Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[NH:25][S:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)(=[O:28])=[O:27])[C:7]([C:37]#[N:38])=[C:6]([CH3:39])[NH:5][C:4]=1[CH3:40])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:37]([C:7]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[NH:25][S:26]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)(=[O:27])=[O:28])[C:3]([C:1]#[N:2])=[C:4]([CH3:40])[NH:5][C:6]=1[CH3:39])#[N:38]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NS(=O)(=O)Cc2ccc(F)cc2)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)Cc4ccc(F)cc4)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
28 mg (0.05 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-3-{[(4-fluoro-benzyl)sulfonyl]amino}-1H-indazole-1-carboxylate (Example 13A), dissolved in dichloromethane (1 ml), were treated with 0.042 ml (0.55 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 10 mg (41% of th.) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH-:34].[Na+]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:3]=[C:2]([OH:34])[N:7]=[CH:6][N:5]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: C[C@@H](c1ccc(-c2cc(Cl)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: [OH-]
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2cc(O)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 110 °C
Yield: 78 %

Procedure:
A mixture of (R)-3-((S)-1-(4-(6-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.0426 mmol) in 15% aq NaOH (5 mL) was heated to 110° C. overnight. Then the solvent was evaporated, and the residue was washed with EtOAc. The solid was filted off and the filtrate was dried, and condensed in vacuum to give the crude product, which was purified by preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15 mg, 78%). LC-MS Method 2 tR=0.91 min, m/z=452, 408. 1H NMR (CD3OD): δ=1.31 (m, 1H), 1.59 (m, 3H), 1.95 (m, 2H), 2.25 (m, 1H), 2.35 (m, 1H), 2.46 (m, 1H), 3.15 (m, 1H), 3.48 (m, 2H), 5.59 (m, 1H), 6.81 (s, 1H), 7.12 (m, 4H), 7.33 (m, 2H), 7.79 (m, 2H), 8.25 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH2:32]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.036 g, 0.062 mmol) in dichloromethane (1 mL), and the reaction mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15% methanol in dichloromethane) to give the desired compound (0.011 g, 0.024 mmol, 38%). The material was dissolved in acetonitrile and treated with 1 N aqueous hydrochloric acid solution (0.048 mL, 0.048 mmol). The solution was lyophilized to give the di-HCl salt as the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.02-9.92 (m, 1 H), 9.53 (s, 1 H), 8.49-8.42 (m, 1 H), 7.74 (d, J=2.0, 1 H), 7.69 (d, J=8.8 Hz, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.51 (dd, J=1.6, 8.4 Hz, 1 H), 7.35 (d, J=9.2 Hz, 1 H), 6.98 (s, 1 H), 6.24 (q, J=6.8 Hz, 1 H), 4.65-4.62 (m, 1 H), 3.67-3.63 (m, 5 H), 3.22-3.16 (m, 4 H), 2.39-2.34 (m, 2 H), 1.97 (d, J=6.8 Hz, 3 H), 1.93-1.78 (m, 3H); MS: (ES) m/z calculated for C24H28Cl2N5O [M+H]+ 472.2, found 472.1.
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O>[CH:3]1([N:7]2[CH2:8][CH2:9][CH:10]([O:13][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:11][CH2:12]2)[CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCN(C2CCC2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC2CCN(C3CCC3)CC2)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a stirred solution of sodium hydride (24.76 g, 60% in mineral oil, 0.619 moles) in dimethylformamide (100 mL) was added 1-cyclobutyl-4-piperidinol (80 g, 0.516 moles, obtained in the above step) in dimethylformamide (300 mL) at 10° C. under a nitrogen atmosphere. The mass was stirred for 1 hour. A solution of 4-fluoronitrobenzene (87.3 g, 0.619 moles) in dimethylformamide (300 mL) was added drop wise to the above reaction mass at room temperature. After completion of reaction, the mass was quenched on to chilled water (2 L) and stirred for 1 hour. The obtained solids were separated and dissolved in ethyl acetate (1 L). The resulting ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The residue, thus obtained, was purified by flash chromatography (methanol:chloroform, 2:8) to afford the title compound 99.7 g (Yield: 70%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][CH2:48][S:49]([NH2:52])(=[O:51])=[O:50])[CH2:41][CH2:42]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(N)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 2) was reacted with 3-piperazin-1-yl-propane-1-sulfonic acid amide dihydrochloride (example 55) to give the title compound. HR-MS (ES, m/z) calculated for C35H46Cl2N7O4S [(M+H)+] 730.2704, observed 730.271.
Reaction SMILES: CN1C=CC(C(O)=O)=C1.[CH3:10][NH:11][C:12]([C:14]1[CH:18]=[CH:17][NH:16][CH:15]=1)=[O:13].[CH:19]1([N:23]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)[CH2:22]C[CH2:20]1.IC1C=CC(OC2CCN(C(C)C)CC2)=CC=1>>[CH:19]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:31]=[CH:32][C:33]([N:16]3[CH:17]=[CH:18][C:14]([C:12]([NH:11][CH3:10])=[O:13])=[CH:15]3)=[CH:34][CH:35]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:20]
Reactant: CNC(=O)c1cc[nH]c1
Reactant: Ic1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: CC(C)N1CCC(Oc2ccc(I)cc2)CC1
Agent: Cn1ccc(C(=O)O)c1
Product: CNC(=O)c1ccn(-c2ccc(OC3CCN(C(C)C)CC3)cc2)c1

