Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.O[N:13]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH2:13])=[O:11]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)Cc1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
2-Iodophenylacetic acid (2.00 g, 7.63 mmol) was dissolved in dry THF (70 mL) and dry DMF (10 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (1.134 g, 8.396 mmol) and EDCI (1.609 g, 8.396 mmol) and N,N-diisopropylethylamine (5.318 mL, 30.53 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (2.933 g, 30.53 mmol) was added in one portion, and the reaction was stirred room temperature for 17 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and the organic layer were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (I38) (1.755 g, 88% yield) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.82 (dd, J=7.9, 0.9 Hz, 1H), 7.42 (s, 1H), 7.36-7.28 (m, 2H), 7.02-6.94 (m, 2H), 3.55 (s, 2H). LCMS Method C: rt 4.77 min; m/z 262.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:31]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 32.7 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 90 mg of 4-methoxyisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 77 mg of the target compound.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([S:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:10]=1)=O)(C)(C)C.[ClH:31]>C(OCC)C>[ClH:31].[NH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([S:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:11]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(NC(=O)OC(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methylphenyl) ester (33a) (70.0 grams, 156 mmol) was dissolved in ethyl ether (500 mL). Anhydrous hydrogen chloride gas was bubbled through the solution while maintaining the temperature between 12 and 17° C. A precipitate formed after about 1 hour. The hydrogen chloride gas treatment was continued for an additional 3 hours at 17-25° C. The resulting mixture was allowed to stir overnight at room temperature and filtered and the product washed with ethyl ether (1.2) and vacuum dried at 40° C. to give 59 g (0.15 mmol, 96% yield) toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methylphenyl) ester hydrochloride (29b): mp: 169° C. (dec); Assay (HPLC): 99.8 area %.
Reaction SMILES: C([S@@]([NH:7][C@@H:8]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1)[CH3:9])=O)(C)(C)C.[ClH:23]>CO>[ClH:23].[C:17]([O:16][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:20]
Reactant: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 2-dram vial was added tert-butyl 4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate (0.0586 g, 0.180 mmol), hydrochloric acid (0.14 mL, 0.54 mmol, 4.0 M in 1,4-dioxane), and methanol (2 mL). The mixture was stirred at rt for 2 h. The solvent was then completely removed to give tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride as a white solid. LC-MS: (FA) ES+ 222.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]C)=[O:10])=[CH:5][CH:4]=1.CN(C=O)C>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[SH:17])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccccc2SC)cc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1ccccc1S
Temperature: 25 °C
Yield: 73 %

Procedure:
To a nitrogen flushed mixture of 1.415 g (4-methoxyphenyl)(2-(methylthio)phenyl)methanone (C) (5.48 mmol) and 3 g sodium thiolate (26.6 mmol) was added 40 ml anhydrous DMF. The mixture was refluxed under nitrogen. After the mixture turned to black, the reaction was refluxed for two more hours, cooled to RT and quenched with water. The mixture was washed ethyl acetate (2×100 ml). The combined organic was brined, dried over magnesium sulfate, filtered and concentrated. Flash column (hexane:ethyl acetate 80:20) yield 0.954 g product (4.0 mmol, 73% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC([O-])(C)C.[K+].[SiH:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: c1ccc2occc2c1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2o1
Yield: 37.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating benzofuran (59 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18 mmol, 0.35 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 45 hours at 60° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 44 mg (38%) of the title compound as a colourless oil. 1H NMR (500 MHz, Acetone-d6) δ 7.64 (ddd, J=7.7, 1.3, 0.7 Hz, 1H), 7.53 (dd, J=8.2, 0.9 Hz, 1H), 7.30 (ddd, J=8.3, 7.2, 1.3 Hz, 1H), 7.22 (ddd, J=7.7, 7.2, 1.0 Hz, 1H), 7.16 (d, J=1.0 Hz, 1H), 1.09-0.98 (m, 9H), 0.92-0.84 (m, 6H). The HSQC spectrum of this reaction product as provided in FIG. 13.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][C:5]1[S:6][C:7]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[C:11]([O:18][CH3:19])=[CH:10][C:8]=2[N:9]=1
Reactant: COc1cc2nc(CCCO)sc2c(OC)c1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2nc(CCCBr)sc2c(OC)c1OC
Reaction time: 1 h

