Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-n2nc(C(=O)O)cc2-c2cccc(F)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: COc1cccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cccc(F)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 80A in analogy to the synthesis of the compound of Example 1. 27 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [K+].[N:2]1([CH2:8][CH2:9][C:10]([O-:12])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(OC(=O)CCN1CCOCC1)C.FC(F)(F)C(O)=O.[C:33]1([C:39]2[CH:44]=[C:43]([CH:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH:42]=[CH:41][C:40]=2[NH:51][C:52]([C:54]2[NH:55][CH:56]=[C:57]([C:59]#[N:60])[N:58]=2)=[O:53])[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:33]1([C:39]2[CH:44]=[C:43]([CH:45]3[CH2:46][CH2:47][N:48]([C:10](=[O:12])[CH2:9][CH2:8][N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:7]4)[CH2:49][CH2:50]3)[CH:42]=[CH:41][C:40]=2[NH:51][C:52]([C:54]2[NH:55][CH:56]=[C:57]([C:59]#[N:60])[N:58]=2)=[O:53])[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C([O-])CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)CCN4CCOCC4)CC3)cc2C2=CCCCC2)n1
Reaction time: 8 h
Yield: 6 %

Procedure:
To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94 mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl ester exactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83 mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To the stirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the crude product was purified by silica gel preparative TLC to afford 10.4 mg (6%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.49-1.93 (m, 5H), 2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m, 4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81 (m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H), 7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C29H36N6O3, 517.28 M+H). found 517.3.
Reaction SMILES: [C:1]([C:5]1[CH:53]=[CH:52][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([O:40][Si](C(C)C)(C(C)C)C(C)C)=[C:35]([F:51])[CH:34]=2)[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([OH:40])=[C:35]([F:51])[CH:34]=2)[CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[CH:52][CH:53]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2cc(F)c(O)c(F)c2)cc1
Temperature: 25 °C

Procedure:
780 mg (1.05 mmol) of methyl E-4-[5-[2-(4-tert-butylbenzyloxy)phenyl]-3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)pent-4-enyl]benzoate are introduced into 20 ml of THF at room temperature under argon, 2.11 ml (2.11 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF are added, and the mixture is stirred at room temperature until reaction is complete. All the volatile components are then removed in vacuo. The resulting crude product is purified by preparative HPLC. 229 mg (37% of theory) of the title compound are obtained.
Reaction SMILES: C([Li])(C)(C)C.I[CH2:7][C:8]12[CH2:25][N:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:23][C:9]1([CH2:36]I)[CH2:10][N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:12]2.CCCCC>C1COCC1>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:11]2[CH2:10][C:9]34[CH2:36][CH2:7][C:8]3([CH2:25][N:24]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH2:23]4)[CH2:12]2)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3(CI)CN(S(=O)(=O)c4ccc(C)cc4)CC3(CI)C2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CC34CCC3(C2)CN(S(=O)(=O)c2ccc(C)cc2)C4)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
t-Butyl lithium (1.7 M pentane) (1.05 mL, 1.76 mmol) was added dropwise to a stirring solution of 3a,6a-bis(iodomethyl)-2,5-bis((4-methylphenyl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole (0.50 g, 0.71 mmol) in THF (10 mL) at −78° C. The resulting orange mixture was stirred at −78° C. for 30 minutes. After this time, additional t-Butyl lithium 1.7 M in pentane (1.05 mL, 1.76 mmol) was added to the reaction mixture at −78° C. After 10 minutes of additional stirring at −78° C., the reaction was quenched with the addition of sat. NH4Cl (aq) (10 mL). The mixture was warmed to r.t., diluted with EtOAc (15 mL) and the layers were separated. The aq. layer was then extracted with EtOAc (3×20 mL) and once with CH2Cl2. The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give 2,5-bis((4-methylphenyl)sulfonyl)tetrahydro-1H,4H-3a,6a-ethanopyrrolo[3,4-c]pyrrole (0.308 g, 0.690 mmol, 97% yield) as a white crystaline solid. LCMS: m/e=447 (M+H)+. LCMS retention time: 2.39 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.). Structure was verified via single crystal X-ray diffraction. 1H NMR (400 MHz, CHLOROFORM-d) □ ppm 7.67 (4 H, d, J=8.28 Hz), 7.34 (4 H, d, J=8.03 Hz), 3.36 (4 H, d, J=9.79 Hz), 2.73 (4 H, d, J=9.79 Hz), 2.47 (6 H, s), 2.00 (4 H, s).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].N([O-])=O.[Na+].[I-:17].[K+]>C1COCC1.Cl.O>[OH:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[I:17])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(I)c(O)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A solution of methyl 4-amino-3-hydroxybenzoate (1 eq.) in THF was diluted with aqueous HCl 3N and cooled to 0° C. Sodium nitrite (1.1 eq.) in H2O was added over 5 min. The reaction mixture was stirred for 25 min at 0° C. and then a solution of potassium iodide (4 eq.) in H2O was added in one portion, and stirred for 15 min. The reaction mixture was partitioned between water and EtOAc, the organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM) to afford methyl 3-hydroxy-4-iodobenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([O:24][CH2:25][CH2:26]Br)[CH3:23].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:23][CH2:22][O:24][CH2:25][CH3:26])[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21

