Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)[N:4]=[CH:5][CH:6]=1.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[CH2:10][C:9]2[CH:17]=[CH:18][CH:19]=[C:7]([N:3]3[N:4]=[CH:5][CH:6]=[N:2]3)[CH:8]=2)=[O:27])[CH:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: c1cc(C[C@@H]2CCCCN2)cc(-n2nccn2)c1
Agent: Cl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCC[C@H]2Cc2cccc(-n3nccn3)c2)c1

Procedure:
The title compound was prepared from (S)-2-(3-[1,2,3]triazol-2-yl-benzyl)-piperidine hydrochloride and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid E-3 following the procedure described for B-28. LC-MS D: tR=0.94 min; [M+H]+=427.92.
Reaction SMILES: [P:1]([O:6]C)([O:4][CH3:5])[O:2][CH3:3].I[CH2:9][C:10]([CH2:12]I)=[CH2:11]>C1C=CC=CC=1>[CH3:3][O:2][P:1]([CH2:9][C:10](=[CH2:11])[CH2:12][P:1]([O:2][CH3:3])([O:4][CH3:5])=[O:6])([O:4][CH3:5])=[O:6]
Reactant: C=C(CI)CI
Reactant: COP(OC)OC
Solvent: c1ccccc1
Product: C=C(CP(=O)(OC)OC)CP(=O)(OC)OC
Yield: 92 %

Procedure:
400 ml of trimethyl phosphite was placed into a 2-1 flask equipped with an addition funnel, a gas inlet tube, and a Vigreux column with distilling head. The phosphite was heated at reflux, then a solution of 131 g (0.425 Mole) of 2-iodomethyl-3-iodopropene [see J. Amer. Chem. Soc., 89, 4688 (1967)] in 200 ml of benzene was added dropwise over a period of 2 h, followed by an additional 100 ml of trimethyl phosphite within 30 min. The reaction was run under nitrogen, and approx. 150 ml of distillate was allowed to collect. Distillation of the reaction mixture afforded 106 g (92%) of the title compound, b.p. 125°-7°/0.08 Torr;
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][CH:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5][N:4]3[C:10]2=[N:11][C:2]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:3]3)[CH2:14][CH2:15]1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(I)nc32)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccccn4)nc32)CC1
Temperature: 100 °C

Procedure:
To a solution of 2-iodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 2A) (50 mg, 0.12 mmoles) in toluene (500 μL) in a screw-capped vial under argon are added 2-(tributylstannyl)pyridine (77 μL, 0.24 mmole), tetrakis(triphenylphosphine)palladium(0) (14 mg, 12 μmole). The reaction mixture is heated at 100° C. overnight. A solution of 10% KF in water is added, and the aqueous phase is extracted three times with CH2Cl2. The organic phase is washed with a solution of 10% KF in water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (99:1:0.1) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 4-(1-methylpiperidin-4-yloxy)-2-pyridin-2-yl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[Li]C(C)(C)C.[I:22]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)C.CCCCC>[I:22][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: II
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Product: COc1cccc(NC(=O)OC(C)(C)C)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To the solution of tert-butyl (3-methoxyphenyl)-carbamate (5 g, 22.4 mmol, 1 eq) in dry diethyl ether (50 mL) was added pentane solution of t-BuLi (35 mL, 49.3 mmol, 2.2 eq) at −20° C., and the mixture was stirred at 3 hours. To this mixed solution was added the solution of iodine (6.83 g, 26.9 mmol, 1.2 eq) in diethylether (60 mL) at −78° C., and after heating the whole solution to room temperature, the solution was stirred for 20 hours. After adding saturated aqueous solution of Na2S2O3 (100 mL), the mixture was extracted three times with diethyl ether (100 mL). The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting concentrate was applied to silica gel (eluate: hexane-AcOEt=90-10) to give white solid of the title compound (5.755 g, yield 74%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C@H:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:11][C:12](=[O:26])[C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(=O)NOC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:31])[C@H:10]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:11][C:12](=[O:26])[C@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H]1CCCN1C(=O)NOC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H]1CCCN1)C(=O)OCc1ccccc1

