoxy phenyl)-3-(2-hydroxyphenyl)-2-propenone functional group was introduced (yield: 82.5%).