Procedure:
To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in N,N-dimethylformamide (1.2 mL) was added cesium carbonate (489 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the mixture was stirred at room temperature for 2 days. Cesium carbonate (326 mg) and 2-bromoethyl ethyl ether (0.113 mL) were added and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:4) to give the title compound (76 mg).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[NH:23][S:24]([C:27]1[C:32]2=[N:33][S:34][N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.O[Li].O.O.Cl>O.C1COCC1>[N:35]1[S:34][N:33]=[C:32]2[C:27]([S:24]([NH:23][C:17]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=3[C:15]([NH:14][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=3)[C:3]([OH:37])=[O:2])=[O:36])(=[O:25])=[O:26])=[CH:28][CH:29]=[CH:30][C:31]=12
Reactant: COC(=O)[C@H](Cc1ccc(Cl)c(Cl)c1)NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid methyl ester (55 mg, 0.079 mmol) in 2:1 water/THF (3 mL) was added LiOH-2H2O (7 mg, 0.158 mmol). The yellow solution was stirred for 2 h and then 20% aq. HCl (2 mL) was added. The mixture was extracted with EtOAc (3×). The organic layers were combined, dried (MgSO4), and concentrated to provide the desired product as a white solid (41 mg, 76%). HPLC: RT=9.77 min. MS (ESI−): mass calcd. for C22H15Cl2IN4O5S2, 677.3; m/z found, 676 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.22 (s, 1H), 8.33 (d, J=7.0, 1H), 8.12 (d, J=8.8, 1H), 7.98 (d, J=0.8, 1H), 7.70 (dd, J=8.6, 7.3, 1H), 7.33 (d, J=8.2, 1H), 7.22 (d, J=8.2, 1H), 7.02 (dd, J=8.2, 1.6, 1H), 6.93 (d, J=8.3, 1H), 6.73 (d, J=7.3, 1H), 4.99 (q, J=6.3, 1H), 3.31 (dd, J=14.2, 5.7, 1H), 3.20 (dd, J=14.2, 5.7).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[OH:23])[CH2:9]1)=O)(C)(C)C.Br[CH2:25][C:26]1[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[CH:15][C:14]([O:23][CH2:25][C:26]2[O:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[C:13]([CH:18]=1)[O:12][CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2O)C1
Reactant: FC(F)(F)c1ccc(CBr)o1
Product: FC(F)(F)c1ccc(OCc2ccc(C(F)(F)F)o2)c(OC2CNC2)c1

