Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:17])[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[C:8]([Cl:15])[C:7]=2[Cl:16].O.[C:19]([OH:22])(=[O:21])[CH3:20]>C([O-])(=O)C.[Ag+]>[C:19]([O:22][CH2:2][CH2:3][C:4]1[C:5](=[O:17])[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[C:8]([Cl:15])[C:7]=2[Cl:16])(=[O:21])[CH3:20]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCl)=C2
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)=C2
Temperature: 105 °C

Procedure:
2-(2-Chloroethyl)-6,7-dichloro-5-methoxy-1H-inden-1-one (18.4 g, 0.0619 mole) and silver acetate (22.7 g, 0.1362 mole) were suspended in acetic acid (225 ml) and water (2 ml) and the mixture stirred and heated at 105° C. for 9 hours and at ambient temperature for 16 hours. The mixture was filtered and the residue on the funnel washed with ethyl acetate. The combined filtrate were evaporated in vacuo and the residue suspended in water. The mixture was extracted first with 10% tetrahydofuran in ether, then with methylene chloride and finally with ethyl acetate. The combined organic extracts were washed with water, then with brine. After drying over MgSO4 the combined organic extracts were evaporated in vacuo. The residue was treated with warm ethyl acetate (10 ml) and tetrahydrofuran (10 ml) and then cooled. The solid that formed was removed by filtration with an equal mixture of ethyl acetate and hexane and dried to give 2-(acetoxyethyl)-6,7-dichloro-5-methoxy-1H-inden-1-one, 8.1 g, m.p. 134°-136° C.
Reaction SMILES: C([NH:11][C:12](=[N:46]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:34]([NH:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:61]>[Pd].CO>[ClH:61].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@@H:17]([C:34]([NH:36][C@H:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][OH:39])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:46])=[O:33])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(N=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenylethyl)-arginine amide (0.250 g; from step (e) above), 10% Pd/C (200 mg) and, instead of HOAc, 50 mL of MeOH with 1 mL of concentrated HCl, yielding 69 mg of the title compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Mg]Br)C.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].N>[Cu]Br.C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:25][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#C[Si](C)(C)C
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [Cu]Br
Agent: CC[Mg]Br
Agent: N
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCc1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 0.67 h

Procedure:
To a solution of THF (20 mL) and trimethylsilylacetylene (850 μL) was added ethyl magnesium bromide (3M diethyl ether solution, 1.9 mL) at room temperature under a nitrogen atmosphere, which was stirred for 40 minutes at 65° C. The reaction solution was cooled to room temperature, after which copper(I) bromide (310 mg) and 4-benzyloxybenzyl chloride (81.0 g) were added to the reaction solution, which was stirred for 8 hours and 45 minutes at 65° C. A saturated aqueous ammonia chloride solution was added at room temperature to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=30:1) to obtain the titled compound (910 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:50])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][O:37][C:38]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:39])=[O:50])=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1CCNCC1
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)Oc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOC(=O)N1CCC(O)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 158.4 %

Procedure:
A solution of 4-hydroxypiperidine (2.21 g, 21.8 mmol) and triethylamine (17.5 mL, 91 mmol) in 100 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 3 (9.0 g, 18.2 mmol) in 100 mL of methylene chloride at room temperature. After the addition the reaction was stirred overnight at room temperature. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 13.16 g of a yellow oil. Purification of the oil on silica gel (230-400 mesh) using hexane-ethyl acetate as the eluent gave 5.87 g (71%) of the title compound as a white waxy solid, mp 48°-55° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH3:33]>CC(O)C>[NH2:33][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Solvent: CC(C)O
Product: Nc1nccn2c(C3CC(CO)C3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 110 °C

Procedure:
A solution of {3-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutyl}-methanol (compound of Formula II-B where Z=cyclobutyl and Q1=2-phenylquinolin-7-yl) (265 mg, 0.6 mmol) in 5 mL of iPrOH was cooled to −78° C. and charged with NH3 gas for 1 min. This sealed tube was equipped with a teflon O-ring, sealed and heated at 110° C. for 3 days. The mixture was cooled to −78° C. and the cap was removed. The salt was filtered off and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluting with 100% ethyl acetate→EtOAc:MeOH=90:10) to obtain the title compound as a light yellow solid, a mixture of cis and trans isomers in the ratio of 5:1; MS (ES+): m/z 422 [MH+]; 1H NMR (CDCl3, 400 MHz): δ=2.42-2.48 (m, 2H), 2.66-2.74 (m, 3H), 3.71-3.85 (m, 3H), 5.25 (br s, 2H), 7.10-7.19 (m, 2H), 7.46-7.57 (m, 3H), 7.91-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, J=8.6 Hz, 1H), 8.42, 8.44 (2×s, 1H, 5:1 ratio).
Reaction SMILES: [N:1]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][C@H:2]1[C:3]([N:5]([CH3:21])[C@@H:6]([C:17]([O:19]C)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>>[N:1]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][C@H:2]1[C:3]([N:5]([CH3:21])[C@@H:6]([C:17]([OH:19])=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 77 %

