Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:26]([CH3:28])[CH3:27])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC(C)C)c(C=O)c1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a mixture of methyl 3-formyl-4-hydroxy-benzoate (10.0 g, 55.5 mmol), potassium carbonate (30.7 g, 222.0 mmol) and N,N-dimethylformamide (62.5 mL) was added 2-iodopropane (18.9 g, 11.1 mL, 111.0 mmol) and the reaction mixture was heated at 60° C. for 18 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give a residue which was dissolved in ethyl acetate (150 mL) and washed sequentially with water (3×75 mL) and brine solution (1×75 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 3-formyl-4-isopropoxy-benzoate (12.2 g, 99%) as a yellow viscous liquid. ESI-MS m/z calc. 222.2. found 223.3 (M+1)+; Retention time: 1.51 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.17 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 4.98-4.83 (m, 1H), 3.85 (s, 3H), 1.38 (d, J=6.0 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.[OH-].[K+]>CCO>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: O=C(O)Cc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(OCC2CC2)c1
Yield: 58.8 %

Procedure:
A mixture containing 2-(3-hydroxyphenyl)acetic acid (1.0 g, 6.6 mmol), (bromomethyl)cyclopropane (0.97 g, 7.2 mmol), potassium hydroxide (0.920 g, 16.4 mmol), KI (22 mg, 0.13 mmol) in EtOH (20 mL) was refluxed for 18 h. The solvent was removed in vacuo, and the residue was dissolved in 50 mL of water and extracted with ether. The aqueous layer was acidified with aqueous 1N HCl and extracted with EtOAc. The organic layers were dried (Na2SO4) and concentrated to afford a residue which was purified by silica gel chromatography (petroleum ether/EtOAc 4:1) to get 2-(3-(cyclopropylmethoxy)phenyl)acetic acid as a white solid (0.80 g, 59%).
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[S:41][C:42]([CH3:45])=[N:43][N:44]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].C(O)C.P([O-])([O-])(O)=O.[K+:54].[K+].O>O1CCOCC1.O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[S:41][C:42]([CH3:45])=[N:43][N:44]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: Cc1nnc(SC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@@H](C(C)(C)OC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@H]3C2)s1
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc(SC2=C(C(=O)[O-])N3C(=O)[C@@H](C(C)(C)O)[C@H]3C2)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 mg) and platinum (IV) oxide monohydrate (50 mg) in a mixture of dioxane (6 ml), ethanol (0.5 ml), 0.1M aqueous dipotassium hydrogen phosphate (2.28 ml) and water (2.5 ml) was shaken for 1.5 hours under a hydrogen atmosphere (40 psi) at ambient temperature. The catalyst was filtered off and the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed three times with diethyl ether and evaporated in vacuo. The residue was dissolved in water (25 ml) and potassium chloride (1.25 g) was added. The aqueous solution was chromatographed on non-ionic adsorption resin, "Diaion HP-20 AG" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) (1.2×22 cm), eluting with water (150 ml) and aqueous isopropyl alcohol (5 to 30%, 100 ml). The fractions, whose UV spectra showed λmax 293 nm, were combined and lyophilized to give potassium (5R,6R)-6-(1-hydroxy-1-methylethyl)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (16.9 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([CH:11]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:14][N:13]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:12]1)=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:45][C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:12]2)=[N:8][N:7]=1
Reactant: COCCC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COCCc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)s1

Procedure:
93 mg (0.185 mmol) of the compound from Example 120A and 150 mg (0.371 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 9 mg (10% of theory)
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[NH:8]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:13][C:6]1([CH3:14])[C:5]2[C:9](=[C:10]([CH3:11])[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:12]
Reactant: Cc1c(Br)ccc2c1NC(=O)C2(C)C
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOCC2)ccc2c1NC(=O)C2(C)C
Temperature: 120 °C

