Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:6])[CH3:5].C1COCC1.CO.O[Li].O>O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:20])=[O:2])(=[O:10])=[O:9])=[CH:12][CH:13]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1ccc(C(C)=O)cc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-2-(4-acetylphenylsulfonamido)-2-methylpropanoate (2.55 g, 8.52 mmol) was charged, and dissolved through addition of THF (20 ml), and methanol (20 ml). LiOH.H2O dissolved in H2O (10 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 2-(4-acetylphenylsulfonamido)-2-methylpropionic acid (2.38 g, 8.35 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:22])=[O:21])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:29][C:30](=O)[O:31]CC.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[N:24]=[CH:25][N:26]([CH3:28])[CH:27]=3)(=[O:22])=[O:21])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[NH:29][CH:30]=[O:31]
Reactant: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccc(Cl)c(Cl)c2)C(NC=O)CC3)c1
Yield: 65 %

Procedure:
Ethyl 1-(3,4-dichlorobenzyl)-7-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (example 3, 60.0 mg, 0.103 mmol) was dissolved in THF (5 ml) and LiAlH4 (7.83 mg, 0.206 mmol) was added at RT. The residue was added to 2N NaOH and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 solution and then with saturated NaCl solution, dried and evaporated. The product was precipitated as an HCl salt from 6N HCl in isopropanol and isopropylether to obtain the product as a white salt (36 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-trifluoromethylbenzoyl chloride (0.60 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml) and filtered to give 0.41 g (46%) of product as an off-white solid: mp 257-259° C.; 1H NMR (DMSO-d6) d 10.86 (s, 1H), 10.45 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 8.24-8.25 (m, 2H), 8.02-7.82 (m, 3H), 7.69 (d, J=7.3 Hz, 1H), 5.14 (dd, J=5.7 and 12.8 Hz, 1H), 2.95-2.82 (m, 1H), 2.67-2.48 (m, 2H), 2.14-2.07 (m, 1H); 13C NMR (DMSO-d6) d 171.75, 168.80, 167.31, 166.06, 163.43, 135.80, 135.60, 134.28, 131.16, 130.71, 129.75, 128.35, 128.29, 126.63, 123.59, 123.52, 118.65, 118.55, 48.84, 30.51, 21.62; Anal. Calcd. For C21H14F3N3O5: C, 56.64; H, 3.17; N, 9.44. Found: C, 56.48; H, 3.15; N, 9.41.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH2:25]([N:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:28][CH3:29])[CH3:26]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:36][CH:35]=2)=[C:9]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:36][CH:35]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: CCN(CC)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(Nc2cc(C(=O)OC)c(C(=O)OC)cc2Nc2ccc(N(CC)CC)cc2)cc1

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.94 g (24 mmol) of 4-(N,N-diethyl-amino)-aniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with dichloromethane/methanol 400:15 and the product fractions are concentrated by evaporation and again chromatographed on silica gel with ethyl acetate/hexane 1:1. The product fractions are concentrated by evaporation, yielding the title compound in the form of green crystals, FAB-MS: 518 [M+ ], 519 [M+ +H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH2:19].C[N+]1([O-])CCOCC1.S([O-])([O-])=O.[Na+].[Na+].[OH2:34]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:34])[CH2:17][OH:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Solvent: CC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
485 mg of the compound [5-1] was dissolved in a mixed solvent of 18 mL of acetone and 3 mL of water, then 460 mg of 4-methylmorpholine 4-oxide monohydrate and 590 μL of osmium tetroxide (0.1M aqueous solution) were added in that order, and the mixture was stirred overnight at room temperature. 10 mL of 10% aqueous solution of sodium sulfite was added thereto, and after the 30 minutes stirring, the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-0/100), to obtain 351 mg of tert-butyl{(1S)-1-[4-(1,2-dihydroxyethyl) phenyl]ethyl}carbamate [7-1] (hereinafter, referred to as the compound [7-1]) as a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Yield: 92 %

Procedure:
To a round-bottom flask with stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmole), methyl 2-bromoacetate (1.1 eq.) potassium carbonate (5 equiv.) and 10 mL of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of solvent gave 4-methoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 92% yield.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:27](=[O:28])[CH2:26][C@H:25]5[NH:29][C@H:22]([CH2:23][CH2:24]5)[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:36]=O>>[CH3:1][NH:2][C:3]([C:5]1[N:30]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[C:27](=[O:28])[CH2:26][C@H:25]5[N:29]([CH3:36])[C@H:22]([CH2:23][CH2:24]5)[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: C=O
Product: CNC(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5C)cn3)nc2n1C1CCCC1
Yield: 98 %

