Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:2]1([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([Cl:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 263, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 7.80 (d, 2H), 7.40-7.20 (m, 6H), 6.90-6.80 (m, 6H), 5.30 (dd, 2H), 4.90 (d, 1H), 3.75 (m, 1H), 3.20 (m, 1H), 3.00-2.80 (m, 5H). MS (EI) for C28H25ClFN5O3 found 534 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:19][OH:20])[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH:19]=[O:20])[N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.4 %

Procedure:
While under nitrogen, a stirred solution of tert-butyl 7-chloro-3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step 6, 270 mg, 0.907 mmol) in methylene chloride (11 mL) was cooled in an ice-water batch and treated dropwise with a solution of Dess-Martin periodinane (461 mg, 1.09 mmol) in methylene chloride (3 mL) over several minutes. The cooling bath was removed, and the resulting clear mixture was stirred at room temperature for 1.5 h. Once complete, the mixture was re-cooled in an ice-water bath, quenched portionwise with a 1:1 mixture of saturated aqueous Na2S2O3 and saturated aqueous NaHCO3 (20 mL total) and stirred for 10 min at room temperature. The layers were separated, the aqueous phase was re-extracted with methylene chloride (20 mL), and the combined organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (40 g column, 10-30% ethyl acetate in hexanes) gave tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (162 mg, 60%) as a clear gum. 1H NMR (DMSO-d6, 400 MHz) δ 9.45 (bs, 1 H), 7.34 (m, 1 H), 7.26 (m, 2 H), 4.78 (m, ˜0.5 H), 4.64 (m, ˜0.5 H), 4.50 (m, 2 H), 3.21 (m, 1 H), 3.05 (m, 1 H), 1.46 (s, ˜4.5 H), 1.38 (s, ˜4.5 H) mixture of rotamers).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CO)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
2-{[4-(Hydroxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 10 and 4-bromobenzylbromide (4.75 g) were dissolved in N,N-dimethylformamide (50 mL), potassium tert-butoxide (2.33 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (4.5 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][C:27](O)=[O:28])=[CH:24][CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:27](=[O:28])[CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 84A]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[4-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[C:15]([Cl:16])=[CH:14][C:5]=2[N:6]=[C:7]1[CH2:9][C:10]([F:12])([F:13])[F:11])[CH3:25]
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (1 g) in DMF (5 mL) was added sodium hydride (85 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added ethyl bromoacetate (363 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-30% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (25.00 g, 106.2 mmol) in CH2Cl2 (320 mL) was added N,N-dimethyl aminopyridine (1.95 g), followed by N-ethyl-N-dimethylamine propylcarbodiimide hydrochloride (22.39 g) in small portions. After 30 min at room temperature, aminomethyl trimethylsilane (11.2 g, 7.87 mL, 108 mmol) was added while maintaining the temperature at 20° C. After stirring over night, water was added and the organic layer was separated. The aqueous layer was extracted twice with CH2Cl2 and the combined organic phases were dried and evaporated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (34.00 g, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2C1CCCNC1)[CH3:2].C([Li])CCC.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C:33]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:12]3)([OH:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCc1cnc2c(C3CCCNC3)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cnc2c(C3(O)CCN(C(=O)OC(C)(C)C)C3)cccc2c1
Temperature: -77 °C
Reaction time: 0.25 h
Yield: 11.5 %

Procedure:
To a well-stirred solution of the title compound of Example 1, Step 1 (2.10 g, 8.9 mmol) in 30 ml of anhydrous tetrahydrofuran chilled to and maintained at −77° C., a 2.5 M solution of n-butyl lithium in hexanes (3.60 ml, 8.9 mmol; Aldrich Chemical Co.) is added dropwise over a 10 minute period. The reaction was stirred at −77° C. for 15 minutes before adding a solution of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.65 g, 8.9 mmol) in anhydrous tetrahydrofuran (10 ml). The reaction mixture was allowed to warm to ambient temperature and stir at that temperature for 3 hours before quenching by cautious dropwise addition (with cooling) of saturated aqueous sodium bicarbonate (50 ml total). The resulting mixture was thoroughly extracted with three 20 ml of ethyl acetate. The combined organic extracts were, in turn, extracted with an equal volume portion of brine, dried (anhydrous sodium sulfate) and, finally, concentrated in vacuo, yielding a viscous syrup. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with methylene chloride/methanol=98:2 in volume) afforded the title compound (352 mg, 11.5% yield) as a viscous yellow oil.