Procedure:
2-(3-Hydroxypropyl)-5,6,7-trimethoxybenzothiazole (388 mg) was dissolved in dichloromethane (5 mL), carbon tetrabromide (590 mg) and triphenylphosphine (431 mg) were added to the solution at room temperature, and the mixture was vigorously stirred for 1 hour. Water was added to conduct extraction with dichloromethane, and the resultant organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:9) to obtain the title compound.
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH3:11].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH3:11]
Reactant: COC(=O)c1c[nH]c(Br)c1C
Reactant: OB(O)c1ccc(F)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c(-c2ccc(F)cc2Cl)c1C
Temperature: 110 °C
Reaction time: 9 h
Yield: 84.6 %

Procedure:
A mixture of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (0.63 g, 2.8 mmol), (2-chloro-4-fluorophenyl)boronic acid (1.0 g, 5.7 mmol), Na2CO3 (0.91 g, 8.6 mmol) and palladium tetrakis(triphenylphosphine) (0.17 g, 0.14 mmol) in toluene/water (10:1, 25 ml) was stirred at 110° C. for 9.0 h under N2. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (6:1 to 1:1 hexane:ethyl acetate) to give the title compound (634 mg, 84%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:22]N1C(=O)CCC1=O>C(Cl)Cl>[Br:22][C:20]1[C:16]([C:14]2[S:15][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)=[N:17][N:18]([CH3:21])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n1
Yield: 79.6 %

Procedure:
To a stirred solution of 3-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1-methyl-1H-pyrazole (0.10 g, 0.31 mmol) in DCM (3 mL, anhyd) was added N-bromosuccinimide (NBS) (56 mg, 0.31 mmol). After 22 h additional NBS (56 mg) was added and stirring was continued at ambient temperature. After 46 h (total) the reaction mixture was concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 20:80 to 40:60) to give the title compound (98 mg, 79%) as a white solid. 1H-NMR (CD2Cl2): δ 8.17 (1H, m), 7.91 (1H, m), 7.82 (1H, m), 7.72 (1H, d), 7.61 (1H, m), 7.50 (1H, s), 7.44 (1H, d), 3.91 (3H, s), 3.08 (3H, s).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][CH:22]([CH2:24][O:25][CH3:26])[CH2:21][NH:20][CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[CH3:27])([CH3:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1.CN1CCCC1=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:23][CH:22]([CH2:24][O:25][CH3:26])[CH2:21][N:20]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[CH2:19]3)[CH2:17][CH2:18]2)=[O:12])=[CH:7][C:6]=1[CH3:27])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COCC1CNCC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: COCC1CN(c2ccc(C(F)(F)F)cc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Temperature: 100 °C
Yield: 9.6 %