Procedure:
Prepared according to Example 1 using 3-(2-hydroxy-5-trifluoromethyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester and 2-bromomethyl-5-trifluoromethyl-furan. MS (ESI): mass calcd. for C16H13F6N3O3, 381.1; m/z found, 382.0 [M+H]+. 1H NMR (CDCl3): 7.21 (dd, J=8.4, 1.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H), 6.79-6.78 (m, 1H), 6.51 (d, J=3.1 Hz, 1H), 5.13 (s, 2H), 5.05-4.99 (m, 1H), 3.94-3.87 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[NH2:24][CH:25]([CH3:32])[CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:24][CH:25]([CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[CH3:32])=[O:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CC(N)C(O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(C)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
250 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.785 mmol), 112 mg of 3-amino-1,1,1-trifluorobutan-2-ol (mixture of four stereoisomers; 0.785 mmol) and 277 mg of TBTU (0.864 mmol) were dissolved in 1.5 ml of dichloromethane, and the mixture was stirred at RT for 48 h. The reaction mixture was concentrated and the residue was taken up in methanol and purified by preparative HPLC (Method 7). This gave 186 mg (53% of theory) of the title compound, which was separated by preparative HPLC on a chiral phase.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].Cl>C(OCC)C.CCCCCC>[F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-trifluoromethoxyiodobenzene (39.28 g.) in anhydrous diethyl ether (200 ml.) was added dropwise at -70° C. to n-butyl-lithium (96 ml. of a 1.6M solution in hexane) over 25 minutes. The solution was stirred for 30 minutes, and then dimethylformamide (14.83 g.) and anhydrous ether (50 ml.) were added over 15 minutes. After 1 hour, the solution was allowed to warm to -20° and was then hydrolysed by the addition of 3N hydrochloric acid (150 ml.). The organic layer was separated, and the aqueous layer was extracted twice with diethyl ether. The ether extracts were combined, washed with water, dried over magnesium sulphate and filtered, and the solvent was evaporated to give a yellow oil. Distillation of this oil gave 4-trifluoromethoxy benzaldehyde, b.p. 75°-7°/8 mm. of mercury, pressure.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCCO)C>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A mixture of 250 mg (1.02 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 210 mg (1.12 mmol) of 4-phenoxyaniline in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 4 hours then stirred at room temperature for 3 days. The reaction mixture is then heated at reflux temperature for an additional 6 hours, then cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 240 mg (60%) of a beige solid, mp 230–233° C.
Reaction SMILES: O[CH:2]([C:5]1[C:13]2[O:12][CH2:11][C@H:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=1[CH3:32])[CH2:3][CH3:4]>[Pd].C(O)(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]([C@@H:10]2[C:9]3[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:31])[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]([CH3:32])=[C:5]([CH2:2][CH2:3][CH3:4])[C:13]=3[O:12][CH2:11]2)=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: CCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 70.7 %

Procedure:
A solution of a diastereo mixture of (+)-N-((3R)-7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (620 mg, 1.42 mmol) obtained in Examples 43 and 44, and 10% palladium on carbon (water content: 50%, 62 mg) in acetic acid (3 mL) was reacted at 80° C. for 2 hours. The catalyst was removed, water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 423 mg (yield: 71%) of the title compound. Melting point: 184-185° C. [α]D20=+41.6° (c=0.51, chloroform).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([CH3:21])([NH2:20])[CH3:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([NH:20][C:33](=[O:35])[CH3:34])([CH3:19])[CH3:21])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)N)ccc2n1CC1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(C)(C)CS(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 4 h
Yield: 78.6 %

