Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[OH:4][CH2:3][C@H:2]([NH:1][C:12](=[O:11])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R)-2-amino-2-phenylethanol (400 mg, 2.91 mmol) in CH2Cl2 (15 mL) was added BOC2O (636 mg, 2.91 mmol) and DIPEA (507 μL, 2.91 mmol). The reaction was stirred at room temperature for 18 hours, diluted with EtOAc (75 mL) and washed with H2O, brine, 1N HCl, brine, saturated NaHCO3, and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 50% EtOAc/hexanes afforded tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate. Rf=0.23 (40% EtOAc/hexane). 1H NMR (CDCl3, 600 MHz) δ 7.27-7.37 (m, 5H), 5.27 (bs, 1H), 4.78 (bs, 1H), 3.83 (bs, 2H), 2.46 (bs, 1H), 1.44 (bs, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]1[C:12]2[CH:13]=[CH:14]C=CC=2N=C1>>[O:8]1[CH2:12][CH:13]1[CH2:14][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: c1ccc2ocnc2c1
Product: c1cncc(OCC2CO2)c1

Procedure:
Compound 73 was prepared in the manner of compound 6 substituting 3-hydroxypyridine for compound 8 in part C-5 of Example 1.
Reaction SMILES: C(Cl)CCl.[CH3:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[C:22]([C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30](O)=[O:31])([CH3:26])[CH3:25])#[N:23].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:22]([C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([CH3:5])=[C:7]([B:13]2[O:14][C:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[O:17]2)[CH:8]=1)=[O:31])([CH3:26])[CH3:25])#[N:23]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccn1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(C(C)(C)C#N)c2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
EDC (1.3 equiv.) was added to a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.), 2-(2-cyanopropan-2-yl)isonicotinic acid (1.2 equiv.), HOAt (1.3 equiv.) in DMF (0.19 M). The mixture was stirred at ambient temperature 3 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated to yield 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isonicotinamide in 97% yield. LCMS (m/z) (M+H)=406.2, Rt=1.10 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][C@@H:37]([C:39]([OH:41])=O)[CH3:38])[C:33]3[C:28](=[CH:29][C:30]([CH3:42])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.FC1C(O)=C(F)C(F)=C(F)C=1F.FC(F)(F)C(O)=O.[CH:67]1([NH:71][C:72]([C@@H:74]2[CH2:78][CH2:77][CH2:76][NH:75]2)=[O:73])[CH2:70][CH2:69][CH2:68]1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][C@H:37]([CH3:38])[C:39]([N:75]3[CH2:76][CH2:77][CH2:78][C@H:74]3[C:72](=[O:73])[NH:71][CH:67]3[CH2:68][CH2:69][CH2:70]3)=[O:41])[C:33]3[C:28](=[CH:29][C:30]([CH3:42])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)O)c3ccc(C)cc3n2)CC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 250 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[4-((R)-1-carboxy-ethoxy)-7-methyl-quinoline-2-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 2.5 ml of DCM, 96 mg of EDC, 92 mg of pentafluorophenol was added and the reaction mixture was stirred for 2 h. Then, 117 mg of (S)-Pyrrolidine-2-carboxylic acid cyclobutylamide trifluoroacetate and 192 mg of NEM in 2 ml of DCM was added. After 2 h the reaction mixture was diluted with water. After filtration through a chem Elut® cartridge by eluting with ethyl acetate the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[C:14]1([C:20]2[C:21]3[C:26]([C:27]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:28]4[C:33]=2[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>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(=O)([O-])[O-].[Na+].[Na+]>[C:14]1([C:20]2[C:33]3[C:28]([C:27]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]4[C:21]=2[CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:3]=2)[CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(-c2cccc(-c3ccc4c(-c5ccccc5)c5ccccc5c(-c5ccccc5)c4c3)n2)cc1
Yield: 84.6 %

Procedure:
2-Bromo-6-phenylpyridine 2.5 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.25 g (0.22 mmol) were dissolved in 60 mL of 12-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 4.5 g (yield: 84%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that the measured value m/e was 483 versus a molecular weight of 483.20 and that it was the aimed compound 1
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:31])([F:30])[CH:27]1[O:29][CH2:28]1>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:28][CH:27]([OH:29])[C:26]([F:31])([F:30])[F:25])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: FC(F)(F)C1CO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(CC(O)C(F)(F)F)c2ccccc2-c2ccccc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
((S)-6-Oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-carbamic acid tert-butyl ester (108 mg, 0.33 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (762 mg, 6.7 mmol) were dissolved in DMF (2 ml) and heated to 90° C. for 4 h in a sealed tube. After addition of another 500 mg of 1,1,1-trifluoro-2,3-epoxypropane, heating was continued for 18 h. The mixture was diluted with ethyl acetate and water (10 ml each), separated and the aqueous phase extracted twice with each 10 ml ethyl acetate. The combine organic phases are dried over magnesium sulfate and evaporated to dryness. Chromatography (silica, eluent heptanes/ethyl acetate gradient from 1 to 30%) afforded the title compound as white solid (76%). MS: m/e=437(M+H+).
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[NH:25]N>>[ClH:1].[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[C:19]2[C:20]=1[C:4]([CH2:5][CH2:6][NH2:7])=[CH:3][NH:25]2
Reactant: Cc1ccc(C)c(NN)c1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: Cc1ccc(C)c2c(CCN)c[nH]c12