Procedure:
N-(t-Butoxycarbamoyl)-(D)-proline N-hydroxysuccinimide ester (10) (1.25 g, 4.0 mmol) and (L)-leucine benzyl ester (0.885 g, 4.0 mmol) were stirred at ambient temperature in acetonitrile (10 mL) for 14 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed with 1N HCl, saturated NaHCO3, and saturated NaCl. After drying over anhydrous MgSO4, evaporation of solvent gave N-(t-butyoxycarbamoyl)-(D)-prolylleucine benzyl ester as a colorless oil. N-(t-Butoxycarbamoyl)-(D)-prolylleucine benzyl ester (1.38 g, 3.3 mmol) was stirred for one hour at ambient temperature with a 30% (v/v) solution of trifluroacetic acid in dichloromethane (20 mL). The solvent was removed by rotary evaporation and the residue partitioned between ethyl acetate and a 50% (v/v) solution of saturated aq. NaHCO3 and saturated aq. Na2CO3. The organic phase was separated, washed with saturated aq. NaCl, and dried over anhydrous MgSO4. Filtration and solvent evaporation gave (D)-prolylleucine benzyl ester as a white semi-solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:23]([Se](C=C)(=O)=O)=[CH2:24]>ClCCl>[O:20]1[CH2:24][CH2:23][O:19][CH2:18][CH:17]1[CH2:16][O:15][C:8]1([CH2:7][N:6]2[C:2]([CH3:1])=[CH:3][CH:4]=[N:5]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=C[Se](=O)(=O)C=C
Reactant: Cc1ccnn1CC1(OCC(O)CO)CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnn1CC1(OCC2COCCO2)CCCCCC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of EXAMPLE 170C (315 mg) in dichloromethane (10 mL) was added NaH (80 mg) at 0° C. The mixture was stirred for 10 minutes. A solution of vinyl selenone (240 mg) in dichloromethane (5 mL) was added to the mixture and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with aqueous NH4Cl, extracted with dichloromethane (2×200 mL), washed with water and brine, and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product which was purified by column eluted with 50% ethyl acetate in hexane) to provide the title compound.
Reaction SMILES: I/[CH:2]=[CH:3]/[CH:4]([O:10][C:11]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.C([Li:44])CCC>CCCCCC>[CH2:24]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])/[CH:3]=[CH:2]/[Li:44])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 5.26 g. of 1-iodo-3-(p-anisyldiphenylmethoxy)-trans-1-octene (Example 956) in 10 ml. of toluene, cooled to -78° C., is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40° C. and is maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium.
Reaction SMILES: [Br:1]Br.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([Br:1])=[CH:9][N:8]=1
Reactant: BrBr
Reactant: N[C@H](CNc1cc(-c2ccncc2)ccn1)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N[C@H](CNc1cc(-c2ccncc2)c(Br)cn1)Cc1ccccc1
Reaction time: 1 h

Procedure:
Bromine (757 mg, 4.7 mmole) in CHCl3 (10 mL) was added in one portion to a stirring solution of 2-((S)-2-amino-3-phenylpropylamino)-4-(4-pyridyl)pyridine (1.44 g, 4.7 mmole) in CHCl3 (30 mL) at room temperature. After 1 hr, the mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic solvent was washed with brine, dried and evaporated. The residue was purified on a column of silica gel (CH2Cl2-MeOH-Conc. NH4OH=1000:110:8). MS (m/z): Calcd. C19H19N4Br (M+): 383, found: 383, 385.1. 1H-NMR (CDCl3, 400 MHz) δ: 8.62(d, 2H), 8.20(s, 1H), 7.30-7.10(m, 7H), 6.32(s, 1H), 5.78(bs, 1H), 3.70-3.30(m, 3H), 2.97(dd, 1H), 2.92(dd, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28]Br)=[N:26][CH:27]=1.CN(C=O)C>C(#N)C>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][O:1][C:2]2[CH:7]=[N:6][N:5]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][O:9]3)[C:4](=[O:14])[CH:3]=2)=[N:26][CH:27]=1
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: BrCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1cc(OCc2ccc(Br)cn2)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.29 g (16.7 mmol) 5-hydroxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (preparation 5a) in acetonitrile is added at RT subsequently 4.63 g (33.4 mmol) potassium-carbonate and 4.20 g (16.7 mmol) 5-bromo-2-bromomethyl-pyridine. The reaction mixture is stirred 3 h at RT and 5 mL DMF is added. The reaction mixture is stirred overnight and the solvent is evaporated. To the residue water and tert-butylmethylether is added. The precipitate is collected and dried.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30]([C:25]5[CH2:29][CH2:28][CH2:27][CH:26]=5)=[O:31])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: O=C(O)C1=CCCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)C1=CCCC1
Yield: 26.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), N,N-dimethylacetamide (4.0 mL), 1-cyclopentenecarboxylic acid (139 mg, 1.24 mmol), O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (704 mg, 1.86 mmol), 1-hydroxybenzotriazole (251 mg, 1.86 mmol) and N,N-diisopropylethylamine (323 μL, 1.86 mmol), and in the same manner as in Example 219, the title compound (69 mg, 21%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid (335 mg, 0.75 mmol) in dimethylformamide (7 ml), 1-hydroxybenzotriazole (121 mg, 0.90 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol), and hydroxylamine (0.229 ml, 3.75 mmol), 216 mg (62%) of the product was isolated as a solid. HR-MS: m/z Calculated for C21H22N2O6S2 463.0992; Found 463.0988.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[O:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH2:5]([C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:9]2[S:8][CH:7]=1)[C:32]1[O:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccoc1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccco3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and 0.027 g of furane are simultaneously dissolved in 2 ml of trifluoroacetic acid; the solution is left to stand for 15 minutes at room temperature and is then diluted with an equal volume of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 3-Furfuryl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is thus obtained, showing the following Rf values in a thin layer chromatogram (silica gel): 0.75 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([N:18]2[CH2:19][CH2:20][C:15]3([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:13][CH2:14]3)[CH2:16][CH2:17]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC2(CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 130 °C
Yield: 72.1 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (150 mg, 0.93 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (244 mg, 1.02 mmol) and DIPEA (1 mL) in EtOH (3 mL) was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (50% EtOAc/isohexane) to give tert-butyl 8-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate as a yellow oil (245 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 3.76 (s, 3H), 3.49-3.39 (m, 2H), 3.30-3.00 (m, 6H), 1.90-1.60 (m, 6H), 1.55 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][C:5]([N:10]2[C:14](=[O:15])[C:13]3[CH2:16][CH2:17][CH2:18][CH2:19][C:12]=3[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(CBr)c(Cl)cc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(COc2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a mixture of 0.6 g (0.0016 mole) of N-(4-chloro-2-fluoro-5-bromomethylphenyl)-3,4,5,6-tetrahydrophthalimide and 0.22 g (0.0016 mole) of potassium carbonate in acetone was added 0.15 g (0.0016 mole) of phenol. The mixture was stirred overnight at room temperature and then was heated at 50° C. for approximately 24 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was washed with water, dried, and the solvent was evaporated under reduced pressure, leaving a residue weighing 0.7 g. Preparative thin layer chromatography was used to separate the components of this residue, eluting with ethyl acetate/heptane (3/7). The product, 0.18 g of N-(4-chloro-2-fluoro-5-phenoxymethylphenyl)-3,4,5,6-tetrahydrophthalimide, was isolated as an oil. The nmr and ir were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=[C:32]2[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:31]=12>>[Cl:29][C:30]1[C:35]([C:36]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[CH:34][N:33]=[C:32]2[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:31]=12
Reactant: Cc1nn(C)c2ncc(C(=O)Cl)c(Cl)c12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: Cc1nn(C)c2ncc(C(=O)N[C@@H](CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c3ccccc3)c(Cl)c12

