Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C@@H:17]3[C:21]([CH3:23])([CH3:22])[C@@:14]([CH3:24])([CH2:15][CH2:16]3)[C:13]=2[N:12]1[CH3:25].[OH-].[Na+]>O1CCCC1.CO>[CH3:25][N:12]1[C:13]2[C@@:14]3([CH3:24])[C:21]([CH3:22])([CH3:23])[C@H:17]([CH2:16][CH2:15]3)[C:18]=2[C:19](=[O:20])[N:11]1[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccccc1Cn1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c2c(c(=O)n1Cc1ccccc1C(=O)O)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A mixture of 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (304 mg, 0.86 mmol) and 1 M NaOH (1.5 mL, 1.5 mmol) in tetrahydrofuran (2.4 mL) and methanol (1.2 mL) was stirred overnight at room temperature. The reaction mixture was partitioned between water (100 mL) and ether (100 mL). The aqueous layer was acidified to pH<3 with 1 M HCl and the resulting mixture was extracted with chloroform (100 mL) and then chloroform containing a small amount of methanol (100 mL). The combined organic extracts were dried (magnesium sulfate), filtered, evaporated, and dried under vacuum to give 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid (188 mg, 64%) as an off-white solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:36])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28](CC3C=CC=CC=3)[N:27]=[N:26][CH:25]=2)=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:36])([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][NH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C=C(c1ccc(-c2cnnn2Cc2ccccc2)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CO
Product: CC(c1ccc(-c2c[nH]nn2)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 84.1 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(4-[1-benzyl-1,2,3-triazol-5-yl]phenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol(0.15 g,0.3 mmol-see Preparation 43) in methanol (100 ml) was hydrogenated at 50 psi (333 kPa) pressure over 10% palladium on charcoal (0.1 g) for 18 hours at 100° C. The cooled mixture was filtered through "Arbocel" and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica by elution with dichloromethane/methanol (19:1). Fractions containing the desired product were combined and evaporated under reduced pressure to yield the title compound as a gum (0.1 g, 81%). The product was a mixture of diastereomers by NMR.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][NH:3][CH2:2]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:3]2[CH2:2][CH2:1][C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:15]([O:17][CH3:18])=[O:16])=[CH:4]2)=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using methyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (Kuehne et al.(1985) J. Org. Chem. 50:919-924) and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.51 (1H, br s), 7.99 (1H, s), 7.62 (2H, m), 7.53 (1H, d), 7.23 (1H, d), 7.10-7.24 (4H, m), 4.22 (2H, t), 3.80 (3H, s), 3.27 (2H, m); MS (ES): 365 (MH1).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]1([CH2:12][C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:15]([C:13]([OH:14])([CH:1]([CH3:3])[CH3:2])[CH2:12][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Product: CC(C)C(O)(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.08 h

Procedure:
According to Example 2, i-PrMgCl (1.10 mL; 1.10 mmol; 1.10 equiv) was reacted with 1,3-diphenylacetone (210 mg; 1.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.0 mL, 1.00 mmol, 1.00 equiv), the conversion was complete after 5 min (GC monitoring). After workup and careful evaporation of the solvents under reduced pressure, the desired product was obtained as white solid, mp=52−53° C. (241 mg, 95%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH:9]([CH:16]([OH:20])[C:17]([OH:19])=[O:18])[O:8][CH:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.O.[C:30]1(C)C=CC(S(O)(=O)=O)=C[CH:31]=1>C(O)C>[CH2:30]([O:18][C:17](=[O:19])[CH:16]([CH:9]1[O:8][CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]1=[O:15])[OH:20])[CH3:31]
Reactant: CC(C)N1C(=O)C(C(O)C(=O)O)OC(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(O)C1OC(c2ccccc2Cl)c2cc(Cl)ccc2N(C(C)C)C1=O
Yield: 841.1 %

Procedure:
A mixture of (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid (0.15 g) obtained in Example 7, p-toluenesulfonic acid monohydrate (7 mg) and ethanol (20 ml) was heated for 24 hours under reflux. Ethanol was distilled off under reduced pressure. The residue was dissolved in a mixture of water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate, then the solvent was was distilled off under reduced pressure to leave (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid ethyl ester (0.14 g) as prisms, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:31]([CH3:32])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: CN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18ClN5O2, 407.9
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[S:8])([O-:3])=[O:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17]CC)=[O:16]>C(O)C>[CH3:22][C:20]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[S:8][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: Cc1nc(-c2cccc([N+](=O)[O-])c2)sc1C(=O)O
Temperature: 70 °C
Yield: 52.9 %

