Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([C@@H:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[CH2:37]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])[CH:38]=[CH2:39]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([C@@H:26]([O:28][C:45](=[O:46])[C@@H:44]([NH:43][C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH3:48])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: C[C@H](O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O
Product: C=CCOC(=O)N[C@@H](C)C(=O)O[C@@H](C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 44 %

Procedure:
In analogy to Example 5, 150 mg (0.29 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((S)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-2-allyloxycarbonylaminopropanoic acid and, after workup and purification, 87 mg (44%) of the title compound were isolated as a colourless foam.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH3:41]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH3:41])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
General Procedure A. To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (2.0 ml) was added K2CO3 (39 mg, 0.28 mmol) and iodoethane (22 μl, 0.28 mmol). The reaction was stirred at room temperature for 48 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [I:1][C@H:2]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12][C@@H:3]1[O:4][Si](CC)(CC)CC.C([Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1I)C.O.FC(F)(F)C(O)=O>C1COCC1>[I:1][C@@H:2]([C@H:15]([C@@H:14]([C@@H:13]([CH2:18][OH:19])[OH:12])[OH:17])[OH:16])[CH:3]=[O:4]
Reactant: CC[Si](CC)(CC)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1I
Agent: CC[Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1I
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C[C@@H](I)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 90 %

Procedure:
Mixture of 2-deoxy-2-iodo-1-O-triethylsilyl-α-D-mannopyranose (IX) and 1-O-triethylsilyl-2-iodo-2-deoxy-β-D-mannopyranose (VIII) (total of 3.55 g) was dissolved in THF (50 mL), water (20 mL) and trifluoroacetic acid (0.7 mL) and stirred at room temperature. Progress of the reaction was monitored by TLC and after substrate disappearance reaction mixture was washed with dichloromethane (5×10 mL). The remaining water solution was lyophilized and such obtained crude solid residue was purified by column chromatography (SilicaGel 60, Merck) using chloroform and chloroform:methanol 9:1, 7:3 as eluents, to give 2.3 g of 2-deoxy-2-iodo-D-mannose (X). Yield 90%.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:33]1[S:37][C:36]([C:38]([O:40]C)=[O:39])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[S:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)s1
Yield: 67.4 %

Procedure:
Following the procedure of Example 1(c), but reacting 1.5 g (3.6 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 400 mg (1.8 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 600 mg (65%) of the expected compound were obtained, which compound had a melting point of 170°-1° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[C:53]1([C@@H:59]([N:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)[C:60](O)=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:51]([N:3]([CH2:1][CH3:2])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:60](=[O:61])[C@@H:59]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)=[O:32])=[CH:26][CH:25]=2)=[CH:19][CH:20]=1)=[O:13])=[O:6])[CH3:52]
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCCC1
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCC3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 37.4 %