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride: ESMS m/e: 587.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[C:11]=[O:12])[CH:5]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]2[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[O:31])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>ClC(Cl)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH2:25][C:26]2[CH:39]=[CH:38][C:29]([C:30](=[O:31])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:28][CH:27]=2)[C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)cc1
Reactant: COC(=O)c1cccc(N=C=O)c1
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.50 mmol 3-isocyanatobenzoic acid methyl ester dissolved in 5 mL dichloroethane was added to the above resin 4-[(4-tert-butylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (500 mg). Shaking the mixture 5 hours at 25° C. followed by filtration and washing of the resin with dichloromethane (2×10 mL), DMF (2× mL) and THF (3×10 mL) afforded the resin bound title compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[K+]>C(O)C.O>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:15][CH:17]1[CH2:18][O:19]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(O)c1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(O)c1cccc(OCC2CO2)c1

Procedure:
19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 28.6 g. epichlorohydrin are dissolved in 25 ml. ethanol and heated to the boil. A solution of 6.6 g. potassium hydroxide in 3 ml. water and 25 ml. ethanol is then added dropwise thereto in the course of 15 minutes. The reaction mixture is boiled under reflux for 2 hours, the solvent is then distilled off and the residue is taken up in water. Extraction is carried out with ethyl acetate, the ethyl acetate phase is washed twice with aqueous sodium hydroxide solution and water, dried and evaporated to give 22.4 g. (89% of theory) of the title compound in the form of an oil.
Reaction SMILES: [O-][CH2:2]C.[Na+].[NH:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:26])[C:15]4[C:20]([S:21](=[O:25])(=[O:24])[C:22]=3[CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][N:7]=[N:6]1.CI>C(O)C>[CH3:2][N:7]1[N:6]=[N:5][C:9]([C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:26])[C:15]4[C:20]([S:21](=[O:24])(=[O:25])[C:22]=3[CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8]1
Reactant: CC[O-]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1

Procedure:
To a solution of sodium ethoxide in ethanol (20 ml) (prepared from 0.46 g sodium) was added 3-(5-tetrazolyl) thioxanthone-10,10-dioxide (6.24g). Methyl iodide (2.84 g) was added and the mixture boiled under reflux for 2 hrs. During the reflux period a yellow product was deposited. On cooling it was filtered off, washed with water and recrystallised twice from acetic acid to give 3-(2-methyl-5-tetrazolyl)thioxanthone-10,10-dioxide as yellow needles, m.p. 204°-205° C.