Procedure:
Condensation of BocProOH (4.63 g.) and MeDTrpOMe (5.00 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MeDTrpOMe in 69% yield. Demethylation of BocPro-MeDTrpOMe (6.33 g.) using aqueous sodium hydroxide gave BocPro-MeDTrpOH in 77% yield. Condensation of BocPro-MeDTrpOH (3.60 g.) and HPheOBz (3.70 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-PheOBz in 83% yield. Debenzylation of BocPro-MeDTrp-PheOBz (4.60 g.) by hydrogenation with palladium catalyst gave BocPro-MeDTrp-PheOH in 100% yield.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:30](=[O:31])[CH2:29][NH:28][CH2:27][C:26]1=[O:32])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(O)(C)C.CO>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:26](=[O:32])[CH2:27][NH:28][CH2:29][C:30]1=[O:31])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNCC1=O)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNCC1=O)[C@H](CCCc1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of 0.072 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-4-methyl-N-(2,6-dioxo-1-piperazinyl)valeramide in a mixture of 5 ml of isopropyl alcohol and 1 ml of methanol was treated with 0.030 g of p-toluenesulphonic acid monohydrate at 0° C. The mixture was left to warm to room temperature and was stirred overnight. Evaporation and trituration of the residue with diethyl ether gave 0.059 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,6-dioxo-1-piperazinyl)valeramide p-toluenesulphonate in the form of an off-white solid.
Reaction SMILES: Br[CH:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3](=[O:11])[C:4]([CH2:9][CH3:10])([CH3:8])[CH2:5][CH2:6]Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:2]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[C:3]2[C:4]([CH2:9][CH3:10])([CH3:8])[CH2:5][CH2:6][O:11]2)=[CH:14][CH:15]=1
Reactant: CCC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(C)CCOC1=C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 14 %

Procedure:
69.9 g (0.19 mole) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone, 26.2 g (0.38 mole) of imidazole and 52.4 g (0.38 mole) of potassium carbonate in 500 ml of toluene are heated at 90° C. for 10 hours. The reaction mixture is then allowed to cool and is poured onto 500 ml of water. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated. The residue is purified by column chromatography (ethyl acetate/cyclohexane=3:1). 8.5 g (14% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(3-ethyl-3-methyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5552 are obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]=2[CH2:18][CH2:19][CH3:20])=[O:12])=[CH:4][C:3]=1[CH3:25].Cl[CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].O>[OH:31][C@@H:28]([CH2:29][OH:30])[CH2:27][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]=2[CH2:18][CH2:19][CH3:20])=[O:12])=[CH:4][C:3]=1[CH3:25]
Reactant: CCCc1c(CC(C)C)csc1C(=O)CCc1cc(C)c(O)c(C)c1
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCc1c(CC(C)C)csc1C(=O)CCc1cc(C)c(OC[C@@H](O)CO)c(C)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 13.8 %

Procedure:
To a solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(4-isobutyl-3-propyl-thiophen-2-yl)-propan-1-one (108 mg, 0.301 mmol) in isopropanol (5 mL), 3 N aq. NaOH (3 mL) followed by (S)-3-chloro-1,2-propanediol (167 mg, 1.51 mmol) is added. The mixture is stirred at 70° C. for 4 h. After 4, 5, 6, 7 and 8 h an additional portion of (S)-3-chloro-1,2-propanediol (5×97 mg, 0.878 mmol) is added. After the last addition, stirring is continued at 60° C. for 16 h. The mixture is diluted with water and extracted with diethyl ether. The organic extract is dried over MgSO4, filtered and evaporated. The crude product is purified by prep. HPLC to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(4-isobutyl-3-propyl-thiophen-2-yl)-propan-1-one (18 mg) as an almost colourless resin; LC-MS: tR=1.09 min, [M+1]=433.40; 1H NMR (CDCl3): δ 7.08 (s, 1H), 6.87 (s, 2H), 4.11-4.03 (m, 1H), 3.90-3.70 (m, 4H), 3.14-3.06 (m, 2H), 2.94-2.82 (m, 4H), 2.60 (s br, 2H), 2.40 (d, J=7.0 Hz, 2H), 2.24 8s, 6H), 1.90-1.78 (m, 1H), 1.56-1.46 (m, 2H), 1.00 8t, J=7.0 Hz, 3H), 0.93 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH:40][C:42](=[O:44])[CH3:43])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NC(C)=O)C(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To (S)-2-Amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-butyric acid cyclopentyl ester (120 mg, 0.216 mmol) in DCM (2 ml) were added acetyl chloride (15 μL, 0.216 mmol) and triethylamine (33 μL, 0.238 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. then at room temperature for 1 hour. The crude mixture was concentrated under vacuum and purified by preparative HPLC to provide the title compound as a mono-TFA salt (67 mg, 52% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22](B5OC(C)(C)C(C)(C)O5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2].[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O.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:1]([C:3]1[CH:4]=[C:5]([CH:37]([CH3:39])[CH3:38])[C:6]2[O:10][C:9]([C:11]3[CH:35]=[CH:34][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][C:22]([CH2:46][C:45]5[CH:48]=[CH:49][C:42]([C:41]([F:51])([F:50])[F:40])=[CH:43][CH:44]=5)=[CH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(B5OC(C)(C)C(C)(C)O5)CC4)cc3)oc12
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+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CC=C(Cc5ccc(C(F)(F)F)cc5)CC4)cc3)oc12
Reaction time: 0.03 h
Yield: 13.5 %

