Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([CH3:11])[CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:22]>C(N(CC)CC)C.[Cu]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>[OH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:29]=[CH:30][C:25]([C:24]([O:23][CH2:21][CH3:22])=[O:32])=[CH:26][CH:27]=2)=[CH:4][C:5]=1[CH3:11]
Reactant: C#Cc1ccc(CO)c(C)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
Using General Procedure F; (4-ethynyl-2-methyl-phenyl)-methanol (Intermediate 136, 100.0 mg, 0.44 mmol) and ethyl-4-iodo benzoate (Reagent A, 125.0 mg, 0.45 mmol) in triethyl amine (4 mL) was treated with copper(I)iodide (29 mg, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (20-40% EtOAc-hexanes) afforded 130.0 mg (99%) of the title compound as an orange solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[OH-].[Li+]>O1CCOCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: COC(=O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reaction time: 24 h
Yield: 95.9 %

Procedure:
Methyl 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoate (12 mg) was dissolved in dioxane (1.5 mL). Lithium hydroxide (1 M in water, 0.5 mL) was added as one portion. After 24 h, quenched with 1N HCl. Extracted with dichloromethane, dried with MgSO4, and concentrated. Isolated 11 mg of 4-(3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoic acid (˜100%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=4)[C:5]=3[N:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1ccc2c(c1)-c1nc(S)sc1CC2
Product: O=C(O)COc1ccc2c(c1)-c1nc(SC(c3ccccc3)c3ccccc3)sc1CC2
Yield: 90 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-8-yl)oxy]acetate and bromodiphenylmethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 90%.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14].[CH2:25]([N:29]([CH2:39][CH2:40][CH2:41][CH3:42])[C:30]([C:32]1[C:36]([Cl:37])=[C:35]([CH3:38])[NH:34][N:33]=1)=[O:31])[CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:37][C:36]1[C:32]([C:30](=[O:31])[N:29]([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:25][CH2:26][CH2:27][CH3:28])=[N:33][N:34]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[O:14])[C:35]=1[CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Reactant: CCOC(=O)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCC)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Temperature: 125 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (645 mg, 1.97 mmol) and N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (1.07 g, 3.94 mmol) in NMP (9.9 mL) was added K2CO3 (1.09 g, 7.88 mmol). The resulting reaction mixture was stirred at 125° C. for 3 h, cooled to room temperature and quenched with 10% aq. LiCl solution. The solution was extracted with EtOAc (3×) and the combined organic extracts were washed with 10% LiCl (3×), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (25% EtOAc/CHCl3) to afford the title compound (930 mg, 81%). 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.32 (s, 0.5H), 8.23-8.13 (m, 1H), 8.11-8.00 (m, 1H), 7.76-7.87 (m, 0.5H), 7.28-7.08 (m, 3.5H), 7.03-6.94 (m, 0.5H), 4.87-4.51 (m, 2H), 4.43-4.27 (m, 2.5H), 3.86-3.75 (m, 0.5H), 3.63-3.32 (m, 3H), 3.23-3.07 (m, 1H), 3.05-2.94 (m, 1H), 2.85-2.62 (m, 2H), 2.27 (s, 2H), 2.22 (s, 1H), 1.48-1.09 (m, 9H), 1.04-0.92 (m, 2H), 0.90-0.82 (m, 3H), 0.70-0.63 (m, 3H); MS(ESI+) m/z 579.4 (M+H)+.
Reaction SMILES: C1COCC1.[CH2:6]([NH:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>O>[CH2:6]([N:13]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 46.8 %

Procedure:
THF (16 mL) and water (4 mL) were added to tert-butyl cis(±)-4-benzylamino-3-methoxypiperidine-1-carboxylate obtained in Example (259a) (1.00 g, 3.1 mmol). While the mixture was stirred, saturated aqueous sodium bicarbonate solution (4 mL) and benzyl chloroformate (0.96 g, 5.6 mmol) were added at room temperature, followed by stirring overnight. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/9, 1/1) to obtain 0.66 g of the title compound as a colorless oily substance (58%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24](OCC)=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][C:31]([CH3:36])([CH2:34][OH:35])[CH2:32][OH:33]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:33][CH2:32][C:31]([CH3:36])([CH3:30])[CH2:34][OH:35])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)COC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 17.7 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 21, 2,2-dimethyl-1,3-propanediol (0.40 g, 3.8 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 130° C. for 24 h. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.020 g, y. 17%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OCC3C=CC=CC=3)=O)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[NH:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[C:10]1[O:11][C:12]2[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(C3CCCN3C(=O)OCc3ccccc3)oc12
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCCN3)oc12
Yield: 13.7 %

