Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1N=C(C)NC=1.C([O-])([O-])=O.[Cs+].[Cs+].BrCCOC1CCCCO1.[I:24][C:25]1[N:26]=[C:27]([CH3:39])[N:28]([CH2:30][CH2:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:29]=1.C([Mg]Br)C.[CH3:44][Sn:45](Cl)([CH3:47])[CH3:46]>CN(C=O)C.C(Cl)Cl>[I:24][C:25]1[N:26]=[C:27]([CH3:39])[N:28]([CH2:30][CH2:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:29]=1.[CH3:39][C:27]1[N:28]([CH2:30][CH2:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH:29]=[C:25]([Sn:45]([CH3:47])([CH3:46])[CH3:44])[N:26]=1
Reactant: C[Sn](C)(C)Cl
Agent: BrCCOC1CCCCO1
Agent: CC[Mg]Br
Agent: Cc1nc(I)c[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc([Sn](C)(C)C)cn1CCOC1CCCCO1
Temperature: 10 °C
Yield: 124.1 %

Procedure:
4-Iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole was prepared by reaction of 4-iodo-2-methyl-1H-imidazole, Cs2CO3, and 2-(2-Bromo-ethoxy)-tetrahydro-pyran in DMF. To a mixture of 4-Iodo-2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazole (500 mg, 1.9 mmol) in DCM (10 mL) was added ethylmagnesium bromide (0.7 ml, 3 mol/L, 2.2 mmol) at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride (2.2 ml, 1 mol/l, 2.2 mmol) was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM, The organic was washed with water twice, dried over anhydrous Na2SO4, concentrated to give 0.44 g of 2-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trimethyl stannyl)-1H-imidazole. Yield=63%. 1H NMR (CDCl3, 400 MHz): δ 7.04 (s, 1H, ArH), 3.71 (s, 2H), 2.43 (s, 3H), 1.24-1.20 (m, 6H), 0.88 (s, 9H), 0.29 (s, 6 H), 0.06 (s, 9H). LC-MS: m/z=375 [M+H+]
Reaction SMILES: C(O[CH2:5][C:6]1[NH:11][C:10]2[N:12]([CH3:16])[NH:13][C:14](=[O:15])[C:9]=2[CH:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Br:24])[CH:18]=2)[C:7]=1[C:25]([O:27]CC)=[O:26])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:24][C:19]1[CH:18]=[C:17]([CH:8]2[C:9]3[C:14](=[O:15])[NH:13][N:12]([CH3:16])[C:10]=3[NH:11][C:6]3[CH2:5][O:26][C:25](=[O:27])[C:7]2=3)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CCOC(=O)C1=C(COC(C)=O)Nc2c(c(=O)[nH]n2C)C1c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)OC1)C2c1ccc(F)c(Br)c1
Yield: 54.7 %