Procedure:
A mixture of 6-bromo-3,3,7-trimethylindolin-2-one (0.63 g, 2.44 mmol), NaOt-Bu (0.33 g, 3.42 mmol), Pd2(dba)3 (0.11 g, 0.12 mmol), morpholine (0.51 mL, 5.86 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.11 mL, 0.29 mmol) in Toluene (2.5 mL) was flushed with N2 for 10 minutes and then heated in a microwave at 120° C. for 80 minutes. The mixture was cooled to rt and concentrated. Purification of the residue by flash chromatography over silica gel, using 40% EtOAc in hexane, gave 3,3,7-trimethyl-6-morpholinoindolin-2-one. 1H-NMR (DMSO-d6) δ 10.27 (1H, s), 7.04 (1H, d, J=8.0 Hz), 6.64 (1H, d, J=8.0 Hz), 3.72 (4H, s), 2.78 (4H, s), 2.13 (3H, s), 1.21 (6H, s). Mass Spectrum (ESI) m/e=261.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:21]([CH2:25][CH3:26])[CH:22](C)C)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC1>CN(C=O)C.O>[N:21]1([C:12]([C:11]2[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:17]=[CH:16][CH:15]=2)=[O:14])[CH2:22][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)N2CCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a stirred solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (1.5 g, 6.32 mmol) in DMF (15 ml) were added N,N-diisopropyl ethylamine (2.208 ml, 12.64 mmol) and o-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (2.398 g, 6.32 mmol) followed by azetidine hydrochloride (1.183 g, 12.64 mmol) at room temperature, under nitrogen atmosphere. The reaction was stirred at room temperature for 24 h and monitored by TLC. To the reaction mixture, water (25.0 ml) was added and extracted with ethyl acetate (30 ml×3). The aqueous layer was re-extracted with ethyl acetate. All organic layers were combined and washed with cold water (20.0 ml) and brine (20 ml); dried over sodium sulphate and solvent was evaporated under vacuum to get the titled compound (1.1 gm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Li+].Cl.[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33]CO.C(N=C=NC(C)C)(C)C>CO.CN(C)C1C=CN=CC=1.C1COCC1>[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)CCO
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1)C(=O)OCC[Si](C)(C)C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
A mixture of (4-nitro-2-phenylbenzoyl)methionine methyl ester (7.69 g, 30 mmol), prepared as in Example 192A and aqueous saturated lithium hydroxide (20 mL) in methanol (50 mL) was refluxed for 6 hours. The reaction mixture was carefully acidified with concentrated hydrochloric acid (10 mL), and extracted with ethyl acetate (4×). The combine extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and THF (10 mL) and 2-trimethylsilylethanol (3.72 g, 31.5 mmol), 1,3-diisopropylcarbodiimide (5.17 mL, 33 mmol) and 4-dimethylaminopyridine (30 mg) were added sequentially. After 4 hours, aqueous hydrochloric acid (0.1 N, 0.5 mL) was added and the reaction mixture was stirred for another 2 hours. The reaction mixture was then filtered through silica gel (40 g), and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (5% ethyl ether-hexane) to give the title compound (8.90 g, 87%).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.FC(F)(F)C(O[C:38]1[C:43]([F:44])=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48])=O.Cl>C(Cl)Cl>[F:44][C:43]1[C:38]([O:12][C:11]([C:8]2[N:9]=[N:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:7]=2)=[O:13])=[C:39]([F:48])[C:40]([F:47])=[C:41]([F:46])[C:42]=1[F:45]
Reactant: CCCCc1nnc(C(=O)O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of the carboxylic acid (24.4 mmol, 8.6 g) in DCM (100 mL) was added pyridine (81 mmol, 6.4 g) followed pentafluorophenyl trifluoroacetate (40.52 mmol, 11.3 g) drop-wise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 8 h. The reaction was added to 1N HCl (100 mL), and the product was extracted with ethyl acetate. The crude product was purified using a mixture of hexanes in ethyl acetate on a 330 g silica gel ISCO column to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (9.0 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:8]([CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21](O)=[O:22])[CH2:16]3)[C:7](=[O:24])[C:6]=12.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:56]([NH2:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C)C=O>[CH2:56]([NH:63][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[N:11][CH:10]=3)[C:5]3=[N:4][O:3][C:2]([CH3:1])=[C:6]3[C:7]2=[O:24])[CH2:16]1)=[O:22])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: NCc1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc2c1c(=O)n(C1CCCC(C(=O)NCc3ccccc3)C1)c1cnccc21
Yield: 96 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexanecarboxylic acid (50 mg, 0.15 mmol) with 1-[3-(dimethyl-amino)propyl]-3ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), 1-hydroxy-7-azabenzo-triazole (23 mg, 0.17 mmol), N,N-diisopropylethyl amine (44 mg, 3.4 mmol), and benzylamine (18 mg, 0.17 mmol) in N,N-dimethyl-formamide (4 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 60 mg (94%) of the desired product as a white solid. MS(ES): (M+1)+ 417.3, 418.3 m/z.
Reaction SMILES: ClCC=CC=C.[CH2:7]([C:10]([CH2:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH3:9].[OH-].[K+].[C:17]1([CH3:23])[CH:22]=[CH:21]C=[CH:19][CH:18]=1>>[CH2:8]([CH:7]([CH2:21][CH:22]=[C:17]([CH3:23])[CH:18]=[CH2:19])[C:10](=[O:11])[CH2:12][CH2:13][CH3:14])[CH3:9]
Reactant: Cc1ccccc1
Reactant: CCCC(=O)CCC
Agent: C=CC=CCCl
Agent: [K+]
Agent: [OH-]
Product: C=CC(C)=CCC(CC)C(=O)CCC