Reaction SMILES: I.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9](=[NH:11])[NH2:10])[CH2:5][CH2:4]1.[Na].CO[C:15]1[C:16](=O)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=[C:21]3[N:11]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(C(=N)N)CC1
Reactant: COc1cccccc1=O
Agent: I
Agent: [Na]
Solvent: CCO
Product: CN1CCN(c2nc3cccccc-3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methyl-1-piperazinecarboximidamide hydroiodide (17.8 g) was suspended in ethanol (15 ml). Sodium (1.5 g) in ethanol (47.8 ml) was added to it. The mixture was stirred at room temperature for 30 min. A solution of 2-methoxy-2,4,6-cycloheptatrien-1-one in ethanol (12 ml) was added dropwise. The mixture was refluxed for 3 hr and evaporated. The residue was taken in water and extracted with ethyl acetate in a continuous extractor. The organic layer was dried and evaporated. The residue was chromatographed through a column of silica gel using 5% methanol in chloroform and the eluates were evaporated. The residue was taken up in diethyl ether and filtered. The precipitate was crystallized from diethyl ether-hexane to obtain the title compound (3.4 g): mp 93°-95° C.; ir (CHCl3) 1600, 1565 and 1523 cm-1 ; uv max (MeOH) 291 (ε7,280), 262(ε28,445) and 238 nm(ε23,970); nmr-(CDCl3) δ 2.3(3H,s), 2.5(4H,t), 4.0(4H,t) and 7.2-8.0(5H,m) and Anal. Calcd for C13H16N4 : C, 68.39 % H, 7.06% N, 24.54% N, 24.54% and Found: C, 68.45% H, 6.99% N, 24.27%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47]C=O)[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])=[C:12]([CH:15]=[CH:16][S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.C(=O)(O)[O-].[Na+].C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>CO.ClCCl.C(OCC)(=O)C.O>[CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH2:47])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([OH:26])=[O:25])=[C:12]([CH:15]=[CH:16][S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3cccnc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSc3cccnc3)CS[C@H]12)c1csc(N)n1
Yield: 4.8 %

Procedure:
To a solution of benzhydryl 7-(2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (2 g) in methanol (20 ml) was added conc. hydrochloric acid (0.85 ml) at ambient temperature and the resultant mixture was stirred at 25°-30° C. for 2 hours. Water and ethyl acetate were added to the reaction mixture and the resultant mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. The separated organic layer was evaporated in vacuo to give a yellowish residue. A mixture of this residue and trifuluoroacetic acid (5 ml) containing anisole (1 ml) in dichloromethane (10 ml) was stirred at 5°-10° C. for an hour. The mixture was poured into diisopropyl ether (100 ml) to give precipitate, which was collected by filtration and dissolved in 5% aqueous sodium bicarbonate at pH 5.5. The resulting solution was chromatographed on macropourous non-ionic resin "Diaion-HP-20" and eluted with 20% aqueous solution of isopropyl alcohol. The fractions containing object compound were concentrated and acidified at pH 2.2 with conc. hydrochloric acid to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(3-pyridyl)thiovinyl]-3-cephem-4-carboxylic acid (syn isomer) (trans isomer) (0.07 g).
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[CH:19]=[C:20]([NH:26][C:27]4[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O.[OH:71][CH:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1>O>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[C:20]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:31]([N:75]5[CH2:76][CH2:77][CH:72]([OH:71])[CH2:73][CH2:74]5)=[O:32])=[CH:34][CH:35]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)O)cc2)c(=O)n(C)c1
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(C(=O)N3CCC(O)CC3)cc2)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
A solution of 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid (7) (56 mg; 0.11 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (58 mg; 0.13 mmol) and N,N-dimethylformamide (2 mL) was stirred at room temperature for 0.5 h. 4-Hydroxypiperidine (56 mg; 0.55 mmol) was added and the mixture was stirred at room temperature for 16 h. Water (15 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL) and brine (1×30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was slurried with diethyl ether and filtered to give 4-tert-butyl-N-(3-{5-[4-(4-hydroxy-piperidine-1-carbonyl)-phenylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-methyl-phenyl)-benzamide (8) as a light brown solid (40 mg), MS 593.41 (M+H)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].O[NH:13][C:14]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:18]([CH3:28])[CH:17]=1)=[NH:15]>>[CH:1]([C:3]1[S:7][C:6]([C:8]2[O:10][N:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH3:28])[C:19]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:20]([CH3:22])[CH:21]=3)[N:13]=2)=[CH:5][C:4]=1[CH3:11])=[O:2]
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Reactant: Cc1cc(C(=O)O)sc1C=O