Procedure:
The product from Example 81A (0.032 g, 0.045 mmol) and (R)-2-phenyl-2-(pyrrolidin-1-yl)acetic acid (0.010 g, 0.05 mmol) were processed as in Example 81A to give 0.015 g (37%) of the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.89 (t, J=7.10 Hz, 6 H) 1.56-1.66 (m, 4 H) 1.74-1.88 (m, 4 H) 1.94-2.09 (m, 4 H) 2.29-2.34 (m, 2 H) 2.57-2.62 (m, 4 H) 3.36-3.50 (m, 4 H) 3.75-3.88 (m, 2 H) 4.21 (s, 1 H) 4.31 (dd, J=7.93, 4.27 Hz, 1 H) 4.38 (dd, J=8.16, 4.50 Hz, 1 H) 4.57 (s, 4 H) 4.68 (s, 1 H) 6.65 (dd, J=9.31, 4.43 Hz, 2 H) 6.92 (t, J=8.93 Hz, 2 H) 7.19 (d, J=8.24 Hz, 4 H) 7.26-7.30 (m, 2 H) 7.31-7.36 (m, 4 H) 7.40 (d, J=7.17 Hz, 2 H) 7.46 (d, J=6.87 Hz, 2 H) 7.53 (d, J=8.24 Hz, 4H) 9.96 (d, J=5.34 Hz, 2 H); MS ESI− m/z 890.5.
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(morpholinomethyl)pyridin-3-yl)benzamide (0.089 g, 53% yield). LCMS: 558.35 (M+1)+; HPLC: 96.52% (@254 nm) (Rt; 4.375; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (s, 1H), 8.18 (t, 1H), 8.01 (d, 1H, J=6.8 Hz), 7.49 (d, 1H, J=8 Hz), 7.33 (s, 1H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=3.6 Hz), 3.59-3.61 (m, 6H), 2.75 (m, 1H), 2.65 (s, 3H), 2.43 (bs, 4H), 2.21 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.70 (bs, 4H), 1.53-1.56 (m, 1H), 1.42-1.44 (m, 1H), 1.09-1.23 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27](Br)[CH:28]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34].C(Cl)Cl.O>C(N(CC)CC)C.CN(C=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:28]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ncc(C#C[Si](C)(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Benzyl-N-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide (0.288 g, 0.58 mmol), (trimethylsilyl)acetylene (0.08 mL, 0.58 mmol), and copper iodide (0.011 g, 0.06 mmol) were combined in triethylamine (3.5 mL), and the solution was purged with N2 for 25 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.042 g, 0.06 mmol) was added, and the reaction was stirred at room temperature overnight. A few drops of DMF was added, and the reaction was stirred at 50° C. for 5 hours, and at 60° C. for 3 hours. The mixture was worked-up with CH2Cl2 and H2O, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give N-benzyl-N-[2-(2-methoxy-5-trimethylsilanylethynyl-pyridin-3-yl)-5-trifluoromethyl-benzyl]-acetamide.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[I-].[K+].[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:27][N:26]=1)[CH:20]=[CH:19]2)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:26]=[CH:27][C:28]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([CH2:2][C:3]([N:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[O:4])[CH2:34][CH2:33]3)=[CH:29][CH:30]=1)[CH:20]=[CH:19]2)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCNCC3)cn2)c1
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(CC(=O)N4CCCC4)CC3)cn2)c1
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a stirred solution of 2-chloro-1-(pyrrolidin-1-yl)ethanone (Intermediate 71) (0.055 g, 0.366 mmol) in DMF (2 mL), potassium iodide (0.023 g, 0.137 mmol), 5-(methylsulfonyl)-1-(5-(piperidin-4-yloxy)pyridin-2-yl)-1H-indole (0.170 g, 0.458 mmol) and potassium carbonate (0.064 g, 0.458 mmol) were added. The resulting mixture was heated at 80° C. for 45 minutes. Reaction was quenched with water and extracted with ethyl acetate. The organic extract was concentrated in vacuo and resultant residue was purified by column chromatography to yield title compound (0.075 g, 33.3%).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]4[C:26]([C:27]5[C:28]([CH3:44])=[C:29]([NH:33]C(=O)OCC6C=CC=CC=6)[CH:30]=[CH:31][CH:32]=5)=[CH:25][N:24]=[C:23]([C:45](=[O:47])[NH2:46])[C:19]=4[NH:20]3)=[CH:16][CH:15]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.O1CCCC1.[Pd]>[NH2:33][C:29]1[C:28]([CH3:44])=[C:27]([C:26]2[C:18]3[C:17]4[C:21](=[CH:22][C:14]([N:11]5[CH2:12][CH2:13][CH:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH2:10]5)=[CH:15][CH:16]=4)[NH:20][C:19]=3[C:23]([C:45]([NH2:46])=[O:47])=[N:24][CH:25]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCC(O[Si](C)(C)C(C)(C)C)C4)ccc3c12
Yield: 84.9 %

