Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([OH:7])[CH:3]=1.C(#N)C.CS(O[CH:16]1[CH2:19][N:18]([C:20]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[CH2:17]1)(=O)=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:16]2[CH2:19][N:18]([C:20]3[N:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:21]=3[C:22]([O:24][CH3:25])=[O:23])[CH2:17]2)[CH:3]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(O)no1
Solvent: CC#N
Product: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cc(C)on2)C1
Temperature: 180 °C
Yield: 16.5 %

Procedure:
To a solution of 5-methylisoxazol-3-ol (33.48 mg, 0.34 mmol) in acetonitrile (0.7 ml) potassium carbonate (60.85 mg, 0.44 mmol) was added followed by addition of methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (120 mg, 0.34 mmol). The reaction mixture was heated at 180° C. under microwave irradiation for 25 min. After solvent evaporation the residue was purified by Biotage SNAP-Si column (10 g) eluting with cycloexane/ethyl acetate from 95/05 to 70/30. Collected fractions were evaporated in vacuo tot afford the title compound (D88) (20 mg)
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]1([C:13]#[N:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][C:31](Cl)=[O:32])=[C:25]([CH3:34])[CH:24]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH3:34])[C:26]([CH2:30][C:31]([N:4]([C:5]2([C:13]#[N:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]2)[O:3][CH2:1][CH3:2])=[O:32])=[C:27]([CH3:29])[CH:28]=1
Reactant: CCONC1(C#N)CCN(OC)CC1
Reactant: Cc1cc(Cl)cc(C)c1CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCON(C(=O)Cc1c(C)cc(Cl)cc1C)C1(C#N)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-ethoxyamino-1-methoxy-piperidine-4-carbonitrile (2.0 g, 10.04 mmol), triethylamine (3.49 ml, 2.54 g, 25.09 mmol) and a catalytic amount of 4-dimethylamino-pyridine in tetrahydrofuran (10 ml) at 0° C. was added a solution of (4-chloro-2,6-dimethyl-phenyl)-acetyl chloride (2.18 g, 10.04 mmol) in tetrahydrofuran (1 ml) dropwise. The suspension was stirred at 0° C. for 15 minutes, and at room temperature overnight. The reaction mixture was evaporated, diluted with ethyl acetate and water, and the layers separated. The aqueous phase was extracted with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The crude material was triturated with diisopropyl ether, filtered and the filtrate concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:1). Yield: 1.53 g of 2-(4-chloro-2,6-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-ethoxy-acetamide (title compound P3ii.49) as a colorless oil, which solidified upon standing, mp 100-103° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cc(N)ncn2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
After suspending 6-(4-nitrophenoxy)pyrimidin-4-ylamine (306 mg, 1.32 mmol), iron powder (369 mg, 6.60 mmol) and ammonium chloride (706 mg, 13.2 mmol) in an ethanol (20 ml)—water (5 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was concentrated to obtain the title compound (266 mg, 1.32 mmol, 100%) as light yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(O)O
Reactant: CSC(c1cc(F)c(C#N)cc1F)S(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(C=O)cc1F
Reaction time: 144 h

Procedure:
2,5-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.8 g, 0.0107 mol; see step (i) above) was dissolved in 100 mL of THF and 6.5 g of concentrated sulfuric acid was added. The mixture was left at room temperature for 6 days and subsequently poured into 500 mL of water. Extraction three times with diethyl ether followed and the combined ethereal phase was washed several times with water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel using heptane:EtOAc (8:2). Yield: 1.2 g (67%). The position of the formyl group was established by use of 13C NMR. The carbon signals from the fluorinated carbons at 160.1 and 158.4 respectively were doublets and not quartets, which they would have been if the formyl group had been in the 2-position.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH3:17].[CH3:18]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:18])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:5]2[CH3:17]
Reactant: Cc1c(-c2ccccc2)[nH]c2ccc(Br)cc12
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(C)c2ccc(Br)cc12
Yield: 92 %

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-3-methyl-2-phenyl-1H-indole (1.413 g, 4.938 mmol) was reacted with k-t-butoxide (0.582 g, 5.185 mmol) and methyl iodide (0.736 g, 5.185 mmol) in DMF (15 ml) to give the desired product (1.364 g, 4.544 mmol, 92%) as an off-white solid, mp 77.5-80° C. 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 3.58 (s, 3H), 7.27 (dd, J=1.8, 8.6 Hz, 1H), 7.42-7.48 (m, 4H), 7.54 (t, J=8.1 Hz, 2H), 7.71 (d, J=1.8 Hz, 1H); [EI], m/z 299/301 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3([CH2:23][OH:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:25][O:26][CH2:27][C@H:28]([NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)[CH3:29]>>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3([CH2:23][OH:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:10]=2)=[CH:4][C:5]([NH:37][C@H:34]2[CH2:33][CH2:32][C@H:31]([NH:30][C@H:28]([CH3:29])[CH2:27][O:26][CH3:25])[CH2:36][CH2:35]2)=[N:6][CH:7]=1
Reactant: COC[C@@H](C)N[C@H]1CC[C@H](N)CC1
Reactant: OCC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Product: COC[C@@H](C)N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4(CO)CCOCC4)n3)c(Cl)cn2)CC1