Procedure:
To a vial charged with (4-isopropoxy-3-methyl-phenyl)-[10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (30.0 mg, 0.08 mmol), 1-bromo-4-(trifluoromethyl)benzene (19.7 mg, 0.088 mmol), Pd2(dba)3 (23 mg, 0.04 mmol), rac-BINAP (24.8 mg, 0.04 mmol) and sodium tert-butoxide (9.8 mg, 0.088 mmol) were added N-methyl-2-pyrrolidone (0.2 mL) and toluene (1.0 mL). The reaction mixture was heated at 100° C. under nitrogen 18 h. The reaction mixture was cooled to room temperature, filtered and purified via HPLC (1-90% CH3CN/5 mM HCl) to provide (4-isopropoxy-3-methylphenyl)(2-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methanone (5.0 mg, 0.0077 mmol, 10%). ESI-MS m/z calc. 520.2549. Found 521.3 (M+1)+; Retention time: 2.21 minutes (3 min run).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:54]=[N+:55]=[N-:56])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.O>[N:54]([C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])=[N+:55]=[N-:56]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CCCC[C@H]1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CCCC[C@H]1N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
Dissolve trans-2-methyl-cyclohexanol (5.0 g, 44.0 mmol) in anhydrous THF (500 mL) and cool to −20° C. Add triphenylphosphine (57.43 g, 218.9 mmol), diethyl azodicarboxylate (38.13 g, 218.9 mmol), and diphenylphosphoryl azide (60.25 g, 218.9 mmol) respectively under nitrogen. Stir the reaction mixture for 6 hours at the same temperature then warm it to room temperature and stir overnight Add water (500 mL), and extract the aqueous layer with EtOAc (3×500 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-25% of EtOAc/Hexane) to give 3.98 g (65%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ 3.08-3.16 (m, 1H), 1.90-1.98 (m, 1H), 1.56-1.78 (m, 3H), 1.16-1.35 (m, 4H), 1.01 (d, 3H), 0.93-1.03 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17]N(C)C)[C:12]2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:28]([NH2:31])(=[NH:30])[CH3:29].C(OCC)(=O)C>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11]3[CH:17]=[N:30][C:28]([CH3:29])=[N:31][C:12]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ncc2c(n1)C1CC2CN(Cc2ccccc2)C1

Procedure:
To a solution of 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one (1.42 mmol) in ethanol was added potassium carbonate (3.8 mmol) and acetamidine hydrochloride (1.6 mmol). The reaction mixture was heated under reflux overnight. After cooling the solvents were removed and dichloromethane and aqueous sodium bicarbonate solution were added. The dichloromethane layer was separated and dried to and oil. Purification by flash chromatography on silica gel eluted with ethyl acetate yielded product (0.23 mmol). 1H NMR (CD3OD, 400 MHz) δ 8.25 (s, 1H), 7.18 (br s, 3H), 6.85 (br s, 2H), 3.60–3.40 (m, 2H), 3.10 (s, 1H), 3.00 (m, 2H), 2.79 (m, 1H), 2.70 (s, 3H), 2.5 (m, 1H), 2.45 (m, 1H), 2.25 (m, 1H), 1.70 (m, 1H); APCl MS m/z 266.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C(N(CC)CC)C.[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32](Cl)=[O:33].Cl>C1COCC1.C(OCC)(=O)C>[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)=[O:33]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1-c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 355 mg (1.27 mmol) of ethyl 5-amino-1-phenyl-1H-indole-2-carboxylate from Example LVII and 141 mg (0.19 ml, 1.39 mmol) of triethylamine are added to 4 ml of THF. The mixture is cooled to 0° C., and a solution of 170 mg (0.18 ml, 1.27 mmol) of 3,3-dimethylbutyryl chloride in 2 ml of THF is added. The mixture is stirred at RT for 2 hours. To bring the reaction to completion, a further 1 eq. of triethylamine and 1 eq. of acid chloride are added and the mixture is stirred at RT for 2 hours. For work-up, the mixture is added to dilute hydrochloric acid and ethyl acetate and extracted. The organic phase is washed with sat. sodium bicarbonate solution, dried with sodium sulphate, filtered and dried under reduced pressure. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 3:1-1:1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[N:10]=[CH:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7]1)=[NH:5])[CH3:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:33][C:34]1[CH:35]=[C:36]([S:47](Cl)(=[O:49])=[O:48])[CH:37]=[CH:38][C:39]=1[NH:40][C:41](=[O:46])[C:42]([F:45])([F:44])[F:43].Cl>CN(C=O)C>[CH2:7]1[C:8]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=[N:10][N:6]1[C:4](=[N:5][S:47]([C:36]1[CH:37]=[CH:38][C:39]([NH:40][C:41](=[O:46])[C:42]([F:43])([F:44])[F:45])=[C:34]([CH3:33])[CH:35]=1)(=[O:49])=[O:48])[NH:3][CH2:1][CH3:2]
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)C(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(C)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.8 %