Procedure:
To a solution of 1-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-2-amine (step G, of EXAMPLE 18, 39 mg, 0.1 mmol) in dichloromethane (0.5 mL) were added pyridine (0.016 mL, 0.2 mmol) and acetic anhydride (0.012 mL, 0.12 mmol) at room temperature. After 4 h, the reaction was quenched by addition of water (10 mL) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL×2) and the combined organic layer was washed with water (10 mL), brine (5 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel TLC eluting with hexane/ethyl acetate (1/5) to afford 33 mg (78%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]3[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]3)[CH:40]=2)[CH:36]=[CH:37][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][C:25]([NH:31][CH2:32][C:33]3[CH:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]5[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]5)[CH:40]=4)[CH:36]=[CH:37][CH:38]=3)=[O:27])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1cccc(-c2cccc(CC3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a solution of 5-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-5-oxopentanoic acid (0.0807 g, 0.200 mmol) in DCM (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (0.0837 g, 0.220 mmol), HBTU (0.0910 g, 0.240 mmol), and TEA (0.0562 mL, 0.400 mmol), and was stirred at room temperature for 16 h. The reaction mixture was concentrated on a Glas-Col evaporator, purified using a Gilson HPLC and concentrated with Biotachi evaporator. The crude product was dissolved in DCM (0.6 mL), and TFA (0.2 mL) was added. The resultant mixture was left at room temperature for 1 h before being concentrated on a Glas-Col evaporator, purified using a Gilson HPLC (acidic conditions: with 0.1% TFA) and basified with an amine cartridge to afford the title compound 0.048 g (35%). LC-MS m/z 680.
Reaction SMILES: O=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4](OCCC)=[O:5].O.[NH2:17][NH2:18]>C(O)C>[C:10]1([C:2]2[CH2:3][C:4](=[O:5])[NH:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCOC(=O)CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccccc2)=NN1
Temperature: 80 °C
Yield: 84.7 %

Procedure:
To a solution of propyl 3-oxo-3-phenylpropanoate (10 g, 48.5 mmol) in ethanol (100 mL) was added hydrazine hydrate (9.71 g, 194 mmol) at room temperature. The reaction was heated to 80° C. for 2 h, cooled to room temperature and concentrated. The residue was crystallized from 20% ethyl acetate/hexane to give the title compound (6.58 g). LCMS m/z=161.08 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.32 (br, 2H), 7.32-7.78 (m, 5H), 12.1 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=1)[CH3:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[CH3:11]
Reactant: COC(=O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CN(CCOc1ccc(CCO)cc1)c1nc2ccccc2o1
Temperature: 0 °C

Procedure:
A solution of methyl 2-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]ethanoate (11.60 g) in dry diethyl ether (200 mL) was added slowly to an ice-cooled, stirred suspension of lithium aluminium hydride (1.36 g) in ether (50 mL) under a nitrogen atmosphere. The mixture was stirred at 0° C. for 20 minutes, then water (10 mL) and hydrochloric acid (2 M; 10 mL) were added dropwise with caution. The mixture was diluted with water (200 mL) and the solution adjusted to pH 4 prior to extraction with ethyl acetate (3×200 mL). The combined ethyl acetate solutions were washed with water (2×500 mL), brine (500 mL), dried (MgSO4) and evaporated to afford the title compound, mp 95-97° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:11])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].C(C1NC=C[N+]=1C)C.Cl[C:26](=[O:31])[C:27]([O:29]C)=[O:28]>O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]([C:26](=[O:31])[C:27]([OH:29])=[O:28])=[CH:9][NH:8][C:7]=12
Reactant: Fc1cnc(Br)c2[nH]ccc12
Reactant: COC(=O)C(=O)Cl
Agent: CCc1[nH]cc[n+]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)C(=O)c1c[nH]c2c(Br)ncc(F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridine (2.0 g, 9.3 mmol) was added to a mixture of AlCl3 (7.5 g, 55.8 mmol) and ethylmethylimidazolium chloride (2.7 g, 18.6 mmol). Methyl chlorooxoacetate (2.1 mL, 18.6 mmol) was added slowly to the above solution and the mixture was stirred at room temperature for 3 h. Reaction flask was placed in an ice bath and water was slowly added until a white precipitate formed. The solid was collected by filtration and washed with water to afford 2-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (2.4g, 92%). LCMS: m/e 287 (M+H)+, ret time 0.91 min (method 1).