Procedure:
4,7-dimethyltryptamine hydrochloride was prepared (0.94 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 2,5-dimethyl-phenylhydrazine hydrochloride (16.8 g) as starting material. ##STR47##
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.[CH3:31][S:32]SC.[Cl-].[NH4+]>C1COCC1>[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([S:32][CH3:31])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CSSC
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 0.250 g, 0.664 mmol) was added to THF (30 mL) and cooled to −78° C. MeLi (0.519 mL, 0.831 mmol) was slowly added, and the reaction mixture was stirred for 10 minutes. Butyllithium (0.332 mL, 0.831 mmol) was added, and the reaction mixture was stirred for 15 minutes. 1,2-Dimethyldisulfane (0.438 g, 4.65 mmol) was added, and the reaction mixture was stirred for 15 minutes. Ammonium chloride was added, and the reaction mixture was extracted with CH2Cl2. The organic layer was purified by silica gel (10-20% EtOAc in hexanes) to give 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(methylthio)pyridin-2-amine (0.170 g, 74.5% yield). A portion of this compound was dissolved in dichloromethane, 2M HCl in ether was added, and the mixture was concentrated to give the title compound. 1H NMR (CDCl3) δ 12.30 (bs, 1H), 7.84 (m, 1H), 7.57 (d, 2H), 7.39 (m, 2H), 7.32 (m, 1H), 7.15 (m, 1H), 6.38 (s, 1H), 5.35 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H). Mass spectrum (apci) m/z=344.0 (M+H-HCl).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][OH:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OCCCCl
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCOc1ccc(-n2ccnc2)cc1

Procedure:
A stirred mixture of 4(1H-imidazol-1-yl)phenol (16.0 g, 0.10 mole), 3-chloropropanol (19.0 g, 0.20 mole), potassium carbonate (28 g, 0.20 mole) and methyl ethyl ketone (100 ml) was heated at reflux temperature for 24 hr. The reaction mixture was cooled, filtered, and the filtrate concentrated. The residue was partitioned between ethyl acetate and 0.01N sodium hydroxide solution. The ethyl acetate layer was dried (magnesium sulfate), diluted with ether, and the solid precipitate collected. The solid was recrystallized from methyl isobutyl ketone to obtain 10.0 g (46%), mp 76°-78° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Br)=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]1[CH:61]=[CH:60][C:39]([CH2:40][CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46](B3OC(=O)CN(C)CC(=O)O3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C(O[Pd]OC(=O)C)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:46]3[CH:45]=[CH:44][C:43]([O:42][CH2:41][CH2:40][C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:61][CH:60]=4)=[CH:48][CH:47]=3)=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[C:15]=2[C@H:23]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1Br
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(Cc3ccccc3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
The diacetoxypalladium (11.3 mg, 0.05 mmol) was added to a argon purged and degassed solution of (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-bromo-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (267 mg, 0.502 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (205 mg, 0.553 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (41 mg, 0.10 mmol), and potassium phosphate tribasic (800 mg, 3.77 mmol) in dioxane (4 mL) and water (0.8 mL) and stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-35% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(4-(4-benzylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 131 mg (39%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.43-7.37 (m, 2H), 7.24-7.22 (m, 2H), 7.18-7.12 (m, 4H), 7.10 (t, J=7.3 Hz, 2H), 6.99-6.92 (m, 3H), 5.92 (s, 1H), 4.97-4.92 (m, 1H), 4.21 (t, J=6.2 Hz, 2H), 3.37-3.37 (m, 4H), 3.06 (t, J=6.2 Hz, 2H), 2.46 (br. s, 2H), 2.42 (s, 3H), 2.02 (s, 3H), 1.70 (t, J=8.8 Hz, 1H), 1.45-1.43 (m, 1H), 1.37-1.34 (m, 1H), 1.29-1.22 (m, 2H), 1.18 (d, J=6.2 Hz, 3H), 1.14 (d, J=3.2 Hz, 3H), 1.09 (m, 9H). UPLC (M+H)=667.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C1C(/C(/C2[C-]=CC(Cl)=CC=2)=N\O)=CC=C(Cl)C=1.C1C(/C(/C2[C-]=CC(Cl)=CC=2)=N\O)=CC=C(Cl)C=1.[Cl-].[Cl-].[Pd+2].[Pd+2].CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:40]2[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=2)=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(Cl)ccc3OCc3ccccc3)ccn2)CC1
Agent: [Pd+2]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)ccc3OCc3ccccc3)ccn2)CC1
Temperature: 130 °C
Yield: 48.5 %