Procedure:
A mixture of benzyl 2-(7-carbamoylbenzo[d]oxazol-2-yl)pyrrolidine-1-carboxylate (68 mg, 0.19 mmol), 10% Pd/C (20 mg) in methanol (30 ml) was stirred at room temperature over 1 atm hydrogen for 2 hr. Then the mixture solution was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by pre-HPLC to give 6 mg of 2-(pyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide. Yield 13%. LC-MS (ESI) m/z: 232 (M+1)+. 1H-NMR (400 MHz, CDCl3): δ 1.24 (brs, 1H), 1.97 (m, 2H), 2.21 (m, 1H), 2.35 (m, 1H), 3.12 (m, 1H), 3.22 (m, 1H), 4.58 (m, 1H), 5.99 (brs, 1H), 7.03 (brs, 1H), 7.43-7.47 (t, J=8 Hz, 1H), 7.85-7.87 (d, J=8 Hz 1H), 8.08-8.09 (d, J=7.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14](I)=[CH:15][C:6]1=2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1>>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][NH:8][C:7]2[N:12]=[CH:13][C:14]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:15][C:6]1=2
Reactant: OB(O)c1cccnc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1c(Cl)cccc1Cl
Product: O=C1CNc2ncc(-c3cccnc3)cc2N1Cc1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (150 mg) was reacted with pyridine-3-boronic acid as in General Procedure 4B to give the title compound as a brown solid. M.p.>200° C., LCMS: m/z=385.48 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.06 (2H, s), 5.45 (2H, s), 7.07 (1H, s), 7.45 (5H, m), 7.85 (1H, d, J=7.8 Hz), 8.01 (1H, s), 8.49 (1H, d, J=4.8 Hz), 8.67 (1H, s) (NMR and LCMS indicate presence of triphenylphosphine impurity)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:38][C:39]([NH:41][C:42]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)=[O:16]>>[CH2:35]([O:34][CH:30]([O:31][CH2:32][CH3:33])[C@@H:29]([N:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2)[C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:38][C:39](=[O:40])[NH:41][C:42]([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH3:37])[CH3:36]
Reactant: CCNC(=O)NN(C)CC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N(Cc1cccc2cccnc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 41 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]1[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:5]1
Reactant: CC(C)(CO)CO
Reactant: COc1cc(Br)c(C=O)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(Br)c(C2OCC(C)(C)CO2)cc1OC
Temperature: 25 °C
Yield: 104.8 %

Procedure:
3.6 g of 2-bromo-4,5-dimethoxybenzaldehyde and 3.22 g of 2,2-dimethyl-1,3-propanediol were dissolved in 200 ml of toluene and boiled at reflux in the presence of 0.8 g of p-toluenesulphonic acid for 3 hrs. Then, the reaction mixture was left to cool to room temperature and was washed with NaHCO3 solution, water and saturated NaCl solution. Subsequently, the solvent was removed in a vacuum and there were obtained 5.1 g of 2-(2-bromo-4,5-dimethoxy-phenyl)-5,5-dimethyl-[1,3]dioxan as yellow-green needles.
Reaction SMILES: [Mg].Br[C:3]1[C:11]2[O:10][C:9]3[CH2:12][CH2:13][CH2:14][CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH2:15]1[C:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:16]([OH:18])=[O:17])[C:11]=3[O:10][C:9]=2[CH2:12][CH2:13][CH2:14]1
Reactant: Brc1cccc2c3c(oc12)CCCC3
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c3c(oc12)CCCC3
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of magnesium (345 mg) in tetrahydrofuran (5 ml) was added 6-bromo-1,2,3,4-tetrahydrodibenzofuran (3.39 g) in tetrahydrofuran (15 ml) dropwise. The mixture was refluxed for 1 hour and cooled to 4° C. Dry ice (2.7 g) was added to the mixture and the mixture was stirred at ambient temperature for 30 minutes. To the mixture was added 3.6% hydrochloric acid and chloroform. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from n-hexane to give 1,2,3,4-tetrahydrodibenzofuran-6-carboxylic acid (2.60 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:3]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH3:29])[C:2]2[N:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]4)=[C:11]([O:21][CH3:22])[CH:10]=3)[N:5]=[CH:6][N:7]=2)=[CH:26][CH:25]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: COc1cc(Nc2ncnc(Cl)n2)ccc1-n1cnc(C)c1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncnc(N(C)c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Yield: 23 %

