Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]3[CH2:22][CH2:21][Si:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([CH:17]3[CH2:18][CH2:19][Si:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](C=Cc3ccc(F)c(F)c3)CC2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
40.0 g of the thus obtained 4-(trans-4-(2-(3,4-difluorophenyl)ethenyl)cyclohexyl)-1-n-pentyl-1-phenyl-1-silacyclohexane was dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of 200 mg of platinum oxide at a pressure of 0.1 MPa of hydrogen. After theoretical consumption of hydrogen, the catalyst was removed by filtration and the resultant filtrate was concentrated to obtain 40.2 g of 4-(trans-4-(2-(3,4-difluorophenyl)ethyl)cyclohexyl)-1-n-pentyl-1-phenyl-1-silacyclohexane. The results of IR analysis of the product are as follows.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])CCCC[CH2:2]1.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CC1[N:53]=[CH:52][NH:51]C=1>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH2:7][C:1]4[N:51]=[CH:52][NH:53][CH:2]=4)[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(NC(Cc1c[nH]cn1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 51 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-His Wang resin (250 mg, 0.4 mmol/g), producing 30 mg of the title compound (51% yield). MS: 584.24 (M−H+) HPLC Procedure A, retention time=11.16 min.
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12]N.C(Cl)Cl.CO>C(O)C>[C:11]([NH:12][N:10]=[C:2]([O:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5][CH3:6])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCCCC(=N)OCC
Reactant: CCOC(=O)NN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCCCC(=NNC(=O)OCC)OCC
Reaction time: 0.33 h

Procedure:
To a solution of 7.0 g (25.3 mmole) of ethyl valerimidate hydrochloride [prepared by method of A. J. Hill and I. Rabinowitz, J. Am. Chem. Soc., 48, 734 (1926)] in 35 ml of dry ethanol stirred under N2 at -78° C. was added dropwise a solution of 24 g (23 mmole) of ethyl carbazate in 35 ml of dry ethanol. Precipitation occurred during the addition, which took 20 minutes and was accompanied by a rise in the internal temperature to -50° C. The mixture was allowed to stand at 5° C. for 60 hours and then filtered. The filtrate was concentrated, and the residue was flash chromatographed on a silica gel column (elution with 98.5:1.5 CH2Cl2 --MeOH), yielding a clear oil, homogeneous by TLC in 97:3 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 217 (M+1)+. NMR suggested a mixture of syn and anti isomers.
Reaction SMILES: C(O[C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]([C:17]([O:19]C(C)(C)C)=O)[CH2:14][CH2:13][CH2:12]2)C.CO[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C[Si](C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:49]>>[ClH:49].[CH2:34]([N:28]1[CH2:27][C@@H:6]2[C@H:5]([C:17](=[O:19])[N:15]3[CH2:14][CH2:13][CH2:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]2[C:16]3=4)[CH2:4]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: ClCCl
Reactant: CCOC(=O)/C=C/c1cccc2c1N(C(=O)OC(C)(C)C)CCC2
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1[C@@H]2CN(Cc3ccccc3)C[C@H]2c2cccc3c2N1CCC3
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of tert-butyl 8-[(1E)-3-ethoxy-3-oxo-1-propenyl]-3,4-dihydro-1(2H) -quinolinecarboxylate (2.55 g, 7.7 mmol) in 50 mL of methylene chloride at 0° C. was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4.6 g, 19.3 mmol) and trifluoroacetic acid (0.24 mL, 3.1 mmol). The cooling bath was removed and the solution was allowed to stir with warming to ambient temperature for 24 h. The methylene chloride was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 5:1 hexane/ethyl acetate) to afford 3.0 g (83%) of the title compound as an oil. LRMS (ES)+: 465.3 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.CC[O:21][CH2:22][CH3:23].[CH3:24][N:25]([CH:27]=[O:28])[CH3:26]>>[CH3:24][N:25]([CH3:26])[C:27]([C:9]1[C:23]2[C:7](=[CH:8][CH:11]=[CH:12][C:22]=2[O:21][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:6]=[CH:5][CH:10]=1)=[O:28]