Procedure:
The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl 1H-pyrrole-3-carboxylic acid was replaced by N-methyl-1H-pyrrole-3-carboxamide and the 1-cyclobutyl-4-(4-iodophenoxy)piperidine by 4-(4-iodophenoxy)-1-isopropylpiperidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:35])([CH3:34])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH:30]([NH:29][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:34])([CH3:35])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)=[O:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 2-(4′-isopropylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (940 mg, 2 mmol) in methanol (15.0 mL) and tetrahydrofuran (16.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(4′-isopropylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (795 mg, 90%) as a white solid: LC/MS m/e calcd for C28H30N2O3 (M+H)+: 443.56, observed: 443.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCc1ncc(Cl)cc1Cl
Reactant: Clc1cc(I)ccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Clc1cnc(COc2ccnc(Cl)c2)c(Cl)c1
Temperature: 105 °C
Yield: 38.2 %

Procedure:
(3,5-Dichloropyridin-2-yl)methanol (2.00 g, 10.4 mmol), 2-chloro-4-iodopyridine (2.49 g, 10.4 mmol), cesium carbonate (4.41 g, 13.5 mmol), CuI (1.97 g, 10.4 mmol) and 1,10-phenanthroline (374 mg, 2.08 mmol) were stirred in toluene (20 mL) and degassed with a nitrogen stream for 10 minutes. The mixture was heated to 105° C. for 16 h, allowed to cool and filtered through a silica plug eluting with ethyl acetate. The filtrate was concentrated, and the resulting residue was purified by column chromatography (80 g ISCO column column eluting with ethyl acetate/hexanes; gradient 100% hexanes to 40% ethyl acetate) to provide the title compound (1.15 g, 38%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=2.1 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.88-6.85 (dd, J=5.8, 2.2 Hz, 1H), 5.31 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](=[O:7])[N:6]=1.[CH2:8](O)[CH:9]([CH3:11])[CH3:10]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH:9]([CH3:11])[CH3:10]
Reactant: O=C1C=CC(O)=N1
Reactant: CC(C)CO
Product: CC(C)COC1C=CC(=O)N1
Temperature: 50 °C

Procedure:
A mixture of 3 g of 5-hydroxy-2H-pyrrol-2-one and 1.5 g of Amberlite IR 120 H in 60 cm3 of isobutanol, is heated to 50° C. for 3 hours, then cooled and filtered, and the solvent is evaporated. After chromatographing the residue on silica (eluent: ethyl acetate), 4 g of the expected product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH:32]1(I)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].CC#N>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:10][C:9]([CH:13]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: IC1CCCC1
Reactant: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1cnc(C(C)N2CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)nc1OC1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-6-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester (90 mg, 0.2 mmol), cyclopentyl iodide (46 μL, 0.4 mmol), and potassium carbonate (138 mg, 1 mmol) in DMF (1 mL) was heated to 90° C. for 1 day. The reaction mixture was then filtered and purified by HPLC (in the absence of TFA) to yield the product. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.58 (m, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.84 (m, 1H), 3.04 (m, 4H), 2.73 (m, 4H), 1.83 (m, 8H), 1.40 (m, 6H); HPLC ret. time 2.80 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 519.5 (M+1)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:13]1[C:14]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]2)=[N:15][C:16]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:17][C:18]=1[O:19][CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](I)I.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:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:1][C:2]([C:13]3[C:14]([NH:27][C@@H:28]4[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]4)=[N:15][C:16]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:17][C:18]=3[O:19][CH3:20])=[N:3][C:4]=2[CH:9]=1)#[N:11]
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Reactant: N#Cc1ccc2scnc2c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C#N)ccc2s1

