Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[NH:5][C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)=[C:7]([C:9]2[CH:18]=[CH:17][C:12]3=[N:13][N:14]([CH3:16])[N:15]=[C:11]3[CH:10]=2)[N:8]=1.Cl.O.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:16][N:14]1[N:13]=[C:12]2[CH:17]=[CH:18][C:9]([C:7]3[N:8]=[C:4]([CH:3]=[O:2])[NH:5][C:6]=3[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[CH:10][C:11]2=[N:15]1
Reactant: COC(OC)c1nc(-c2ccc3nn(C)nc3c2)c(-c2cccc(C)n2)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2[nH]c(C=O)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
5-[2-Dimethoxymethyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-2-methyl-2H-benzotriazole (700 mg, 1.92 mmol) was dissolved in 40 ml anhydrous tetrahydrofuran. 6M hydrochloric acid solution in water (3.2 ml, 19.2 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added until approximately pH 8. The organic solvent was removed by rotary evaporation. The residue was dissolved in water and then extracted three times with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to afford 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carbaldehyde (600 mg, 98% yield) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.N.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:40][CH3:39])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CCOP(=O)(C#N)OCC
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Agent: N
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and ammonia using diethyl cyanophosphonate as a coupling reagent. Mass: 532.17 (M+H).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: Oc1ccc(OCCCn2ccnn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(C=Cc2nc(COc3ccc(OCCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 27 %

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(3-[1,2,3]triazol-1-yl-propoxy)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 8 ml water the resulting precipitate was collected and purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 4:1) to yield 70 mg (27%) colorless powder.
Reaction SMILES: Br[C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([Li])CCC.[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].OS(O)(=O)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[C:27]([C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:33])[CH3:32]
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)[C@@H](C)CN(CC)C2=O
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)c(OC)c2n1[C@@H](C)CN(CC)C2=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
(S)-Ethyl 6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.70 mol) was dissolved in THF (4500 ml) at 20° C. Molecular sieves (4 Å; 250 g) were added. The mixture was stirred for 30 min at 20° C., and was then cooled to −78° C. A solution of n-Butyllithium (2.5 M; 0.77 mol) was added dropwise below −65° C. The mixture was stirred for 1 h at −78° C. Diethyl oxalate (1.6 mol) in THF (600 ml) was added dropwise below −65° C. and then it was stirred for 3 h. The mixture was poured into a solution of aqueous H2SO4 (4200 ml, 2 M) and THF (3500 ml). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (3×2000 ml). The combined organic layers were collected and evaporated. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate from 100:0 to 1:1). The pure fractions were collected and the organic solvent was evaporated. Yield: 170 g (67% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[Br:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[N:21][N:20]([CH3:33])[C:19]=1[CH2:34]O.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:34][C:19]3[N:20]([CH3:33])[N:21]=[C:22]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=4)[C:18]=3[Br:17])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(Br)c(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[4-bromo-2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH3:16])[CH2:14][N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12]3)=[C:8]([C:21]([NH2:23])=[O:22])[CH:7]=[N:6][N:5]2[CH:24]=1.[CH3:25][NH:26][C:27](=[O:43])[C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH3:16][C@H:15]1[CH2:14][N:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:24]=[C:2]([C:31]3[CH:30]=[N:29][C:28]([C:27](=[O:43])[NH:26][CH3:25])=[CH:33][CH:32]=3)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:21]([NH2:23])=[O:22]
Reactant: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1ccc(-c2cc3c(N[C@@H]4CN(S(C)(=O)=O)C[C@@H]4C)c(C(N)=O)cnn3c2)cn1

Procedure:
The title compound was prepared from 6-bromo-4-((3S,4S)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide using the method previously described in Step 2 of Example 191 and by replacing 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide. LCMS (method H) retention time=1.09 min. (MH+472.2). 1H NMR (500 MHz, DMSO-d6, appeared as rotomers) δ 11.19 (d, J=7.9 Hz, 1H), 9.11 (d, J=2.0 Hz, 1H), 8.70 (q, J=4.5 Hz, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.41 (dd, J=8.2, 2.2 Hz, 1H), 8.31 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.87 (br. s., 1H), 7.48 (d, J=1.5 Hz, 1H), 7.23 (br. s., 1H), 5.04-4.92 (m, 1H), 3.86-3.63 (m, 2H), 3.38 (d, J=1.5 Hz, 1H), 3.03 (t, J=9.9 Hz, 1H), 2.89 (s, 3H), 2.84 (d, J=5.0 Hz, 3H), 2.72-2.64 (m, 1H), 1.09 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18]C(C)(C)C(C)(C)[O:15]2)=[CH:10][CH:9]=1.Cl>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:23][C:7]1([C:8]2[CH:9]=[CH:10][C:11]([B:14]([OH:15])[OH:18])=[CH:12][CH:13]=2)[CH2:2][CH2:1]1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: OB(O)c1ccc(C2(O)CC2)cc1
Temperature: -78 °C
Reaction time: 12 h