Procedure:
According to the procedure described in Example 1, from 116.6 g of 1-chloro-2,4-pentadiene and 114.2 g of dipropyl ketone (heptan-4-one) in the presence of 200 g of powdered potassium hydroxide in 600 ml of toluene there are obtained 91.9 g of crude 5-ethyl-8-methyl-7,9-decadien-4-one which are subjected to a fractional distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(Cl)=[S:27]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:26]=[S:27]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(-c2nc(-c3ccccn3)no2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
To a solution of 1.09 g of 5-(4-aminophenyl)-3-(2-pyridyl)-1,2,4-oxadiazole in 200 ml of dry tetrahydrofuran containing 0.42 g of triethylamine, 0.50 g of thiophosgene is added and the mixture stirred at room temperature for 6 hours. After filtration, the solution is evaporated in vacuo to give the crude product. It is crystallized from petroleum ether to give 0.65 g (54%) of the title product, m.p. 145°-146°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[I:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH2:27](Br)[CH:28]=[CH2:29].Cl>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH2:29]([N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[I:16])[C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C=CCN(CCc1cc(OC)ccc1I)C(=O)C(F)(F)F
Reaction time: 3.5 h
Yield: 77.8 %

Procedure:
A solution of N-trifluoroacetyl-2-iodo-5-methoxyphenethylamine (23.8 g, 63.8 mmol) in toluene (425 mL) was sequentially treated with K2CO3 (12.4 g, 89.8 mmol), KOH (11.6 g, 207 mmol), n-Bu4NBr (2.2 g, 6.9 mmol) and allyl bromide (10.7 g, 89.8 mmol). The mixture was stirred at 80 C for 3.5 hours, cooled to 20 C, acidified with 10% aqueous HCl, separated and the aqueous phase extracted with ether (500 mL). The combined organic phases were washed with brine (200 mL), dried with Na2SO4 and concentrated to give 20.5 g of a brown oil. 1H NMR (400 MHz, CDCl3), mixture of rotamers d 7.67 (m, 1H), 6.80 (m, 1H), 6.57 (m, 1H), 5.9-5.6 (bm, 1H), 5.27 (m, 2H), 4.11 (d, J=6 Hz, 0.5H), 3.85 (d, J=6 Hz, 0.5H), 3.77 (m, 3H), 3.55 (m, 2H), 3.00 (m, 2H). MS calculated for C14H15F3INO2+H: 414, observed: 414.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:40]1([C:46]2[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][N:47]=2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[OH:30])[C:8]([N:10]2[C@H:14]([C:15]([NH:52][C:49]3[CH:48]=[N:47][C:46]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[N:51][CH:50]=3)=[O:17])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnc(N2CCOCC2)nc1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1cnc(N2CCOCC2)nc1