Procedure:
Following the same procedure as in step 3 of Example 121 using 1,3-benzothiazole-5-carbonitrile (56.1 mg, 0.35 mmol, 1.80 equiv), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.19 mmol, 1.00 equiv), copper iodide (6.7 mg, 0.035 mmol, 0.18 equiv), cesium Carbonate (0.37 g, 6.00 equiv, 1.14 mmol) and Pd(PPh3)4 (40.4 mg, 0.035 mmol, 0.18 equiv) in DMF (6.0 mL). The crude product was purified by flash chromatography on silica gel, eluting with a mixture of 10-20% ethyl acetate in petroleum ether to give the title compound as a white solid. MS m/z [M+H]+ (ESI): 552.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)([OH:5])=[O:3]
Reactant: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)OCC)c2)cc1CCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(Oc2cccc(C(=O)O)c2)cc1CCC(=O)O
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A solution of 510 mg of 5-(3-ethoxycarbonylphenoxy)-2-(decyloxy)benzenepropanoic acid in 20 ml of ethanol was treated with an excess of potassium hydroxide in a small amount of water. After stirring for 18 hours, the solution was concentrated in vacuo. Diethyl ether and water added, the layers were separated, and the aqueous layer was acidified with lN hydrochloric acid. The aqueous layer was extracted with diethyl ether, and this extract was dried over sodium sulfate and concentrated in vacuo. Two crystallizations from ethyl acetate/hexane provided 200 mg of the desired title product, m.p. 102°-104° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[CH2:30]([O:2][C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=[O:3])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccccc3)(CC1)CC2
Reaction time: 1 h
Yield: 79.8 %

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) was dissolved in N,N-dimethylformamide (1.0 mL) and cesium carbonate (45.3 mg) was added to the solution. Benzyl bromide (17.5 mg) in N,N-dimethylformamide (0.5 mL) was then added while the mixture was chilled in an ice bath and the mixture was stirred for 1 hour. Subsequently, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-(4-benzyloxycarbonyl bicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.6 mg).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.S(Cl)(Cl)=O.[CH3:24][C@@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26]O>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH2:24][C@@H:25]([CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCCCCC[C@H](C)CO
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: O=S(Cl)Cl
Product: CCCCCC[C@H](C)COC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
4'-Acetoxybiphenyl-4-carboxylic acid (5.80 g) was converted to an acid chloride using thionyl chloride, and the acid chloride was reacted with (S)-2-methyloctanol. The reaction mixture was extracted with diethyl ether, and the ethereal layer was thoroughly dried. Benzylamine was added thereto in small portions at room temperature. Hydrochloric acid was further added thereto, and the mixture was washed with water. The solvent was removed from the reaction mixture by distillation, and the resulting crude product was decolored by passing through a silica gel column (solvent: n-hexane-ethyl acetate mixture) and recrystallized from n-hexane to obtain 6.2 g of (S)-2-methyloctyl 4'-hydroxybiphenyl-4-carboxylate as white crystals having a melting point of 89° C.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][CH:7](/[CH:10]=[C:11](\[C:22]3[NH:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[CH:23]=3)/[C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH2:6]2)[O:4]CC1>[Pd].CO>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:22]2[NH:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[CH2:10][CH:7]2[CH2:8][CH2:9][C:5](=[O:4])[CH2:6]2)=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)c1ccc(/C(=C/C2CCC3(C2)OCCO3)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 6.3 %

Procedure:
A mixture of (Z)-2-[2-(1,4-dioxa-spiro[4.4]non-7-yl)-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (enantiomer 1, prepared as in Example 78, 140 mg, 0.33 mmol) and 10% palladium on activated carbon (50 mg) in methanol (125 mL) was heated at 50° C. under hydrogen (50 psi) for 96 h. The mixture was cooled to 25° C., the catalyst was filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.05% trifluoroacetic acid in water) afforded 3-[2-(4-methanesulfonyl-phenyl)-2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-cyclopentanone (diastereomer 1, 8 mg, 6%): LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 383.0; 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=4.5 Hz, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.63 (d, J=7.8 Hz, 2H), 7.05 (dd, J=7.7, 4.9 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 4.75-4.84 (m, 1H), 4.59 (br. s., 1H), 4.38 (t, J=7.8 Hz, 1H), 3.08 (s, 2H), 2.37-2.49 (m, 1H), 2.05-2.30 (m, 4H), 1.88-1.99 (m, 1H), 1.58-1.71 (m, 1H), 1.22-1.38 (m, 1H), 0.90 (t, J=6.6 Hz, 1H).
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)C(Cl)=O.CC1C=C(C=C(C)C=1)C(Cl)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:46]=[C:47]([Cl:49])[CH:48]=1)[C:27]([C:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44]C)=[CH:40][CH:39]=1)=[O:28]>>[Cl:49][C:47]1[CH:46]=[C:26]([CH:25]=[C:24]([Cl:23])[CH:48]=1)[C:27]([C:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][C:30]=1[C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)=[O:28]
Reactant: COc1ccc(-c2oc3ccccc3c2C(=O)c2cc(Cl)cc(Cl)c2)cc1
Agent: Cc1cc(C)cc(C(=O)Cl)c1
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Product: O=C(c1cc(Cl)cc(Cl)c1)c1c(-c2ccc(O)cc2)oc2ccccc12

Procedure:
Substitution of 3,5-dichlorobenzoyl chloride in the procedure of Example 7 for 3,5-dimethylbenzoyl chloride followed by demethylation of the 3-(3',5'-dichlorobenzoyl)-2-p-methoxyphenylbenzofuran as described above gave 3-(3',5'-dichlorobenzoyl)-2-p-hydroxyphenylbenzofuran.