Procedure:
The product from Example 32A (0.09 g) and potassium carbonate(0.03 g) in methanol (10 mL) were stirred at ambient temperature for 1 hour. The solvent was evaporated under reduced pressure and the obtained residue was chromatographed on silica gel eluting with 10% EtOH/CH2Cl2 to provide 0.04 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H), 4.76 (s, 1H), 4.9 (q, 2H), 7.23 (m, 2H), 7.42 (dd, 1H), 9.51 (bs, 1H), 9.78 (s, 1H); MS (ESI−) m/z 378 (M−H)−; Anal. calcd for C15H11N3BrFO3.0.5 C2H6O: C, 47.66; H, 3.50; N, 10.42. Found: C, 48.10; H, 2.97; N, 10.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([O:24]CC)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:27])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([OH:24])=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:27])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc2c(c1)c1ncccc1c(=O)n2Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)O)ccc32)cc1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
The compound (200 mg, 0.51 mmol) prepared in step 3 of Example 5 was dissolved in methanol, added with 1 N sodium hydroxide (5 ml). The resulting mixture was refluxed for 18 hours cooled to room temperature. The mixture was concentrated under reduced pressure and added with water. Water layer was acidified with 1 N hydrochloric acid and extracted with ethylacetat. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. With no separate purification process, title compound (140 mg, yield: 76%, white solid) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14]Cl>O>[Cl:14][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: ClCl
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCCC(C)(C)N1Cl
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
20 g of 2,2,6,6-tetramethylpiperidine are mixed with water and 6.42 g, 0.6 eq., of calcium hydroxide, and the suspension is cooled to 5° C. Over a period of 1.5 hours, 10.8 g, 1.1 eq. of chlorine gas are introduced, then nitrogen gas is used to drive out the excess chlorine and the mixture is warmed to RT. After separating the phases, washing the aqueous phase with 25 ml of dichloromethane, drying the combined organic phases with magnesium sulphate and distilling off the dichloromethane in vacuo, 24.2 g, 99%, of 1-chloro-2,2,6,6-tetramethylpiperidine are obtained.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1.CN(C1CCCCC1)C1CCCCC1.[C:34]([O:39][CH2:40][CH3:41])(=[O:38])/[CH:35]=[CH:36]/[CH3:37]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[CH2:40]([O:39][C:34](=[O:38])/[CH:35]=[C:36](/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1)\[CH3:37])[CH3:41]
Reactant: C/C=C/C(=O)OCC
Reactant: Brc1ccc(-c2ncccn2)cc1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(\C)c1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
Dioxane (2 mL) was added to a mixture of 2-(4-bromophenyl)pyrimidine (0.59 g, 2.51 mmol, prepared as described in U.S. Pat. No. 5,780,473), tri-t-butylphosphonium tetrafluoroborate (36 mg, 0.12 mmol), and tris(dibenzylideneacetone)dipalladium(0) (57 mg, 0.062 mmol). N-Methyldicyclohexylamine (0.64 mL, 2.99 mmol) and ethyl crotonate (0.62 mL, 4.99 mmol) were added and the mixture was stirred for 18 h at room temperature. The mixture was diluted with ethyl acetate, filtered through a small plug of silica gel which was washed with additional ethyl acetate, and the combined filtrates were concentrated. Purification by chromatography (SiO2, 5:1 hexane/ethyl acetate) provided 0.47 g (70%) of the title compound as an off-white solid. MS 269 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:27])[CH3:26])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:30])[C:9]([C@@H:10]([CH3:28])[CH2:11]2)=[CH:8][C:7](=[O:29])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41].CO>C(Cl)Cl>[C:25]([O:24][C@:16]1([C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:30])[C:9](=[CH:8][C:7](=[O:29])[CH:6]=[CH:5]2)[C@@H:10]([CH3:28])[CH2:11]3)[CH2:14][CH2:15]1)[C:17](=[O:20])[CH2:18][O:19][C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])(=[O:27])[CH3:26]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@]1(C(=O)COC(=O)CC(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
In 4 ml of methylene chloride was dissolved 208 mg of 11β,21-dihydroxy-17α-acetoxy-6α-methyl-1,4-pregnadiene-3,20-dione obtained according to the method as described in Example 6. To this solution was added 202 mg of triethylamine and the solution was cooled externally with ice. To this solution was added slowly a solution of 120 mg of isovaleryl chloride in 1 ml of methylene chloride, and the mixture was stirred for 1.5 hours. To the reaction liquid was added 1 ml of methanol, and the mixture was further stirred for one hour. The reaction liquid was concentrated under reduced pressure and the resultant residue was directly subjected to preparative thin layer chromatography (silica gel) for purification and then recrystallized from ether-hexane whereby 195 mg (yield: 78.0%) of the title compound was obtained as colorless fine needle crystals. Shown below are physical properties and various analytical data of this compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:41])([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42](OC)=[O:43].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>>[CH:46]1([N:49]2[CH2:2][C:3]3[C:12]4[CH:11]=[CH:10][C:9]([C:13]([OH:41])([C:17]5[N:18]=[CH:19][NH:20][CH:21]=5)[CH:14]([CH3:16])[CH3:15])=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]=3[C:42]2=[O:43])[CH2:48][CH2:47]1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Reactant: NC1CC1
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C1CC1)C3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (1.32 g) and cyclopropylamine (3.0 ml), the title compound (0.58 g) was obtained as a colorless amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12]>C(OCC)C>[C:11]([N:14]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:2][C:3]([OH:5])=[O:4])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CN
Solvent: CCOCC
Product: CC(C)CN(CC(=O)O)C(C)(C)C
Reaction time: 1 h
Yield: 82 %