Procedure:
(3S)-2-((2R)-3-Cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-[2-(4-morpholinyl)-5-pyrimidinyl]-3-pyrazolidinecarboxamide was prepared according to Example 111, utilizing (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid in place of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid, and 2-(4-morpholinyl)-5-pyrimidinamine in place of 3-pyridazinamine in part A. LCMS: (M+H)+: 476.0.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])O[C:5]1=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>CO>[OH:14][CH2:13][CH2:15][N:16]1[C:3](=[O:12])[CH:2]2[CH:6]([CH:7]3[O:10][CH:1]2[CH:9]=[CH:8]3)[C:5]1=[O:11]
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Reactant: NCCO
Solvent: CO
Product: O=C1C2C3C=CC(O3)C2C(=O)N1CCO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
The anhydride, 4,10-dioxa-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione, (2.00 g, 12.0×10−3 mol) was suspended in 50 mL of MeOH and the mixture cooled to 0° C. A solution of ethanolamine (0.72 mL, 12.0×10−3 mol) in 20 mL of MeOH was added dropwise (10 min) and the resulting solution was stirred for 5 min at 0° C., then 30 min at room temperature and finally refluxed for 4 h. After cooling to room temperature the solvent was removed under reduced pressure, the white residue was dissolved in 150 mL of CH2Cl2 and washed with 3×100 mL of water. The organic layer was dried over MgSO4 and filtered. Removal of the solvent under reduced pressure furnished the desired product (1.04 g 5.0×10−3 mol, 42% yield) as white solid that was used for the next step without further purifications. An analytical sample was obtained by flash chromatography (CC, SiO2, 100% ethyl acetate, Rf(6)=0.26). m.p. 139-141° C. (dec). IR (neat): 3472, 1681, 1435, 1405, 1335, 1269, 1168, 1100, 1053, 1013, 959, 916, 875, 850, 807, 722, 705, 654 cm−1. 1H NMR (400.03 MHz, CDCl3, 298 K) δ 1.90 (bs, 1H, OH); 2.90 (s, 2H, CH), 3.69-3.72 (m, 2H, CH2), 3.76-3.78 (m, 2H, CH2), 5.28 (t, J=0.9 Hz, 2H, CH), 6.52 (t, J=0.9 Hz, 2H, CHvinyl). 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=41.77 (2C, NCH2), 60.18 (2C, OCH2), 47.50 (2C, CH), 81.04 (2C, CH), 136.60 (2C, CHvinyl), 176.97 (2C, C). Anal. Calcd. for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found C, 57.16; H, 5.37; N, 6.62.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO.C(Cl)Cl>[C:27]1([C:26]2[N:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution of {1-[4-(3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol) in MeOH (0.45 mL) and CH2Cl2 (0.75 mL) was added a 4 molar solution of HCl in dioxane (0.57 mL, 2.2 mmol, 20 5equiv). The resulting solution was stirred at room temperature for 12 h, then was concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 10 g SNAP cartridge: 100% CH2Cl2 4.0 min., gradient to 95% CH2Cl2/5% MeOH 9.5 min., gradient to 90% CH2Cl2/10% MeOH 6.1 min.) to give 1-[4-(3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutylamine (18 mg, 47%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:11](=[CH:19]\[C:20](=O)[CH3:21])/[C:10]2=[O:23])=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26].N1C=CN=C1>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:11](=[CH:19]\[C:20](=[N:25][OH:26])[CH3:21])/[C:10]2=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)/C(=C/C(C)=O)C2c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC(C)O
Product: COc1ccc(N2C(=O)/C(=C/C(C)=NO)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a suspension of 9.2 g of (E)-1-(4-methoxyphenyl)-3-(2-oxopropylidene)-4-phenyl-2azetidinone in 200 ml of isopropyl alcohol were added 3.1 g of hydroxylamine hydrochloride and 3.1 g of imidazole, and then the mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration, and recrystallized from isopropyl alcohol to give 8.8 g of (E)-1-(4-methoxy-phenyl)-3-(2-hydroxyiminopropylidene)-4-phenyl-2azetidinone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH3:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:26]
Reactant: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCNCC1

Procedure:
A solution of methyl N-tert-butoxycarbonyl-4-(3-methylbenzoyl)piperidine-4-carboxylate (77 mg) in ethyl acetate (10 mL) at 0° C. was saturated with hydrogen chloride gas. The resultant solution was stirred at 0° C. for 2.5 h. The product solution was concentrated under vacuum to provide the title compound.
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C(O)(=O)C>C(O)C.O>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:29][C:28]2[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: N#Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccc(C#N)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (2.0 g) was added to a suspension of estrone (1:352 g, 5.0 mmol) and 4-cyano-benzaldehyde (655 mg, 5.0 mmol) in ethanol (40 mL). The resulting orange solution was stirred for 4 hours at room temperature, then acetic acid (5 mL) and water (5 ml) were added (colour changes to yellow). The product precipitated and was filtered off, washed with water (50 mL), ethanol (50 mL) and diethyl ether (50 mL) and dried under high vacuum. Yield: 1.795 g (94%) pale yellow solid. 1H-NMR (DMSO-d6, 400 MHz). δ: 0.91 (s, 3H, —CH3), 1.30-1.66 (m, 5H), 1.82-1.90 (m, 1H), 1.94-2.02 (m, 1H), 2.14-2.22 (m, 1H), 2.30-2.38 (m, 1H), 2.58-2.92 (m, 3H), 6.45 (d, J=2.3 Hz, 1H), 6.51 (dd, J=8.6, 2.3 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 7.36 (s, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 9.03 (s, 1H, —OH). LRMS (FAB+): 384.1 (100, [M+H]+). LRMS (FAB−): 383.2 (100, [M]−).