Procedure:
A 3.0 M solution of ethylmagnesium bromide in diethylether (7.6 mL) is added to a stirred solution of titanium(IV) isopropoxide (2.2 mL) in diethylether (70 mL) chilled to −78° C. The resultant solution is stirred at −78° C. for 1.5 h, before 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-benzoic acid methyl ester (2.0 g) is added. The reaction mixture is warmed to ambient temperature and stirred for an additional 12 h. Then, 1 M aqueous hydrochloric acid is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is dissolved in acetone (60 mL) and 0.1 M aqueous NH4OAc solution (50 mL) followed by NaIO4 (2.3 g) is added. The resulting reaction mixture is stirred at room temperature for 18 h. After removal of the acetone, the residue is extracted with ethyl acetate. The combined extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is purified by chromatography on silicagel (cyclohexane/ethyl acetate).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzonitrile (1.08 g, 6.50 mmol, 1 equiv), 1-isopropylpiperazine (1.0 g, 7.80 mmol, 1.2 equiv), and K2CO3 (2.69 g, 19.50 mmol, 3 equiv) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between excess water and EtOAc, and then the layers were separated. The aqueous layer was extracted with EtOAc 2×, and the combined organic layer was washed with brine 1×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 2-(4-isopropylpiperazin-1-yl)-5-nitrobenzonitrile (1.76 g, 99% yield) as a brown oil that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: OCCO
Reactant: O=Cc1occc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Brc1ccoc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
3-Bromo-2-furaldehyde (14.22 g, 81.3 mmol) is combined with ethylene glycol (6.55 mL, 117.4 mmol) and para-toluene sulfonic acid monohydrate (772 mg, 4.06 mmol) in benzene (200 mL) and heated to reflux with a Dean-Stark trap for 5 h. Additional ethylene glycol (1.64 mL, 29.41 mmol) and benzene (150 mL) are added and the solution is heated for an additional 2 h. The mixture is cooled to rt, treated with saturated NaHCO3 and stirred for 0.5 h. The layers are separated and the organics are dried over Na2SO4 and concentrated to a brown oil (18.8 g). The crude material is chromatographed over 700 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 16.45 g (92%) of 2-(3-bromo-2-furyl)-1,3-dioxolane as a yellow-orange oil. MS (EI) m/z: 218 (M+).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH2:15]([O:14][C:12]([NH:11][C@@H:10]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH:7]=[CH:8][CH2:9]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1CC=CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@H]1CC=CC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 3 h
Yield: 83.6 %

Procedure:
A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methyl ester (91.4 g) was dissolved in MeOH (500 mL) prior to the dropwise addition of NaOH (25.3 g) in water (95 mL). After 3 h, the solution was partially concentrated and an Et2O/water mixture was added. The aqueous layer was separated and was acidified (pH 2) with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine before they were dried, filtered, and concentrated to give (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72.7 g). MS found: (M+H)+=276.2.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[N:10]=[C:6]2[C:5]([Br:15])=[N:4][CH:3]=1.C[Si](C)(C)[NH:18][C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[F:29].CS(C)=O>C(#N)C>[F:29][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:19]=1[NH:18][S:11]([C:9]1[N:10]=[C:6]2[C:5]([Br:15])=[N:4][CH:3]=[C:2]([Br:1])[N:7]2[N:8]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1nc2c(Br)ncc(Br)n2n1
Reactant: COC(=O)c1cccc(F)c1N[Si](C)(C)C
Solvent: CS(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Reaction time: 1 h