Procedure:
t-Butyl bromoacetate (8.4 ml, 10.1 g) was added under an atmosphere of argon to a solution of isobutylamine (50 ml, 36.8 g) in diethyl ether (100 ml) at −40° C. with stiming over 5 min. The solution was stirred at this temperature for 1 hr and then at ambient temperature for 18 hr. The mixture was filtered and the filtrate distilled at ambient pressure to remove ether and subsequently excess isobutylamine (b.p. 64-66° C.) and then under reduced pressure to give the product Yield 82% b.p. 68° C./3 mm NMR (CDCl3 300 MHz, ppm) 3.28(2H, s), 2.4(2H, d), 1.72(1H, m), 1.48(9H,s), 0.92(6H,d). m/Z 188.3 (M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC>[N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3([NH2:16])[CH2:2][CH2:1]3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc2ncccc2c1
Agent: Cl
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: NC1(c2ccc3ncccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethylmagnesium bromide (7.7 mmol, 3 M in ethyl ether) was added to a solution of quinoline-6-carbonitrile (O-4) (540 mg, 3.5 mmol) and Ti(Oi-Pr)4 (3.9 mmol, 1.16 mL) in Et2O (15 mL) at −70° C. The resulting yellow solution was stirred for 10 mins, warmed to room temperature over 1.5 h, and then was treated with BF3.OEt2 (7 mmol, 0.88 mL). The resulting mixture was stirred for 1 h. Then 1N aqueous HCl (11 mL) and ethyl ether (40 mL) were added, followed by NaOH (10% aq, 30 mL). The mixture was extracted with ethyl ether. The combined ethyl ether layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the crude title compound, which was used for the next step without further purification. MS (m/z): 185 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:24]#[N:25])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[C:24]([C:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc3ccccc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccc3ccccc3c2)CCNCC1

Procedure:
Combine 1-tert-butoxycarbonyl-4-cyano-4-(naphth-2-yl)-piperidine (3.12 mmol) and HCl in dioxane (10 mL, 40 mmol, 4N, 13 eq.) at ambient temperature for 1 h. Concentrate the solvent in vacuo and dry under high vacuum to give the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([C@@H:40]([OH:42])[CH3:41])[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:43]1[CH2:48][CH2:47][N:46]([CH2:49][C:50](O)=[O:51])[CH2:45][CH2:44]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>CN(C=O)C>[OH:42][C@@H:40]([CH3:41])[C@H:9]([NH:8][C:50](=[O:51])[CH2:49][N:46]1[CH2:47][CH2:48][O:43][CH2:44][CH2:45]1)[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11]
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H](N)[C@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](NC(=O)CN2CCOCC2)[C@H](C)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To (2S,3S)-2-amino-3-hydroxy-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)butanamide TFA salt (0.207 mmol assumed) was added 2-morpholinoacetic acid (48.0 mg, 0.331 mmol), HATU (0.126 g, 0.331 mmol), and DMF (1 mL). The mixture was cooled to 0° C. and DIEA (0.177 mL, 0.104 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (25,35)-3-hydroxy-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)butanamide (80 mg, 63%) as a colorless solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([S:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: CCSc1ccc(C(=O)O)nn1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A stirred mixture of 6-ethylsulfanyl-pyridazine-3-carboxylic acid (0.37 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.77 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 2 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-Ethylsulfanyl-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.78 g, 86% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.43 min (96.78%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.38 (t, J=7.3 Hz, 3H, CH3), 1.98-2.13 (m, 1H, CHH), 2.43-2.69 (m, 2H, CHH, CHH), 2.79-3.00 (m, 1H, CHH), 3.24-3.42 (m, 2H, CH2), 4.69 (d, J=6.2 Hz, 2H, CH—), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.75-7.93 (m, 4H, Ar), 7.97 (d, J=9.1 Hz, 1H, Ar), 9.98 (t, J=6.3 Hz, 5H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.18, 21.99, 24.01, 30.93, 42.42, 48.99, 122.15, 123.53, 124.92, 126.89, 129.85, 131.57, 133.60, 147.19, 149.74, 162.99, 165.00, 166.97, 167.12, 169.82, 172.73; LCMS: MH=454; Anal Calcd for C21H19N5O5S: C, 55.62; H, 4.22; N, 15.44. Found: C, 55.43; H, 4.09; N, 15.22.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:45]/[O:46][CH3:47])/[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:28])=[C:15]([C:18]4[S:19][C:20]5[C:25]([N:26]=4)=[CH:24][CH:23]=[CH:22][N:21]=5)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[Na]>>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:45]/[O:46][CH3:47])/[C:8]([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[S:28])=[C:15]([C:18]4[S:19][C:20]5[C:25]([N:26]=4)=[CH:24][CH:23]=[CH:22][N:21]=5)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4cccnc4s3)CS[C@H]12)c1nsc(N)n1
Agent: [Na]
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(O)=S)=C(c3nc4cccnc4s3)CS[C@H]12)c1nsc(N)n1
Yield: 73.2 %