Procedure:
A solution of benzyl 3-(7-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)-1-carbamoyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.1164 g, 0.179 mmol) and 10% Pd/C (0.019 g, 0.018 mmol) in methanol (6.7 mL) and tetrahydrofuran (2.2 mL) under hydrogen was stirred for 45 min. After purging with nitrogen, the reaction was filtered through a pad of CELITE® and rinsed with MeOH. The filtrate was concentrated in vacuo, dissolved in CH2Cl2 (75 mL) and washed with brine (25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (0.0782 g, 0.152 mmol, 85% yield) as a brick-red solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:18])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-phenylhexanoic acid [5581-75-9] (1.45 g, 7.6 mmol) in CH2Cl2 (15 ml) was treated with oxalyl chloride (0.72 ml, 8.6 mmol) in the presence of a catalytic amount of DMF. The solution was stirred for 2 h at ambient temperature. The solvent was evaporated to give crude 6-phenylhexanoic acid chloride, which was used without further purification in the next step.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[C:22]1([CH3:32])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[C:30]#[CH:31].ClOC(C)(C)C.[F:39][P-:40]([F:45])([F:44])([F:43])([F:42])[F:41].[K+]>ClCCl>[F:39][P-:40]([F:45])([F:44])([F:43])([F:42])[F:41].[CH3:21][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH+:9]1[CH:31]=[C:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:32])[N:11]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[NH:10]1
Reactant: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Reactant: C#Cc1c(C)cc(C)cc1C
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C)c(C2=C[NH+](c3c(C)cc(C)cc3C)NN2c2c(C)cc(C)cc2C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8b (5.63 g, 20 mmol) and mesitylacetylene 9b (5.76 g, 40 mmol) in dry dichloromethane (100 mL) in the dark at −78° C. is added tert-butyl hypochlorite (3.33 mL, 30 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. Volatiles are evaporated under reduced pressure, and the crude solid is redissolved in acetone (50 mL), to which is then added potassium hexafluorophosphate (3.68 g, 20 mmol). The mixture is stirred at room temperature for ca. 1 hour, filtered, and the solid residue is washed with dichloromethane. The collected filtrate is evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether afford, after drying under vacuum, triazolium salt 10bb as an off-white solid (10.10 g, 88%). Analytical samples were obtained after recrystallization by vapor diffusion of diethyl ether in an acetonitrile solution of 10bb. 1H-NMR (CD3CN, 300 MHz): δ=8.94 (s, 1H), 7.27 (s, 2H), 7.10 (s, 2H), 7.05 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 2.25 (s, 6H), 2.17 (s, 6H), 2.06 (s, 6H). 13C-NMR (CD3CN, 75 MHz): δ=145.2, 144.5, 144.3, 143.9, 139.6, 135.7, 135.2, 132.4, 131.7, 131.5, 131.3, 131.1, 130.9, 119.0, 21.5, 21.4, 21.3, 19.1, 17.9. HR-MS (ESI): Calcd. for C29H34N3 [M+]: 424.2747. found 424.2758.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10](OC)=[O:11])[C:6](=[O:18])[N:5]([CH3:19])[N:4]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C)=O.[OH-].[Na+]>ClCCl.O>[OH:11][CH2:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[N:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH3:19])[C:6]1=[O:18]
Reactant: COC(=O)c1ccccc1-n1c(OC)nn(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: COc1nn(C)c(=O)n1-c1ccccc1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution containing 6 g of the title compound of Step C dissolved in 120 mL of dichloromethane and cooled to -78° C. under a nitrogen atmosphere was added 68.4 mL of 1.0 M of diisobutylaluminum hydride. The reaction was stirred at -78° C. for 1 h, then was allowed to warm to room temperature and was stirred overnight. The reaction was then cooled to -78° C. and 10 mL of acetone was added dropwise. To this mixture at -78° C. was added 10 mL of 1N sodium hydroxide dropwise. The reaction mixture was allowed to warm to room temperature and was then poured into water, and the resulting mixture was extracted with dichloromethane. The organic extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was then evaporated to obtain 4.15 g of the title compound of Step D as a white solid melting at 117°-127° C. 1H NMR (400 MHz, CDCl3): δ 3.472 (s,3H), 3.969 (m,4H), 4.4-4.56 (m,2H), 7.19 (d,1H), 7.423 (t,1H), 7.485 (t,1H), 7.547 (d,1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:22])(=[O:21])[NH2:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:19](=[O:22])(=[O:21])[NH2:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
To a solution of 3-nitro-4-phenyl-5-sulfamylbenzoic acid (8.5 g) in acetic acid (100 ml), palladium (10%) on carbon (1.5 g) is added, and the mixture is hydrogenated. After 2-2.5 hours the theoretical amount of hydrogen has been absorbed, and the hydrogen uptake has subsided. The catalyst is removed by filtration, and the filtrate is evaporated in vacuo. The residue is recrystallized from acetic acid to give 3-amino-4-phenyl-5-sulfamylbenzoic acid with a melting point of 232.5°-237° C.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:1]([O:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 76.8 %

Procedure:
A solution of tert-butyl 3-(trityloxy)propanoate (3.5 g, 9.01 mmol) and 6M NaOH (3.00 ml, 18.02 mmol) in ethanol was heated to reflux for 3 hours. After cooling the solvent was removed under vacuum and the residue was partitioned between DCM and aqueous 3% citric acid. The organic layer was washed with brine dried over Na2SO4. The solvent was evaporated and the crude was triturated with iPr2O and filtered affording 3-(trityloxy)propanoic acid (2.3 g, 6.92 mmol, 77% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=O)[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41].P([O-])([O-])([O-])=O>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH3:35])[CH:9]([CH3:23])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:22])[CH:19]=1)[N:16]([C:40](=[O:41])[C:39]1[CH:43]=[CH:44][C:45]([Cl:46])=[C:37]([Cl:36])[CH:38]=1)[CH2:15][CH2:14]2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide (97 mg) in methylene chloride (1 ml) and pyridine (1 ml) was added 3,4-dichlorobenzoyl chloride (84 mg), and the mixture was stirred at room temperature for 20 hours. The pH of the reaction mixture was adjusted to pH 7 with phosphate buffer solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (4/1) as eluent to give 98 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]-1-(3,4-dichlorobenzoyl)indoline-7-carbonitrile as an oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5]1.[CH3:18]S(C)=O>>[O:3]1[C:4]2([CH2:9][CH2:8][CH2:7][C@@H:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:5]2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(=O)C1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Me3SOI (56.2 mmol) in DMSO (80 ml) was added NaH (51.5 mmol) and stirred at room temperature for 2 h until the solution become clear. The resulting solution was added tert-butyl 3-oxocyclohexylcarbamate (23.4 mmol) and stirred at rt overnight. The reaction was quenched with water and extracted with hexane. The extracts were combined and dried using anhydrous sodium sulfate. The product was purified using Biotage. The final products, isomer 1 and isomer 2, were well separated on silicon column with 15%-20% ethyl acetate in hexane. Each single diastereomer was used for the next step.