Procedure:
Following general reductive alkylation method 1, 7-cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide was combined with formaldehyde which gave 7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (100 mg) in 98% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:24][CH2:23]1>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]([O:1][CH2:2][C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]3)=[CH:5][CH:4]=2)=[O:31])[CH2:26][CH2:27]1
Reactant: O=C1CCc2ccc(CO)cc2N1
Reactant: O=C(O)CCN1CCN(c2cccc(Cl)c2Cl)CC1
Product: O=C1CCc2ccc(COC(=O)CCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1

Procedure:
(2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl 3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propanoate (38b) (Scheme 7) was prepared from the carbinol 37 and the carboxylic acid 18b according to the protocol described for the compound 38a (Example 55). Colorless oil, 0.39 g (99%). 1H NMR (400 MHz, CDCl3): δ 2.55-2.60 (m, 4H); 2.62 (broad s, 4H); 2.78 (t, J=7.6 Hz, 2H); 2.93 (t, J=7.6 Hz, 2H); 3.00 (broad s, 4H); 5.05 (s, 2H); 6.83 (s, 1H); 6.90-6.93 (m, 1H); 6.98 (dd, J=1.2, 7.6 Hz, 1H); 7.09-7.13 (m, 3H); 9.22 (broad s, 1H). MS (ESI): m/z=462.10 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]#CCO)[CH3:2].C[C:10]([CH3:12])=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O.C[C:23](C)=[O:24]>O>[CH3:23][O:24][C:10](=[O:11])[C:12]#[C:2][CH2:1][O:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCOCC#CCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCC#CC(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-ethoxy-but-2-yn-1-ol (1 g, 8.76 mmol) in acetone (26 mL) at 0° C. was added dropwise Jones reagent. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with methyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated. The resulting 4-ethoxy-but-2-ynoic acid was methylated (TMSCHN2 (2 M), MeOH/toluene, room temperature, 3 hours) to afford 0.66 g of the title compound as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: c1ccc(CN2CCNCC2)cc1
Product: c1ccc(CN2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Yield: 83.4 %

Procedure:
In the same manner as described in Reference Example 4, N-benzylpiperazine (20 g) and 2-chloromethylbenzimidazole (9.0 g) are reacted, and the crude crystal thus obtained is recrystallized from ethyl acetate to give 2-(4-benzyl-1-piperazinyl)methylbenzimidazole (13.8 g) as pale yellow needles, m.p. 195°-201° C.
Reaction SMILES: C1(C[N:8](CC2C=CC=CC=2)[C:9]2[C:18]3[N:19]=[C:20]([CH3:26])[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]=3[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=2)C=CC=CC=1.C([O-])=O.[NH4+].CO.[OH-].[NH4+]>Cl.[OH-].[OH-].[Pd+2]>[CH3:26][C:20]1[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:8])[C:18]=2[N:19]=1
Reactant: Cc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3c(c2n1CC(C)C)CCCC3
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: Cc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3
Temperature: 25 °C
Yield: 99.4 %