Procedure:
Using 335 mg of diphenylmethyl 7-{(Z)-2-(5-amino1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido}-3-(thiazolo[5,4-b]pyridin-2-yl)thio-3-cephem-4-carboxylate, the reaction and purification process of Inventive Example 1 (d) was repeated to obtain 187 mg of the title compound as a sodium salt (yield, 70%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[O:11].N1C2C(=CC=CC=2)C=C1C(OCC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=Cc1cc2ccccc2[nH]1
Agent: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1

Procedure:
1H-indole-2-carbaldehyde derivatives (1) may be prepared by reduction of commercially available or well known ethyl 1H-indole-2-carboxylate derivatives (12) with a reducing agent such as LAH in an aprotic solvent such as THF to give the corresponding (1H-indol-2-yl)methanol derivative (13). Oxidation with an oxidizing agent such as active manganese dioxide in an aprotic solvent such as DCM gives the desired 1H-indole-2-carbaldehyde derivatives (1).
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26]CC)=[O:25].[O-]CC.[Na+:35]>C(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:22]([CH2:29][CH2:30][CH3:31])=[C:23]([C:24]([O-:26])=[O:25])[N:3]=[N:2]3)=[CH:20][CH:19]=2)=[O:9])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[Na+:35]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCOCC2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1c(C(=O)[O-])nnn1-c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Azido-N-(2-morpholin-4-ylethyl)benzamide obtained in Example 61a) and ethyl 3-oxohexanoate (1.07 ml, 6.35 mmol, 1.25 eq.) were dissolved in ethanol (23 ml), sodium ethoxide (480 mg, 6.35 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 20 min, and then at 60° C. for 13 hr. The resulting solid was suspended in ethyl acetate, and the insoluble material was collected by filtration, washed with ethyl acetate and dried to give the title compound as a grayish white powder (2.44 g, 5.09 mmol, quant.).
Reaction SMILES: [Cl:1][C:2]([Cl:38])=[CH:3][CH2:4][O:5]/[N:6]=[C:7](/[C:13]1[N:14]=[C:15]([NH:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:16][CH:17]=1)\[C:8]([O:10][CH2:11][CH3:12])=[O:9].O>C(O)=O>[NH2:18][C:15]1[S:16][CH:17]=[C:13](/[C:7](=[N:6]/[O:5][CH2:4][CH:3]=[C:2]([Cl:38])[Cl:1])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:14]=1
Reactant: CCOC(=O)/C(=N\OCC=C(Cl)Cl)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CCOC(=O)/C(=N\OCC=C(Cl)Cl)c1csc(N)n1
Yield: 84.3 %

Procedure:
Ethyl (Z)-2-(3,3-dichloroprop-2-en-1-yloxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetate (622 mg, 1.09 mmol) was dissolved in 98% formic acid (5 ml) and treated with water (1.5 ml). After stirring for 2 h the formic acid and water were removed under reduced pressure. Toluene was added and the process repeated. The residue was chromatographed on silica-gel eluting with ethyl acetate/hexane mixtures to give the title compound (298 mg, 84%) m.p. 135°-136°; [Found C, 37.25; H, 3.46; N, 13.12. C10H11Cl2N3O3S requires C, 37.05; H, 3.42; N, 12.96%]. νmax (CH2Cl2) 3475, 3380, 3110, 1735, 1605, 1530, 1375, 1180, and 1025 cm-1 ; δH (60 MHz, CDCl3) 1.30 (3H, t, J ca 7 Hz), 4.37 (2H, q, J ca 7 Hz), 4.72 (2H, d, J ca 6.5 Hz), 5.83 (2H, broad s), 6.1 (1H, t, J ca 6.5 Hz), and 6.66 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:19]1([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1cccnc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 ml), 4-pyridinylboronic acid (64.1 mg, 0.52 mmol), 1M sodium carbonate (1.04 mL, 1.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (36.2 mg, 0.03 mmol). The vial was sealed and heated to 100° C. for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 41 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1F
Yield: 62 %

Procedure:
The title compound is prepared from 4-amino-3-fluoro-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 62% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=311 [M+H]+.