Reactant: ClCc1ccc(C=Cc2ccccc2)cc1
Reactant: CN(C)C=O
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Product: CN(C)C(=O)c1cccc2cccc(OCc3ccc(C=Cc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-hydroxynaphthalene-1-(N,N-dimethyl)carboxamide (100 mg, 0.46 mmol) in dry DMF (4 mL) was added sodium hydride (12 mg, 0.51 mmol, 1.1 eq). The sodium hydride was added as 20 mg of a 60% dispersion in mineral oil that had been previously washed with 3×heptane portions under an inert atmosphere. The mixture was stirred for 30 minutes at room temperature, and 4-chloromethylstilbene (117 mg, 0.51 mmol, 1.1 eq) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured onto ice/water (100 mL) and the aqueous-DMF layer was extracted into ethyl acetate portions. The combined organic layers were washed (brine), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, eluant:ethyl acetate/heptane mixtures) to give the desired ether (yield: 108 mg, 0.27 mmol, 58%);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:22](=[O:23])[C:21]5=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]5[C:19]4=[O:28])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:29]=1.[BH4-].[Na+].CCCCCCC.CCOC(C)=O>CCO.ClCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[CH:22]([OH:23])[C:21]5[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:19]4=[O:28])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2csc3cc(F)ccc23)CC1
Agent: ClCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(O)N1CCN1CCN(c2csc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of N-[2-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]-ethyl]phthalimide (2.7 g, 6.6 mmol) in a mixture of 200 ml absolute EtOH and 50 ml CH2 Cl2 under N2 was added Sodium Borohydride (0.56 g, 14.8 mmol) in one portion. The mixture was stirred at room temperature for 15 minutes, during which time the solids dissolved. At the end of 15 minutes, TLC [silica, 1:1 heptane:EtOAc] showed no starting material remained and a major, lower Rf spot had appeared.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].Br[CH2:17][CH2:18]Br.O>C1COCC1.CCCCCC>[CH3:1][C:2]1[CH:10]([CH:13]([CH:12]2[C:11]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[CH:8]=[C:17]2[CH3:18])[CH3:14])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1=Cc2ccccc2C1
Reactant: [Li]CCCC
Reactant: BrCCBr
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1=Cc2ccccc2C1C(C)C1C(C)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 g (33 mmol) of 2-methylindene was dissolved in 80 ml of THF in a 500 ml-glass reactor. While the solution was being cooled, a solution of 1.6M of n-butyl lithium in 21 ml of hexane was gradually dropped into the reactor. After the above substances had been agitated together at room temperature for 1 hour, they were again cooled. Thereafter, 3.1 g of 1, 2-dibromoethane was gradually dropped in. Then, the above substances were agitated together at room temperature for 12 hours, and 50 ml of water was added. Thereafter, the organic phase was separated, and dried. The organic phase was then washed with heptane several times, and dried, thereby obtaining 2.9 g of bis-(2-methylindenyl) ethane.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][N:19](C(OCC5C=CC=CC=5)=O)[CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.Br>O1CCOCC1.CC(O)=O.CCOCC>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][NH:19][CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCOC21CCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCOC21CCNC1
Reaction time: 24 h

Procedure:
To a stirred solution of Example 36 (0.388 g, 0.763 mmol) in 1,4-dioxane (5 mL) was added 33 wt % HBr in AcOH (1 mL) at room temperature. After 24 h, the resulting white slurry was diluted with Et2O (50 mL), filtered and dried to afford desired product as 1:1:1 product:HBr:dioxane adduct 0.3521 g, 85%). 1H NMR (500 MHz, DMSO-d6) δ: 12.30 (1H, s), 9.48 (1H, t, J=6.4 Hz), 9.17 (1H, s), 7.39-7.36 (2H, m), 7.20-7.15 (2H, m), 4.57-4.48 (2H, m), 4.08-4.04 (2H, m), 3.94-3.84 (2H, m), 3.75-3.69 (1H, m), 3.60-3.49 (6H, m), 3.47-3.31 (4H, m), 2.69-2.62 (1H, m), 2.44-2.38 (1H, m). HRMS (M+H) calcd for C18H20N4O4F: 375.1469; found: 375.1466.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:15]([O:17]C)=[O:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].CO>C(OCC)(=O)C.O>[CH2:1]([O:8][CH2:9][C@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:11]([NH:13][C@@H:14]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:15]([OH:17])=[O:16])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 5 h