Procedure:
730 mg of 3-Nitrothiobenzamide was dissolved in 5 ml of ethanol, 725 mg of ethyl 2-chloroacetoacetate was added to the solution, and the mixture was heated under reflux for 18 hours. After the reaction mixture was cooled, the precipitated crystal was collected by filtration and recrystallized from a mixed solvent consisting of 10 ml of ethanol and 5 ml of ethyl acetate. 800 mg out of 898 mg of the resulting crystal was suspended in 10 ml of ethanol, 10 ml of an aqueous 1N sodium hydroxide solution was added to the suspension, and the mixture was heated at 70° C. for 2 hours. After the completion of the reaction, ethanol was removed by distillation, and the residue was neutralized with 1N hydrochloric acid. The precipitated crystal was collected by filtration and recrystallized from an aqueous 50% ethanol solution to give 560 mg of 4-methyl-2-(3-nitrophenyl)-5-thiazolecarboxylic acid (yield: 59%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:50]=[CH:49][C:24]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH:35]([C:46]([O-:48])=[O:47])[CH2:34]4)=[O:32])=[CH:27][CH:26]=3)=[CH:23][CH:22]=2)=[CH:10][CH:9]=1>ClCCl>[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13][C:12]=2[C:11]([C:21]2[CH:22]=[CH:23][C:24]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH:35]([C:46]([OH:48])=[O:47])[CH2:34]4)=[O:32])=[CH:29][CH:30]=3)=[CH:49][CH:50]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CC1C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CN(C(=O)c2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-(4′-Dibenzofuran-4-ylbiphen-4-yl-carbonyl)-piperazine-1,2-dicarboxylic acid, 1-tert-butyl ester (135 mg) in anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours (TLC control). The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as a white solid (112 mg, 100%): Rf 0.10 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.18 (2H, t, J=9 Hz, Ar—H), 8.04 (2H, d, J=9 Hz, Ar—H), 7.92 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.75 (2H, t, J=8 Hz, Ar—H), 7.61 (2H, m, Ar—H), 7.53 (2H, t, q, J=8 Hz, Ar—H), 7.43 (1H, t, J=8 Hz, Ar—H), 4.34 (1H, m, CHN), 3.40 (4H, m), 3.18 (2H, m); ESI-LCMS e/z calcd for C30H24N2O4 476.530, found 477 (M+H)+, 499 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].Cl.[CH:27]1([NH:31][NH2:32])[CH2:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20]1[N:31]([CH:27]2[CH2:30][CH2:29][CH2:28]2)[N:32]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as orange oil. MS (ESI): m/z=438.3 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[C:6]2(SCCCS2)[C:5]1=[O:19]>C(O)C.O1CCCC1.[Ni]>[Cl:1][CH2:2][CH2:3][N:4]1[C:17]2[C:12](=[CH:13][C:14]([F:18])=[CH:15][CH:16]=2)[CH2:6][C:5]1=[O:19]
Reactant: O=C1N(CCCl)c2ccc(F)cc2C12SCCCS2
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1Cc2cc(F)ccc2N1CCCl
Reaction time: 3 h

Procedure:
1-(2-chloro-1-ethyl)-1,3-dihydro-5-fluoro-2-oxo-2H-indole-3-spiro-2'-1,3 dithiane was dissolved in a mixture of ethanol/tetrahydrofuran (3:2). Raney nickel was added and the mixture was heated under reflux with vigorous stirring for 3 h. The cooled solution was filtered, evaporated under reduced pressure and triturated with ether to give 1-(2-chloro-1-ethyl)-5-fluoro-1,3-dihydro-2H-indole-2-one as a white solid, melting point 127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:36])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cncc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cncc(Br)c1
Reaction time: 4 h
Yield: 67.2 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (500 mg, 2.7 mmol) and triphenylphosphine (840 mg, 3.2 mmol) are dissolved in 12 mL of DCM and NBS (570 mg, 3.2 mmol) is added. The mixture is stirred for 4 hrs and the solvent is removed. The residue is purified by flash column chromatography to give 455 mg of 3-bromo-5-bromomethyl-pyridine.
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:3]1[CH2:7][O:6][CH2:5][CH:4]1[C:8]([OH:10])=O.[NH2:33][OH:34]>>[OH:34][NH:33][C:8]([C@H:4]1[C@@H:3]([N:2]([CH3:1])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:7][O:6][CH2:5]1)=[O:10]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)C3COCC3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3COC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 21 %

Procedure:
According to the procedure of Example 24, Step 3, 4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid (0.160 g, 0.35 mmol) and hydroxylamine gave (3S,4R)-4-{methyl-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl]-amino}-tetrahydro-furan-3-carboxylic acid hydroxyamide as an amorphous white solid (0.035 g, 21%) after purification using Biotage Flash 40S chromatography, eluting with 5% methanol in ethyl acetate. MS: 472 (M+H)+
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:28](=[O:31])[CH:29]=[CH2:30])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reaction time: 8 h