Procedure:
To a solution of 0.23 g N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine in 5 mL dry DMF was added 0.87 mL (3.0 equiv.) BEMP and the light brown mixture was stirred for 10 minutes at room temperature. Subsequently, 0.33 g (1.1 equiv.) 3-methyl-4-(2,2,2-trifluoro-acetylamino)-benzenesulfonyl chloride was added in one portion and the resulting bright yellow solution was stirred overnight at room temperature. The mixture was cooled in an ice bath, acidified with 1 N HCl, and then extracted three times with EtOAc/Et2O 1:1. The combined organic layers were washed once with water, then with brine, dried over Na2SO4 and evaporated onto silica. Purification with flash chromatography (EtOAc/PA 4:6→5:5) yielded 0.18 g (39%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.2 Hz, 3H), 1.63-1.86 (m, 8H), 2.33 (s, 3H), 3.43-3.52 (m, 2H), 3.83 (s, 2H), 6.77-6.85 (br.s., 1H), 6.83 (s, 1H), 7.73-7.79 (m, 2H), 7.86 (d, J=8.3 Hz, 1H), 8.10 (br.s., 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22](=[O:23])[N:21]([C@@H:19]2[C@@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:20]2)[CH2:32][CH3:33])=[CH:26][CH:27]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of 804 mg (1.4 mmol) 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester and 1.6 g (14 mmol) TFA in 25 mL DCM was stirred for 5 h at room temperature. Water and 2N NaOH aq. was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered off and evaporated to yield 577 mg (87%) of the title compound as yellow foam. MS m/e: 474.3 [M+H]+.
Reaction SMILES: C(OC1C=CC(C([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=O)=CC=1)CCCCCC.[OH-].[Na+].CO.CC(O)=O>C1COCC1>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[C:24](=[O:43])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:27][CH:26]=2)=[CH:20][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)cc1
Reaction time: 1 h
Yield: 56 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-5 (6.38 g, 8.83 mmol) in THF (50 mL) was added 1N NaOH (16 mL). The reaction was stirred for 1 h. MeOH (10 mL) was added causing the turbid reaction mixture to clarify. The reaction was stirred for 3 h then neutralized with AcOH. The crude mixture was concentrated then diluted with DCM (60 mL) and washed with brine (30 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to afford 2.5 g (56%) of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-7. LCMS-ESI (m/z) calculated for C29H32N2O6: 504; found 503 [M−H]−, tR=2.09 min. (Method 3). 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 9.41-9.29 (m, 1H), 7.69-7.59 (d, J=8.1 Hz, 2H), 7.42-7.20 (m, 4H), 7.19-6.96 (m, 2H), 6.91-6.84 (m, 2H), 6.76-6.68 (m, 2H), 4.58-4.35 (m, 2H), 3.90-3.76 (m, 2H), 3.71 (s, 3H), 3.57 (s, 2H), 1.49-1.21 (m, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:9][C@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].[Si:25]([O:32][C@@H:33]([C@H:35]1[C:62](=[O:63])[N:37]2[C:38]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:39](S(C3C=CC=CC=3)=O)[CH2:40][C@@H:36]12)[CH3:34])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][C@@H:33]([C@H:35]1[C:62](=[O:63])[N:37]2[C:38]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:39]([S:10][C@H:8]3[CH2:9][C@@H:5]([C:3](=[O:4])[N:2]([CH3:24])[CH3:1])[N:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])[CH2:7]3)[CH2:40][C@@H:36]12)[CH3:34])([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)C[C@@H]12
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@@H]12
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 18, but using (2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine and the crude 4-nitrobenzyl (5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 47, but used before purification by column chromatography) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like solid in a yield of 89%.