Procedure:
To a mixture of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl]methyl}benzamide (70 mg, 0.133 mmol, INTERMEDIATE 9), 4-trifluoromethylbenzyl bromide (30 mg, 0.126 mmol), and 2M sodium carbonate (0.15 ml, 0.300 mmol) in toluene (2 ml), water (0.6 ml), and ethanol (0.25 ml) was added tetrakis(triphenylphosphine)palladium(0) (4 mg, 3.46 μmol). The mixture was microwaved at 100° C. in a sealed tube for 30 min, at which point LC/MS analysis showed a new peak at the product molecular weight. The organic phase of the reaction mixture was added directly to a 25 samplet and purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. This product was repurified by reverse-phase HPLC on a Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (9.4 mg, 0.017 mmol, 25.3% yield). Mass spectrum (ESI) 558.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8.5 Hz, 2H); 7.93 (d, J=8.5 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H); 7.53 (d, J=8.0 Hz, 2H), 7.51 (s, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.28 (br t, J=5.5 Hz, 1H), 5.48 (br s, 1H), 3.47 (septet, J=7.0 Hz, 1H), 3.44 (br t, J=6.0 Hz, 2H), 3.32 (s, 1H), 2.24 (m, 1H), 1.80-1.98 (m, 7H), 1.46 (d, J=7.0 Hz, 6H), 1.30-1.42 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[CH2:36][CH2:37][O:38]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[OH:35][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:36][CH2:37][OH:38])[CH:11]=1)[CH2:16][NH:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:23][CH:24]=2)[CH2:19]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)c(CCOCc3ccccc3)c1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(O)c(CCO)c1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
Ethyl 2-[(2S)-2-[[(2RS)-2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (200 mg) and 10% palladium on activated carbon (30 mg) was suspended in acetic acid (1.5 ml), and the suspension was stirred for 6 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtrated to remove the catalyst, and the filtrate was concentrated in vacuo. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: dichloromethane/ethanol=10/1) gave ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (Compound 3) (120 mg) as an amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:22][O:21][CH2:20][CH2:19][O:18][C@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:33][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:23])=[CH:32]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COCCO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: COCCO[C@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C1

Procedure:
The title compound was prepared from (3S)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 451.2 (MH+); HPLC Rf: 4.357 min.; HPLC purity: 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:9]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:10]=1[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)c1ccc(OC)cc1C(O)c1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ccc(OC)cc1Cc1cccc(F)c1
Reaction time: 8 h

Procedure:
To a solution of 2-[(3-fluorophenyl)(hydroxy)methyl]-4-methoxy-N-methylbenzamide (500 mg) in methanol was added 500 mg of Pd/C (10%). The reaction was stirred overnight under H2 (1 atm), then filtered through celite and concentrated to give 2-(3-fluorobenzyl)-4-methoxy-N-methylbenzamide, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl

Procedure:
A mixture of 2,3,5-trichlorobenzoic acid (90 g, 0.4M) and dimethylformamide (1 ml) in thionyl chloride (200 ml) was heated to reflux for 2 hours. The cooled solution was evaporated down in vacuo and the residue distilled under nitrogen. Yield 89.2 g (90%), b.p. 158°-160° C. at the pressure of 30 mm of mercury.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:19]#[CH:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC#N.CC#N.Cl[Pd]Cl.O.C(#N)C>[C:7]1(=[O:11])[C:8]2[C:4](=[CH:3][C:2]([C:20]#[C:19][CH2:18][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: C#CCOC1CCCCO1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C1CCc2cc(C#CCOC3CCCCO3)ccc21
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 5-bromo-1-indanone (10.0 g), cesium carbonate (40.3 g), 2-(2-propynyloxy)tetrahydropyran (10.0 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.40 g), bis(acetonitrile)palladium(II) dichloride (246 mg) and acetonitrile (200 ml) was stirred at 90° C. for 6 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (7.87 g) as a brown oil.