Procedure:
tert-Butyl 4-(4-(2-(benzyloxy)-5-chlorophenyl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 116, 1.10 g, 2.29 mmol), 4-(trifluoromethyl)phenylboronic acid (866 mg, 4.58 mmol), di-μ-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino)methyl]phenyl]palladium (II) dimer (93 mg, 0.114 mmol), tri-tert-butylphosphonium tetrafluoroborate (66 mg, 0.228 mmol), potassium carbonate (635 mg, 4.60 mmol) and tetrabutyl ammonium hydroxide (1M in methanol, 0.46 mL, 0.46 mmol) were combined in a microwave vial. Dimethylformamide (12 mL) was added and the vial was sealed. The mixture was heated at 130° C. for 2 hours in a microwave and then partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, washed with brine (5 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in dimethylformamide (12 mL) and 4-(trifluoromethyl)phenylboronic acid (866 mg, 4.58 mmol), di-mu-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino)methyl]phenyl]palladium (II) dimer (93 mg, 0.114 mmol), tri-tert-butylphosphonium tetrafluoroborate (66 mg, 0.228 mmol), potassium carbonate (635 mg, 4.60 mmol) and tetrabutyl ammonium hydroxyde (1M in methanol, 0.46 mL, 0.46 mmol) were added. The mixture was heated at 130° C. for 1 hour in microwave and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oil residue was purified on silica gel by Biotage (5% to 80% ethyl acetate in heptane over 20 CV) to give the title compound as a white solid (655 mg, 48%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[C:9]([O:13][CH2:14][O:15][CH3:16])[CH:8]=[C:7]([O:17][CH2:18][O:19][CH3:20])[C:6]=1[C:21](=[O:30])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:23]([NH:22][C:21](=[O:30])[C:6]1[C:7]([O:17][CH2:18][O:19][CH3:20])=[CH:8][C:9]([O:13][CH2:14][O:15][CH3:16])=[C:10]([CH2:11][CH3:12])[C:5]=1[CH2:4][CH2:3][OH:2])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCc1c(OCOC)cc(OCOC)c(C(=O)NCc2ccccc2)c1CC(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)NCc2ccccc2)c1CCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
The above-obtained [2-(N-benzylcarbamoyl)-6-ethyl-3,5-bis(methoxymethoxy)phenyl]acetic acid methyl ester (46 mg, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0° C. The obtained solution was added with 1.0 mol/L lithium aluminum hydride-tetrahydrofuran solution (0.20 mL, 0.20 mmol) followed by stirring at 0° C. for 0.5 hour. The reaction mixture was added with saturated aqueous sodium sulfate solution, and was extracted with ethyl acetate 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain N-benzyl-3-ethyl-2-(2-hydroxyethyl)-4,6-bis(methoxymethoxy)benzamide (30 mg, 74%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][C:13]1[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)=O)C.C(OCC)(=O)C.O>O1CCCC1>[OH:9][CH2:10][CH2:12][C:13]1[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1
Reactant: CCOC(=O)CC1=CCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(CCO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.22 g (32.1 mM) of lithium aluminum hydride in 150 ml of tetrahydrofuran was added a solution of 8.201 g (32.122 mM) of tert-butyl 3-(ethoxycarbonylmethyl)-2,5-dihydropyrrole-1-carboxylate in 50 ml of tetrahydrofuran dropwise under ice-cooling and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added ethyl acetate with ice-cooling to decompose the excess lithium aluminum hydride, and water was added until a white precipitate had formed. The precipitate was filtered off with the aid of celite and the celite was washed with ethyl acetate. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](O)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: OCc1ccccc1
Reactant: CC(C)(C)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)OCc1ccccc1
Yield: 62 %

Procedure:
To a suspended toluene (2 ml) solution of 2-chloro-1-methylpyridinium iodide (306 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), pivalic acid (102 mg, 1.0 mmol) and tri-n-butylamine (444 mg, 2.4 mmol) in toluene (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl pivalate was isolated in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:28]([N:12]([CH2:11][CH2:10][NH:9][CH2:8][CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)[S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:14])=[O:15])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(CCNCC=Cc2ccc(Cl)cc2)S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
0.4 g of the crystals obtained in Example 172, 0.276 g of anisyl alcohol and 0.524 g of triphenylphosphine were dissolved in 10 ml of tetrahydrofuran, and to the solution was added dropwise a solution of 0.404 g of diisopropyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. The reaction mixture was warmed to a room temperature and was allowed to stand overnight and then evaporated under a reduced pressure to remove the solvent. The resulting residue was dissolved in 30 ml of ethyl acetate, and the mixture was extracted twice with 30 ml of 1N hydrochloric acid. The extract was alkalized with sodium bicarbonate and extracted twice with 30 ml of ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. The resulting residue was applied to a silica gel column and eluted with 1% methanol in chloroform, to obtain 0.22 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12]([OH:14])=O)=[CH:6][CH:5]=1.[F:33][CH:34]([F:37])[CH2:35][NH2:36]>>[F:33][CH:34]([F:37])[CH2:35][NH:36][C:12](=[O:14])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:9][CH:8]=1
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Reactant: NCC(F)F
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCC(F)F)c1ccc(OCCC(F)(F)F)cc1
Yield: 80.9 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (233 mg) prepared in Example 70 (70a) and 2,2-difluoroethylamine (49 mg) to give 214 mg of the title compound (white powder).