Procedure:
To crude (S)-methyl 2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino) propanamido)-3-(4-methoxyphenyl)propanoate (3.39 mmol assumed) was added aqueous lithium hydroxide (5 mL of a 2 N solution) and methanol (5 mL). The reaction mixture was stirred for 5 h then diluted with ethyl acetate and water, washed with ethyl acetate (1×), acidified with citric acid, extracted with DCM, washed with brine, dried with sodium sulfate, filtered, and concentrated to provide (S)-2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoic acid as an amorphous off-white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]2[NH:12][CH:13]=[CH:14][C:5]=12)[CH3:2].C(O[C:18](=[O:30])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([CH2:27][C:28]#[N:29])[CH:20]=1)C.N1CCCCC1.[CH2:37]([OH:39])[CH3:38]>>[CH2:37]([O:39][C:18](=[O:30])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([C:27]2[C:28](=[NH:29])[N:3]([CH2:1][CH3:2])[C:4]3[C:9](=[CH:8][N:7]=[C:6]4[NH:12][CH:13]=[CH:14][C:5]4=3)[CH:10]=2)[CH:20]=1)[CH3:38]
Reactant: CCNc1c(C=O)cnc2[nH]ccc12
Reactant: CCO
Reactant: CCOC(=O)c1cc(CC#N)cc(OC)c1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc(OC)cc(-c2cc3cnc4[nH]ccc4c3n(CC)c2=N)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
4-Ethylamino-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1 g, 5.3 mmol) and 3-cyanomethyl-5-methoxy-benzoic acid ethyl ester (1.3 g, 5.8 mmol) are dissolved in ethanol (4 mL) and piperidine (2 mL, 21.2 mmol) is added at room temperature. The reaction mixture is heated at 120° C. and stirred for 24 h. The reaction mixture is then concentrated and dried to yield the crude product. The crude product is used for the next step without any further purification. MS m/z 391.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2cccc(CO[Si](C)(C)C(C)(C)C)c2c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.2 %

Procedure:
To a solution of 0.220 g (0.940 mmol) of 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester in 5 mL of DMF was added 0.156 g (1.034 mmol) of t-butyldimethylsilyl chloride and 0.160 g (2.350 mmol) of imidazole and the reaction was stirred at room temperature for 14 h. The reaction mixture was diluted with water and extracted with ether. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.315 g of 4-tert-butyl(dimethyl)silyloxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.[Cl:26][C:27]1[CH:32]=[C:31](I)[C:30]([F:34])=[CH:29][N:28]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:31]3[C:30]([F:34])=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Reactant: Fc1cnc(Cl)cc1I
Product: Cc1cc(-c2cc(Cl)ncc2F)cc(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 2-Chloro-5-fluoro-4-iodpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=346.1, 348.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>C(O)CCC>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:15]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: NCc1cccc(F)c1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: CCCCO
Product: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Yield: 18.4 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol) and 3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15.0 mL) was heated to reflux for 16 h under argon atmosphere. Butanol wad distilled in vacuo, the residue was triturated with EtOAc, cooled and filtered the precipitate. It was washed with cold EtOAc, and dried to give 0.86 g of the title compound as a pale yellow powder: 1H-NMR (CD3OD/400 MHz) δ 7.31 (m, 1H), 7.0-6.85 (m, 2H), 6.83 (d, 1H, J=9.6 Hz), 5.96 (d, 1H, j=2.0 Hz), 5.80 (d, 1H, J=2.0 Hz), 5.30 (s, 2H), and 2.24 (s, 3H); ESMS m/z 234 (MH+).