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.3 g, 1.12 mmol) in dichloromethane (10 mL), triethylamine (0.19 mL, 1.34 mmol) and acryloyl chloride (0.11 mL, 1.23 mmol) were added successively and the mixture was stirred overnight. The reaction was hydrolysed, and the organic phase washed with water, dried over magnesium sulfate and concentrated under reduced pressure. A minimum amount of dichloromethane was added to the crude, diethylether was added and the resulting solid collected by filtration. LCMS Method: 2: RT: 4.23 min, 323 [M+1].
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]([CH3:19])[CH:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]2[CH:8]([CH3:19])[CH:9]([CH2:14][CH2:15][C:16](=[O:18])[O:17][N:26]3[C:30](=[O:31])[CH2:29][CH2:28][C:27]3=[O:32])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)C2C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)ON1C(=O)CCC1=O)C2C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of 297 mg (0.88 mmol) of 3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in 20 mL of anhy. CH2Cl2 under argon was added 246 mg (2.14 mmol) of N-hydroxysuccinimide (Aldrich) and the reaction stirred for 15 min. 408 mg (2.14 mmol) of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (Sigma) was then added and the reaction stirred at RT for 3 hr. The reaction was diluted to five times the volume with CH2Cl2, washed with 0.1N aq. HCl that had been saturated with NaCl, followed by sat. aq. NaCl, followed by sat. aq. NaHCO3 (×3), dried and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 1:1 EtOAc-CH2Cl2. The product fractions were combined and evaporated under reduced pressure and dried under high vacuum to give 297 mg (78%) of 1-[3-(3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-yl)-1-oxopropoxy]-2,5-pyrrolidinedione as a white foam. HR (+) FAB MS: Calc (M+H), 432.2386; Observed, 432.2413.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@@H:8]2[C@H:11]([NH:12][C:13](=[O:29])/[C:14](=[N:21]\[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:15]3[N:16]=[C:17]([NH2:20])[S:18][CH:19]=3)[C:10](=[O:30])[N:9]2[S:31]([OH:34])(=[O:33])=[O:32])[C:3]1=[O:35].Cl.[N:37]1([C:42](=N)[NH2:43])C=CC=N1>>[NH2:20][C:17]1[S:18][CH:19]=[C:15](/[C:14](=[N:21]/[O:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])/[C:13]([NH:12][C@@H:11]2[C:10](=[O:30])[N:9]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:8]2[CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:42]([NH2:43])=[NH:37])[C:3]2=[O:35])=[O:29])[N:16]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@H](N)C1=O)c1csc(N)n1)C(=O)O
Agent: Cl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1CC[C@H](NC(=N)N)C1=O)c1csc(N)n1)C(=O)O

Procedure:
Prepared in analogous manner to example 20 using 2-(((Z)-(2-(((2R,3S)-2-(((S)-3-amino-2-oxopyrrolidin-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid and 1H-pyrazole-1-carboximidamide HCl. LCMS: m/z=576.2 (M+1); 1H NMR (400 MHz, D2O): δ 6.95 (s, 1H), 5.31 (d, J=6.0 Hz, 1H), 4.72-4.57 (m, 1H), 4.27 (t, J=9.6 & 9.2 Hz, 1H), 3.85 (dd, J=9.6 Hz, 1H), 3.59 (t, J=9.2, 8.8 Hz, 1H), 3.49 (q, 1H), 3.34 (dd, 1H), 2.46 (m, 1H), 1.88 (m, 1H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 mL) was added 4-Chloro-benzaldehyde (1.5 g, 10.7 mmol). The resultant solution was heated at 60° C. overnight. The reaction mixture was cooled to 0° C. and to it was added NaBH4 (629 mg, 10 mmol). After 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered and concentrated to provide the crude product as an oil. The crude product was used in the subsequent reaction without further purification. LCMS (retention time=1.27, ES+311)
Reaction SMILES: [OH-].[Li+].[CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH3:17])([CH3:5])[CH3:4]>O1CCCC1.O>[CH:3]([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH3:17])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(OC(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1OC(C)C
Temperature: 65 °C
Yield: 90.9 %

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (1.0 g, 59.8 mmol) in dry DMF (62 mL) was added finely ground potassium carbonate (33.1 g, 239.3 mmol) followed by 2-iodopropane (20.3 g, 12.0 mL, 119.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled and diluted with ether (350 mL), and filtered over celite. The filtrate was washed with water (3×100 mL) and brine (100 mL) solution. The layers were separated and organics were dried over MgSO4. The solvent was evaporated and resulting residue was purified by silica gel using 0-30% EtOAc/hexanes mixtures as eluent to give methyl 4-isopropoxy-3-methylbenzoate as a colorless oil (11.2 g, 89%). ESI-MS m/z calc. 208.25. Found 209.2 (M+1)+; Retention time: 1.93 minutes (3 min run). Lithium hydroxide (4.4 g, 181.6 mmol) was added to a solution of methyl 4-isopropoxy-3-methylbenzoate (11.2 g, 53.8 mmol) in tetrahydrofuran (31 mL) and water (31 mL). The mixture was rapidly stirred and heated at 65° C. for 6 hours. The reaction mixture was cooled, diluted with water (75 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified to pH 2 with 6N aq. HCl and extracted with ethyl acetate (4×75 mL). The combined organics were washed with water (75 mL) and brine solution (75 mL) and layers were separated. The organics were dried over MgSO4 and concentrated in vacuo to give 4-isopropoxy-3-methyl-benzoic acid (9.5 g, 82%) as colorless crystals. ESI-MS m/z calc. 194.2. Found 195.3 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.78-7.71 (m, 2H), 7.02 (d, J=8.6 Hz, 1H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 2.15 (s, 3H), 1.30 (d, J=6.0 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][CH2:25][C:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:35]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][CH2:25][C:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde to give the title compound.