Procedure:
Following the same procedure as in Example 1b using (4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-yl)methanol (from step 4) and trans-N1-((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine, the desired product was obtained. LCMS (m/z): 518.2 (MH+), retention time=0.47 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:21]3[CH:16]([C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=4[CH2:19][CH2:20]3)[C:15]3[CH:14]=[C:13]([C:26]#[N:27])[CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[BH4-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1>[NH2:27][CH2:26][C:13]1[CH:12]=[CH:11][C:10]2[NH:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:28][CH3:29])[CH:4]=3)[CH:21]3[CH:16]([C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=4[CH2:19][CH2:20]3)[C:15]=2[CH:14]=1
Reactant: COc1cc(C2Nc3ccc(C#N)cc3C3c4ccccc4CCC23)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2Nc3ccc(CN)cc3C3c4ccccc4CCC23)ccc1O

Procedure:
6-(4-Hydroxy-3-methoxy-phenyl)-5,6,6a,7,8,12b-hexahydro-benzo[k]phenanthridine-2-carbonitrile (0.1 mmol; 38.2 mg) was added at 10° C. to a mixture obtained by pre-treating sodium borohydride (600 mg) in 4 mL of THF with a mixture of THF (2 mL) and TFA (1.2 mL). The reaction mixture was reacted overnight before quenching with 1 mL of 10% HCl solution. The mixture was further heated for 1 hour before it was extracted using ammonium hydroxide and water. The organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was purified using HPLC to yield compound 4-(2-Aminomethyl-5,6,6a,7,8,12b-hexahydro-benzo[k]phenanthridin-6-yl)-2-methoxy-phenol. Mass spectrum 369(M−17);in the presence of 0.1M ammonium acetate 385 (M−1) observed for negative ion mode.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:36])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:35])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:35][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:36])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccccc3Cl)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
Lithium hydroxide monohydrate (0.014 g, 0.32 mmol) was added to a stirred solution of {6-chloro-4-[4-(2-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.041 g, 0.082 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-4-[4-(2-chloro-benzenesulfonyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.031 g, 78%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.49 (br. s., 1 H), 8.39 (d, J=7.82 Hz, 1 H), 8.09 (d, J=7.82 Hz, 2 H), 7.97 (d, J=8.80 Hz, 1 H), 7.91 (s, 1 H), 7.68-7.84 (m, 3 H), 7.54 (d, J=7.82 Hz, 2 H), 7.49 (d, J=8.80 Hz, 1 H), 6.95 (s, 1 H), 3.85 (s, 2H), 2.05 (s, 3 H). MS calcd. for C25H17Cl2O4S [(M−H)] 483, obsd. 483.4.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:4]=1.CN(C)C=O.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>C(#N)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[C:11]([C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[O:10])=[CH:12]1
Reactant: O=C(c1cccnc1)c1c[nH]c2ccccc2c1=O
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cccnc3)c(=O)c3ccccc32)c1

Procedure:
Compound 4hh was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.40 mmol) of sodium hydride (60%), 75 mg (0.30 mmol) of 3-(pyridine-3-carbonyl)-1H-quinolin-4-one, 3 mL of anhydrous dimethylformamide, and 74.0 mg (0.4 mmol) of 3-methylbenzylbromide. The crude product was purified by flash chromatography to yield 35 mg of 4hh as a colorless solid: LC-MSD, m/z for C23H18N2O2, [M+H]+=355.4, [M+2H]+=356.4; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=1.710 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.36 (s, 3H), 5.41 (s, 2H), 7.00 (d, 2H), 7.12-7.28 (m, 2H), 7.34-7.45 (m, 3H), 7.60 (m, 1H), 8.09 (m, 1H), 8.42-8.46 (m, 2H), 8.71 (m, 2H), 8.99 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:29][C:30]1[C:35]([F:36])=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:34][C:35]=1[F:36]
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cnc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white solid. HPLC (Condition 4) tR=5.69 min, UPLC-MS (Condition 7) m/z=511.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.65 (m, 1H) 1.84 (m, J=5.90 Hz, 1H) 2.15-2.28 (m, 1H) 2.98 (dd, J=10.95, 7.04 Hz, 1H) 3.11-3.41 (m, 5H) 4.61 (t, J=5.28 Hz, 1H) 7.34 (d, J=9.38 Hz, 2H) 7.83 (d, J=9.38 Hz, 2H) 7.99-8.09 (m, 2H) 8.35 (d, J=1.00 Hz, 1H) 8.76 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([B:24]([OH:29])[OH:25])[CH:18]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with n-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled to −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring at −78° C. was continued for 3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirring at −78° C. continued for 30 min before removing the cooling bath. When the internal temperature of the reaction reached −40° C., 5N hydrochloric acid was added (75 ml) and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2-fluorobenzeneboronic acid (25 g, 76%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C1C=CC=CC=1.C(Cl)Cl>[CH2:16]([NH:18][C:19]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:20])[CH3:17]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 78.1 %