Reaction SMILES: [Mg].II.[CH3:4][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:6][OH:7].C([Mg:15][Cl:16])CCC.CCCC>C(Cl)CCC>[CH3:4][CH:5]([CH2:8][CH2:9][CH3:10])[CH2:6][O:7][Mg:15][Cl:16]
Reactant: CCCC[Mg]Cl
Reactant: CCCC(C)CO
Agent: II
Agent: [Mg]
Solvent: CCCC
Solvent: CCCCCl
Product: CCCC(C)CO[Mg]Cl
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Following the procedure of Example 1, 24.31 gm of magnesium metal powder (1.0 mole) was placed in a 3-necked 3 liter reactor flask, along with 1600 ml of isoparaffinic solvent (Isopar E) having a boiling range of 116°-139° C. and 0.25 gm of iodine crystals. This mixture was heated under an argon atmosphere to reflux temperature for about 60 minutes for metal activation. 105 ml of n-butyl chloride (1.OM) was then gradually added to the reaction slurry in 40 minutes, then reaction was continued for two hours at reflux temperature. Addition of 180 ml (1.4 moles) of 2-methyl-1-pentanol to the reaction slurry was started. The reaction slurry became thick and viscous at reflux temperatures when 60 ml of the 180 ml of the 2-methyl-1-pentanol was added. At this point the reaction slurry was cooled down to 65° C. At 65° C. the remaining 120 ml of 2-methyl-1 -pentanol was added along with 400 ml of solvent (Isopar E) with good agitation to reduce the viscosity of the slurry. The 2-methyl-1-pentanol reacted with BuMgCl as was evidenced by the release of butane. Butane was distilled off through reflux condensor to maintain the reaction temperature close to the reflux temperature of solvent Isopar E. The reaction was continued for two hours. The slurry was filtered while hot, 90°-100° C. The filtration rate was fast and complete in about 10-15 minutes. Final volume of filtrate was about 2100 ml. Fine gray suspended particles as solid were collected on the filter. The clear filtrate was analyzed and found to have 0.435 molar magnesium concentration with 91.40+% magnesium recovery. This filtrate was found to be stable at 0° to 40° C. on storage.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][C@H:10]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([N:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([N:52]3[CH2:56]C[C@@H:54]([N:57]([CH3:59])[CH3:58])[CH2:53]3)=[O:51])[CH2:45]1)=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C[N:61](C)[C@@H:62]1CCN[CH2:63]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][C@H:10]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][C:23]([N:44]1[CH2:48][CH2:47][C@@H:46]([NH:49][C:50]([N:52]3[CH2:53][CH2:54][N:57]([CH2:58][CH2:63][C:62]#[N:61])[CH2:59][CH2:56]3)=[O:51])[CH2:45]1)=[N:24][C:25]=2[NH:29][CH2:30][CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N5CC[C@@H](N(C)C)C5)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N5CCN(CCC#N)CC5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to (R)-3-dimethylamino-pyrrolidine-1-carboxylic acid {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-amide trifluoroacetate (Example 134) by replacing dimethyl-(R)-pyrrolidin-3-yl-amine with the appropriate amine. (MH+ 697.4)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
Dimethylsulfamoyl chloride (90 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (250 mg) (starting material Example 16) and diisopropylethylamine (184 mg) in methylene chloride (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum and the residue triturated with diethylether to give the title product as a white solid (0.23 g); 1H NMR. Spectrum: (DMSO d6) 1.72-1.86 (m, 2H), 2.00-2.12 (m, 2H), 2.76 (s, 6H); 3.12-3.23 (m, 2H), 3.40-3.51 (m, 2H), 3.94 (s, 3H), 4.68 (m, 1H), 7.19-7.30 (m, 2H), 7.43-7.54 (m, 2H), 7.85 (s, 1H), 8.37 (s, 1H), 9.52 (s, 1H); Mass Spectrum: (M+H)+ 510.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:38][O:39][CH3:40])[C:13]([NH:15][C@@H:16]2[C:36](=[O:37])[N:18]3[C:19]([C:33]([O-:35])=[O:34])=[C:20]([CH2:23][N+:24]4[N:28]5[CH2:29][CH2:30][CH2:31][NH:32][C:27]5=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:11]=1>C(O)C>[S:1]([OH:5])([O-:4])(=[O:3])=[O:2].[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12](=[N:38][O:39][CH3:40])[C:13]([NH:15][C@@H:16]2[C:36](=[O:37])[N:18]3[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][N+:24]4[N:28]5[CH2:29][CH2:30][CH2:31][NH:32][C:27]5=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:14])[N:11]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4n3CCCN4)CS[C@H]12)c1csc(N)n1
Reactant: O=S(=O)(O)O
Solvent: CCO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccc4n3CCCN4)CS[C@H]12)c1csc(N)n1
Product: O=S(=O)([O-])O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2M sulfuric acid (1.52 ml) and ethanol (1.52 ml) was added 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer) (0.76 g) at room temperature. The mixture was stirred at ambient temperature for 4 hours, and the resulting precipitate was collected by filtration to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (462 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[C:28]([CH3:33])[N:29]=[C:30]([CH3:32])[CH:31]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: Nc1cc(F)c(F)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(F)c(F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from commercially available 4,5-difluoro-1,2-phenylendiamine (400 mg, 2.78 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (903 mg, 2.78 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light brown solid (860 mg, 82%).