Procedure:
This compound was prepared from (4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 4-chloro-N-methylaniline in analogy to example 1c. Chromatography on Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the title compound as a colorless solid in 23% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[O:36][C:35]([C:37](Cl)=[O:38])=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:37]([C:35]3[O:36][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=3)=[O:38])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc([N+](=O)[O-])o3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 5-nitro-2-furoyl chloride: ESMS m/e: 519.2 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=[O:43].[Li]CCCC>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:42]([C:38]2[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1ccnc1C=O
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: [Li]CCCC
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3nccn3C)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1-methyl-imidazole-2-carbaldehyde and n-BuLi
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)/[C:5](=[N:7]/[OH:8])/[NH2:6].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C@@H:23]([CH3:27])[C:24](O)=O.C(=NC1CCCCC1)=NC1CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:27]([C@@H:23]([N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13]3=[O:12])[CH3:24])[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: N/C(=N\O)c1cccc(Cl)c1
Reactant: C[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C[C@@H](c1nc(-c2cccc(Cl)c2)no1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
To a stirred solution of (Z)-3-chloro-N′-hydroxybenzimidamide (500 mg, 2.93 mmol) and (S)-2-(1,3-dioxoisoindolin-2-yl)propanoic acid (642 mg, 2.93 mmol) was added N,N′-methanediylidenedicyclohexanamine (1.1 eq, 665 mg, 3.22 mmol) and allowed to reflux at 100° C. for 12 hours. Concentrate in vacuo, dilute w/EtOAc, filter washing w/EtOAc, wash w/water, brine, concentrate in vacuo. Flash column chromatography (silica, 40 g) eluting w/0-10% EtOAc/DCM afforded 300 mg. HRMS m/z 353.0567
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[C:12]([C:20](=[O:34])[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([O:32]C)=[O:31])[CH:25]=3)[OH:23])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Li+]>CO>[Cl:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[C:12]2[C:20](=[O:34])[CH:21]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([OH:32])=[O:31])[CH:25]=1)[OH:23]
Reactant: COC(=O)c1cccc(C(O)=CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(C(O)=CC(=O)c2c[nH]c3ccc(Cl)cc23)c1

Procedure:
The carboxylic acid in Example 100 was esterified to 1-(1-benzenesulfonyl-5-chloroindol-3-yl)-3-(3-methoxycarbonylphenyl)-3-hydroxy-propen-1-one. The compound was hydrolyzed with lithium hydroxide in methanol to give the titled compound.
Reaction SMILES: COC([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=O.[C:24]([O:28][C:29]([NH:31][C@@H:32]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:33]([OH:35])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH3:24][O:28][C:29]([CH:6]1[CH2:7][C@@H:8]2[C@@H:13]([CH2:12][CH2:11][CH2:10][C@@:9]2([O:23][C:33](=[O:35])[C@@H:32]([NH:31][C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])[C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[NH:5]1)=[O:30]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@H]2NC(C(=O)OC)C[C@H]21

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanoic acid to yield (3aR,4S,7aR)-4-((2S,3S)-2-tert-butoxycarbonylamino-3-methyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-carboxylic acid methyl ester. This NBoc-protected product was then stirred in hydrochloric acid dioxane solution (4M, 10 equiv.) at room temperature for 6 hrs. Subsequently the solvent was removed the residue dissolved in dichloromethane and washed with saturated sodium hydrogencarbonate solution. The organic layer was tried with sodium sulfate, filtrated and evaporated. The crude product was subjected to silica gel flash chromatography (ISCO CombiFlash; dichloromethane/methanol; 100/0 to 95/5) to yield (3aR,4S,7aR)-4-((2S,3S)-2-amino-3-methyl-pentanoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=5.703 min; HPLC Method I
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]1[C:7]([C:21](O)=[O:22])=[C:8]2[N:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:21]([C:7]2[C:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=3[CH3:27])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)=[O:22])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(F)cccc1Cc1c(C(=O)O)c2ccccn2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of the crude compound obtained in step 4 (125 mg, 0.35 mmol), 1-tert-butoxycarbonyl-piperazine (67.9 mg, 0.37 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (73.4 mg, 0.38 mmol) and 1-hydroxybenzotriazole (61.3 mg, 0.40 mmol) in DMF (2 ml) was added N-methyl-morpholine (0.115 ml, 1.04 mmol). The mixture was stirred at room temperature overnight, then quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (HEP/EA) to give 158 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12](I)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:15][N:16](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:16]
Reactant: COCc1cc(I)cc(C(=O)OC)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COCc1cc(C#N)cc(C(=O)OC)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
After bubbling argon into a solution of methyl 3-(methoxymethyl)-5-iodobenzoate (316 mg, 1.03 mmol) in N,N-dimethylformamide (3 mL) for 5 minutes, zinc cyanide (133 mg, 1.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (119 mg, 0.010 mmol) were added. The reaction mixture was heated at 80° C. for 15 minutes under argon. Following cooling, the reaction mixture was diluted with ethyl acetate and then the precipitate that formed was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 10-30% ethyl acetate/hexanes afforded 184 mg (86%) of methyl 3-cyano-5-(methoxymethyl)benzoate as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:19](=[O:21])C)[C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14]C=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22]OC(C)(C)C>C(Cl)(Cl)Cl>[C:1]1([NH:7][N:8]=[C:9]([CH2:10][C:11]2[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]([Cl:22])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OCl
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(Cc1ccccc1)=NNc1ccccc1

Procedure:
The foregoing procedure was repeated, but using 12.1 gms. 1-phenyl-2,3,4-pentanetrione-3-phenylhydrazone, 100 ml. chloroform, and 6 ml. tert-butyl hypochlorite. Upon recrystallization from 100 ml. methanol there was obtained 6.3 gms. of compound having a melting point at 132° to 134°C.