Product: Cc1cc(-c2nc(-c3cc(C)c(CCC(=O)O)c(C)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid; LC-MS: tR=1.03 min; [M+1]+=371.04; 1H NMR (D6-DMSO): δ 2.36-2.42 (m, 8H), 2.65 (s, 3H), 2.89-2.95 (m, 2H), 7.70 (s, 2H), 8.06 (s, 1H), 10.16 (s, 1H), 12.26 (m, 1H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C@H:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]2[N:22]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)[N:24]=3)[CH2:16]1)[CH3:14].C(N(CC)CC)C.[C:55](O)(=[O:59])[C@H:56]([CH3:58])[OH:57].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:25]2[N:24]=[C:23]3[C:28]([N:29]=[C:21]([N:17]4[CH2:18][CH2:19][N:20]([C:55](=[O:59])[C@@H:56]([OH:57])[CH3:58])[C@H:15]([CH2:13][CH3:14])[CH2:16]4)[N:22]3[CH2:43][C:44]([F:47])([F:46])[F:45])=[C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:26]=2)=[CH:37][N:38]=1
Reactant: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 27.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72.4 mg, 0.38 mmol) was added to an N,N-dimethylformamide solution (5 ml) of 5-{8-[(3R)-3-ethylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (124 mg, 0.25 mmol), triethylamine (0.087 ml, 0.63 mmol), L-lactic acid (27.2 mg, 0.30 mmol), and 1-hydroxybenzotriazole (42.6 mg, 0.28 mmol), the resulting mixture was stirred at room temperature for 17 hours followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (72.4 mg, 0.38 mmol), and the resulting mixture was stirred at 40° C. for 8 hours. The resulting mixture was partitioned with ethyl acetate and water and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform:methanol=90:10) to give the title compound (38.9 mg) as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1F)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>C(#N)C>[F:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:7][C:8]1[CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])[CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:32]([N:34]([CH3:36])[CH3:35])=[O:33]
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(C)C(=O)c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N(C)C)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
Potassium carbonate (276 mg) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (291 mg) and 3,4-difluoro-N,N-dimethylbenzamide (204 mg) in acetonitrile (3.5 mL) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 15 h. The mixture was allowed to return to ambient temperature and pressure, the acetonitrile evaporated, and the residue chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound (63 mg). 1H NMR δ (d6-DMSO): 1.22 (d, 3H), 2.94 (s, 6H), 3.49 (m, 2H), 3.76 (s, 3H), 4.54 (m, 1H), 4.83 (t, 1H), 6.53 (m, 1H), 6.76 (m, 1H), 7.14 (s, 1H), 7.24 (m, 2H), 7.40 (s, 1H), 7.47 (d, 1H), 7.57 (m, 1H), 10.83 (br s, 1H). m/z 457 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)=[CH:4][N:3]=1.C(O)C.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH:38]([OH:41])[CH2:39][CH2:40]2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: [H][H]
Agent: [Pd+2]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(-c2csc3c(CCCN4CCC(O)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 26.7 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-(4-hydroxypiperidin-1-yl)prop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (130 mg, 0.23 mmol), ethanol (25 mL), and acetic acid (0.65 mL) were combined in a hydrogenation vessel, purged, and palladium hydroxide on carbon (45 mg, 50% weight dispersion in oil, 0.16 mmol) was added. 50 Psi of hydrogen was applied for 16 hours. The mixture was filtered and purified by RP-HPLC to yield the title compound (35 mg, 25% yield) after lyophilization: 1H NMR (DMSO, 400 MHz) δ 9.50 (s, 1H), 7.98 (d, 1H), 7.70–7.72 (m, 2H), 5.59 (d, 1H), 7.54 (s, 1H), 7.07–7.35 (m, 3H), 5.34 (bs, 2H), 4.58 (bs, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 2.71 (t, 2H), 2.28 (t, 2H), 1.97 (t, 2H), 1.90 (s, 3H), 1.82 (t, 2H), 1.70 (m, 1H), 1.40 (q, 2H); RP-HPLC (Conditions i) Rt 10.0 min. MS: 568.3 MH−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][C:18](OCC)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of ethyl (R)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (3.03 g, 10.00 mmol) in anhydrous tetrahydrofuran (75 mL) at −78° C. under nitrogen was added dropwise a solution of diisobutylaluminum hydride (1.0 M in hexanes, 22.0 mL, 22.0 mmol, 2.2 eq). The resulting solution was stirred at −78° C. under nitrogen for 30 minutes. The reaction solution was then allowed to warm to room temperature over the course of 2 hours. A saturated solution of sodium hydrogen carbonate (50 mL) was added, and the aqueous mixture was extracted with ethyl acetate (3×50 mL). The extracts were combined, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue with diethyl ether/hexanes [1:1] afforded the title compound as a clear colorless oil (1.41 g, 5.40 mmol, 54%): 1H NMR (CDCl3) δ 7.40-7.25 (m, 5H), 5.75-5.53 (m, 2H), 5.20-5.00 (m, 2H), 4.38 (br m, 1H), 4.06 (br d, J=13.7 Hz, 2H), 3.45 (br t, J=7.0 Hz, 1H), 2.03-1.68 (m, 4H); [α]25=+34° (MeOH, c=1.0); HRMS calculated for C15H19NO3 261.1365, found 261.1356.