Procedure:
To a stirred and chilled (15°-20° C.) solution of 0.024 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of dry benzene was added dropwise 1.99 g (0.028 mole) of ethyl isocyanate. The reaction mixture was stirred at room temperature overnight and was diluted with 50 ml of methylene chloride. The solution was washed with 5% sodium hydroxide (2×50 ml), water (50 ml), saturated sodium chloride (25 ml), dried over sodium hydroxide, and concentrated in vacuo. The residue (9.6 g) was twice recrystallized from ethyl acetate-isopropyl ether to give 5.4 g of a white solid, m.p. 125°-126° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:44]([S:41]([N:38]1[CH2:37][CH2:36][CH:35]([C:26]2[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=[C:23]([C:10]4[CH:9]=[N:8][CH:7]=[C:6]([CH2:5][NH:4][CH2:3][CH:2]([CH3:1])[CH3:21])[CH:11]=4)[CH:24]=3)[NH:28][CH:27]=2)[CH2:40][CH2:39]1)(=[O:43])=[O:42])[CH3:45]
Reactant: CC(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC(C)C)c4)cc23)CC1
Yield: 35 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1>CO>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCCl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.6 %

Procedure:
31 mg (0.773 mmol, 1 eq) of sodium hydroxide are added to a solution of 389 mg (0.773 mmol, 1 eq) of methyl 3-[2-(3-chloropropoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate in 10 ml of methanol. The reaction mixture is stirred at room temperature for 18 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 2N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (10 g FlashSmart column) eluted with 98/2 dichloromethane/methanol. The product is crystallized from heptane, the filtrate is evaporated and 21 mg of 3-[2-(3-chloropropoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a whitish oil. Yield=6%
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11][S:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]([CH3:21])[CH:31]=3)=[CH:35][CH:36]=2)(=[O:41])=[O:42])[CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1C(N)C2CCC1N2C(=O)OC(C)(C)C
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1C(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 23.5 %

Procedure:
To a mixture of 3-amino-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester (0.2 g, 0.87 mmol] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (0.4 g, 1.0 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 0° C. was added N,N-diisopropylethylamine (0.4 mL, 2.23 mmol). The solution was allowed to warm up to 25° C. over 19 h. The DMF was removed in vacuo and the solid was partitioned between ethyl acetate (100 mL) and water (30 mL). The aqueous layer was washed with ethyl acetate (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on a Biotage Flash 40S chromatography, eluting with 1:4 ethyl acetate-hexanes, to afford 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzene sulfonylamino]-7-aza-bicyclo [2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester-2-methyl ester as a white solid (0.150 g, 23.5%). MS: 582 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][OH:36])=[CH:33][CH:32]=1.O>CN(C)C=O>[N:13]1([C:4]2[N:3]=[C:2]([O:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:32][CH:33]=3)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1Cl
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of ethyl 4-chloro-2-(2,3-dihydro-1H-indol-1-yl)-5-pyrimidinecarboxylate (520 mg, 1.72 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (829 mg, 6 mmol) and 4-(trifluoromethoxy)benzyl alcohol (384 mg, 2 mmol) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was allowed to cool to room temperature and water was added, which was followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was applied to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1) to give the title compound (420 mg, 53%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C>CS(C)=O>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])([O-:18])=[O:17]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)[C@@H]1CCCN1c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 80.4 %

Procedure:
There were dissolved, in 25 ml of dimethyl sulfoxide, 1 g of L-proline and 1.23 g of 1-fluoro-2-nitrobenzene, then 1.65 ml of triethylamine was added to the resulting solution and the mixture was stirred with heating at 60° C. for 16 hours. The reaction solution was cooled to room temperature then poured into ice water and washed with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ether. After washing the organic phase with water, the phase was dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was treated by silica gel column chromatography, followed by elution with methanol/chloroform (1/49) to give 1.65 g (yield: 80.3%) of the title compound.