Procedure:
N,N-Bis(phenylmethyl)-6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (820 mg, 1.87 mmole), palladium hydroxide on carbon (200 mg, Pearlman's catalyst), ammonium formate (472 mg, 7.48 mmole) and methanol (50 mL) were combined and heated at reflux for 48 hours. During the course of the reaction additional catalyst (200 mg) and ammonium formate (472 mg) were added. The reaction mixture was cooled to ambient temperature then filtered through a layer of celite. The filtrate was evaporated to provide a residue which was dissolved in 3N hydrochloric acid. The solution was made basic (pH 9) with ammonium hydroxide then extracted with methylene chloride (3×200 mL). The extracts were combined, washed with water, dried over magnesium sulfate then concentrated to provide 480 mg of a white solid. This solid was recrystallized from ethyl acetate to provide 260 mg of the desired product as a white solid, m.p. 170°-172° C. Analysis: Calculated for C15H22N4 +1/2H2O: %C, 68.16; %H, 8.64; %N, 21.2; Found: %C, 68.47; %H, 8.14; %N, 21.08.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:54][C@@H:55]2[CH2:60][O:59][CH2:58][CH2:57][O:56]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:56]1[CH2:57][CH2:58][O:59][CH2:60][C@H:55]1[CH2:54][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3=[CH:14][C:15]4[CH2:19][CH2:18][O:17][C:16]=4[CH:20]=[C:10]23)[C:2]1=[O:21]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCC3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCC3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2R)-1,4-dioxan-2-ylmethyl]-6,7-dihydrospiro[benzo[1,2-b:4,5-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (97%) as a colorless solid: mp 162-164° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.302, 7.298 (ddd, J=7.8, 7.7, 1.3 Hz, 1H), 7.17-7.14 (m, 1H), 7.07-7.02 (m, 2H), 6.79 (s, 1H), 6.12, 6.09 (s, 1H), 4.91, 4.90 (d, J=8.9 Hz, 1H), 4.66, 4.65 (d, J=8.9 Hz, 1H), 4.48 (t, J=8.7 Hz, 2H), 3.98-3.78 (m, 4H), 3.75-3.55 (m, 4H), 3.45-3.37 (m, 1H), 3.14 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.9, 177.7, 155.1, 155.0, 154.92, 154.88, 142.8, 142.7, 132.3, 132.2, 128.94, 128.89, 128.84, 128.80, 127.8, 127.7, 123.9, 123.8, 123.5, 109.6, 109.4, 107.19, 107.16, 104.0, 103.9, 80.0, 79.9, 73.3, 71.7, 69.4, 69.2, 66.8, 66.7, 66.52, 66.48, 58.46, 58.43, 41.9, 41.8, 30.4; MS (ES+) m/z 380.0 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])([CH3:26])[CH3:25])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19]#[N:20])[NH:17][C:16]2=[O:21])=[O:13])[N:10]=1)=[O:4].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:19]([C@H:18]1[NH:17][C:16](=[O:21])[C@H:15]1[NH:14][C:12](=[O:13])[C:11]([C:9]1[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])[S:7][CH:8]=1)=[N:22][O:23][C:24]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([CH3:26])[CH3:25])(=[O:40])[NH2:20]
Reactant: OO
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C#N)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1C(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 2 ml of dimethyl sulfoxide is dissolved 0.38 g of (3S,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-4-cyano-2-azetidinone and, following addition of 0.1 ml of 30% aqueous hydrogen peroxide and 0.1 ml of 1 N sodium hydroxide, the mixture is stirred at approx. 25° C. for 30 minutes. The reaction mixture is chromatographed on an XAD-II column (eluant: 30% ethanol) to give 0.12 of (3S,4S)-4-carbamoyl-3-[2-(2-chloroacetamidothiazol-4-yl)-2-(1-p-nitrobenzyloxycarbonyl-1-methylethoxyimino)acetamido]-2-azetidinone.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1.CN(C)C=O>[F:21][C:19]1[CH:20]=[CH:13][C:14]([C:15]#[N:16])=[C:17]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:18]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
To a solution of imidazole (4.45 g, 65.4 mmol) in tetrahydrofuran (30 mL) and dimethylformamide (10 mL) was added potassium carbonate (9.95 g, 72 mmol) and the mixture was stirred for 30 min at room temp. To this was added 2,4-difluorobenzonitrile (10.0 g, 72 mmol) and the mixture stirred at 90° C. for 3 h then at room temp for 2 days. The mixture was filtered and concentrated and the residue was purified by flash chromatography (SiO2) eluting with 20% to 70% ethyl acetate/hexane to give the title compound as white needles (1.1 g, 9% yield). 1H-NMR (500 MHz, CDCl3) δ ppm: 7.94 (1H, s), 7.84 (1H, dd, J=8.7, 5.6 Hz), 7.37 (1H, t, J=8.7, 5.6 Hz), 7.37 (1H, t, J1=1.4 Hz), 7.29 (1H, t, J=1.1 Hz), 7.27–7.21 (2H, m). LCMS [M+H]+ calcd for C10H7N3F: 188.058. found: 188.12.
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[N:11]1([CH2:17][C:18]#[C:19][C:20](=O)[CH3:21])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Cl>CCO>[CH3:21][C:20]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[C:18]([CH2:17][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:19]=1
Reactant: CC(=O)C#CCN1CCOCC1
Reactant: N#CCC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CN2CCOCC2)c(C#N)c(=O)[nH]1
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6 N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The reamaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 15% CH2Cl2/20%(5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:26][CH:27]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with tert-butyl N-(4-formylphenyl)carbamate was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give tert-butyl N-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenyl]carbamate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([C:53](O)=[O:54])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([C:53](=[O:54])[NH:23][C:19]3[C:17]4[S:18][C:14]([C:12](=[O:13])[NH:11][C:9]5[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:8]=5[O:24][CH3:25])=[CH:15][C:16]=4[CH:22]=[CH:21][CH:20]=3)=[CH:51][CH:52]=2)(=[O:46])=[O:45])[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(S(=O)(=O)N5CCN(C(=O)OC(C)(C)C)CC5)cc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 42 h
Yield: 14.3 %

Procedure:
7-Amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (0.100 g, 0.223 mmol), 4-(4-carboxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.160 g, 0.432 mmol), HOBT (0.060 g, 0.444 mmol) and EDC (0.080 g, 0.417 mmol) were dissolved in DMF (7.0 mL) and stirred at room temperature under an Ar atmosphere for 42 h. The reaction mixture was transferred to a separatory funnel containing water and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water, NH4Cl, brine and dried over MgSO4. The solvent was filtered and evaporated on a rotary evaporator. The resultant crude product was purified by chromatography (60% EtOAc/hexane) to give the desired 4-{4-[2-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-benzo[b]thiophen-7-ylcarbamoyl]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (25.5 mg).