Procedure:
A solution of 0.75 g (20 mmol) of 5,8-dibromo-2-chlorosulfonyl[1,2,4]triazolo[1,5-a]pyrazine in 8 mL of dry acetonitrile was placed in a flask equipped with a drying tube and was treated sequentially with 6.0 mL (6.0 mmol) of a 1M solution of N-trimethylsilyl-2-fluoro-6-methoxycarbonylaniline in acetonitrile and 25 μL (0.35 mmol) of dimethyl sulfoxide at room temperature with stirring. The reaction became progressively darker and after 1 hour, the volatiles were removed by evaporation under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by flash column chromatography on silica gel using a 0.5 to 4 percent ethanol/dichloromethane gradient as eluent to obtain 715 mg (70 percent of theory) of the desired product as an orange glassy solid melting at 190°-195° C.; Mass Spectrum, m/e 510 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[C:7][C:8]1[CH:12]=[CH:11][O:10][CH:9]=1)(=O)[CH3:2].Br[C:14]1C=CO[CH:15]=1>C1COCC1.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.[Cl-].[Zn+2].[Cl-]>[O:4]1[CH:1]=[CH:2][C:6]([C:7]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)=[C:14]=[CH2:15])=[CH:5]1
Reactant: Brc1ccoc1
Reactant: CC(=O)OCC#Cc1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=C=C(c1ccoc1)c1ccoc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
To a mixture of 3-(3-acetyloxy-l-propynyl)furan (1.44 g, 8.7 mmol), 3-bromofuran (2.55 g, 0.017 mol), and Pd(P(C6H5)3)4 (1.0 g, 0.8 mmol) in THF was added added zinc chloride (0.5M in THF, 34 ml, 0.017 mol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica column chromatography (methylene chloride/hexane, 2:1) to afford 1.25 g (85%) of [1,1-di(3-furyl)]-1,2-propadiene (Formula III: R3 and R4 together form =CH2 ; R5 =R6 =3-furanyl) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Na+].[I-].CCN(CC)CC.C([O-])(O)=O.[Na+]>CC#N>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
A 250 mL round bottom flask was charged with 4-bromoacetophenone (1.99 g, 10.0 mmol), TBSCl (6.03 g, 40.0 mmol) and NaI (6.00, 40 mmol). The flask was capped with a rubber septum and placed under an atmosphere of Argon. After the addition of 200 mL MeCN, NEt3 (6.13 mL, 44.0 mmol) was introduced and the reaction mixture was stirred for 16 h at rt until TLC monitoring indicated complete conversion. The reaction mixture was poured onto sat. NaHCO3 solution and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated to yield a brown slurry. Hexanes was added and the obtained heterogeneous mixture was filtered through a short plug of silica using hexanes to afford the title compound as a colorless oil (3.02 g, 96% yield). Rf=0.49 (1% EtOc/hexanes); 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 4.88 (s, 1H), 4.44 (s, 1H), 1.00 (s, 9H), 0.21 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 155.2, 137.0, 131.4, 127.1, 122.4, 91.6, 26.0, 18.5, −4.4; HR-MS(ESI): calcd. For C14H21ObrSi (M+): 312.0545; found: 312.0542.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.O>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (2.22 g, 10.0 mmol), 4-hydroxybenzotrifluoride (1.21 g, 7.45 mmol), tri-n-butylphosphine (2.26 g, 11.2 mmol) and 1,1′-(azodicarbonyl)dipiperidine (2.82 g, 11.2 mmol) were dissolved in benzene (20 ml), and the mixture was stirred at room temperature for 2 days. To which water was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and thereafter filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) ro afford tert-butyl 4-(4-trifluoromethylphenoxy)piperidine-1-carboxylate (1.13 g, yield 44%) as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16](=[CH2:20])[CH2:17][S:18](=O)[C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:39]C(=O)C)(=[O:38])[CH3:37]>C(Cl)(=O)C.C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:34](=[O:35])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:16]([CH2:20][O:39][C:36](=[O:38])[CH3:37])=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 10 ml. of dry toluene were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylene-cepham-4-carboxylate-1-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The mixture then was refluxed at 110°-112° C. for 18 hours. The resulting reaction mixture then was treated as in Example 1 to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate as well as a minor amount of the corresponding Δ3 isomer.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].C(O[CH2:39][CH3:40])(=O)C.[C:41](OCC)(=O)[CH3:42]>>[ClH:34].[CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]3[C:30](=[CH:41][CH:42]=[CH:39][CH:40]=3)[CH:31]=2)=[CH:22][CH:21]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Product: N[C@@H](Cc1ccc(-c2ccc3ccccc3c2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
To a solution of N-tert.-butoxycarbonyl-4-(4-fluorophenyl)-L-phenylalanine benzyl ester (700 mg) in ethyl acetate (3.2 ml) was added 4.1N hydrogen chloride/ethyl acetate (3.8 ml). The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo to give 3.1 g (82%) of the titled compound (reference compound No. 1-1).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[S:22]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mL) at 0° C. under nitrogen, p-toluenesulfonyl chloride (4.87 g, 25.55 mmol) was added in one portion. The reaction was stirred at 0° C. for 100 minutes before warming to RT. After 18 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with aqueous hydrochloric acid (2×100 mL, 1.0 M solution), saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to yield the title compound (7.87 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](OC)=[O:32])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:31]2=[O:32])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCCCCc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCCc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 7-(pyridin-3-yl)heptanoate (2.0 eq., prepared in Synthetic Example 14) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[5-(3-pyridyl)pentyl]-1,8-naphthyridin-2(1H)-one, mp 155° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.