Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=1)[CH2:11]2
Reactant: CCCCc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 4-butyl-benzylamine (0.088 mL, 0.5 mmol), and K2CO3 (0.083 g, 0.6 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-butyl-benzyl)-2,3-dihydro-isoindol-1-one (0.063 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.88 (t, 3H), 1.34 (m, 2H), 1.56 (m, 2H), 2.58 (t, 2H), 4.16 (s, 2H), 4.76 (s, 2H), 7.14-7.36 (m, 6H), 7.85 (d, 1H). GC-MS: m/z 405 (M)+, 348(M−57)+.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:15]=[O:16]>>[O:1]([CH2:8][CH:9]1[O:12][C:15](=[O:16])[NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(O)COc1ccccc1
Reactant: CN(C)C=O
Product: O=C1NCC(COc2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
422 mg of N,N'-carbonyldiimidazole were added, whilst ice-cooling, to a solution of 500 mg of 3-phenoxy-2-hydroxypropylamine in 5 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting concentrate. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using ethyl acetate as the eluent, to give 490 mg of the title compound, melting at 110° C. to 111° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH3:12])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][NH:11][CH3:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CNC(=O)CCC1CC=CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCCC1CC=CCC1
Yield: 66 %

Procedure:
A solution of 3-cyclohex-3-enyl-N-methyl-propionamide (15.5 g, 92.7 mmol) in 55 ml of tetrahydrofuran was added dropwise over a period of 25 min to a suspension of lithium aluminium hydride (95% purity, 5.3 g, 139 mmol, corrected) in 120 ml of tetrahydrofuran at 0° C. under stirring. The mixture was refluxed for 4 hours, stirred overnight at room temperature and quenched with 2 M aqueous NaOH, diluted with tetrahydrofuran, stirred and filtered. The filtrate was concentrated and the residue was acidified with 1 M aqueous HCl and washed with dichloromethane. The aqueous phase was basified with 1 M aqueous NaOH, and extracted with ethyl acetate. The organic extract was dried and concentrated to obtain the title compound (9.38 g, 66% yield) as pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@H]1CC[C@@H](CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(cis-4-Amino-cyclohexyl)-methanol (73 mg, 0.56 mmol) and triethylamine (225 μl, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (98.7:1.3:0.13, by volume). The product was triturated with ethyl acetate (3 ml) to give 5-fluoro-N-(cis-4-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (111 mg) as a white solid.
Reaction SMILES: C(Cl)Cl.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1B(O)O.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([Cl:28])=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:28][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([C:5]2[O:4][CH:8]=[CH:7][CH:6]=2)=[N:14][CH:15]=1
Reactant: OB(O)c1ccco1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1cnc(-c2ccco2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Yield: 5 %

Procedure:
The mixture of Pd(dppf)Cl2.CH2Cl2 (100 mg, 0.12 mmol, 0.15 eq), furan-2-ylboronic acid (116 mg, 1.04 mmol, 1.3 eq), 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (215 mg, 0.80 mmol, 1.0 eq) and aq Na2CO3 (10 mL) in dioxane (20 mL) was heated to 95° C. for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, and extracted with THF. The combined layers were purified by prep-HPLC to afford compound 5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(furan-2-yl)pyrimidin-4-amine (Compound 164) (12 mg, 9%). LC-MS (m/z)=302 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.73-0.76 (m, 2H), 0.95-0.98 (m, 2H), 1.93-1.97 (m, 1H), 6.53 (s, 1H), 6.68-6.70 (m, 1H), 7.15 (d, J=2.8 Hz, 1H), 7.91 (s, 1H), 8.41 (s, 1H), 9.24 (s, 1H), 12.24 (s, 1 Hz).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[C:29](=[O:33])[C:30]([NH2:32])=[O:31])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:32][C:30](=[O:31])[C:29]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[CH2:27][CH3:28])=[O:33]
Reactant: CCc1c(C(=O)C(N)=O)c2cc(OCCCC(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C(=O)C(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 63.1 %

Procedure:
A solution of 450 mg (0.97 mmol) of 4-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid tert-butyl ester in 75 mL of methylene chloride and 1 mL of trifluoroacetic acid was stirred at room temperature for 2.25 hours and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with EtOAc to give 250 mg (63% yield) of 4-([3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp 173-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=2[N:25]=[N:24]1)([CH3:22])[CH3:21]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:30]1[CH:29]=[CH:28][C:27]2[N:23]([CH:20]([CH3:21])[CH3:22])[N:24]=[N:25][C:26]=2[CH:31]=1)=[O:33]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: CC(C)n1nnc2cc(C(=O)O)ccc21
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)nnn2C(C)C

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 1-isopropyl-1H-benzotriazole-5-carboxylic acid. MS: 447.3 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=2)[N:19]=1.C(N(CC)CC)C>>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:31]1[CH2:32][CH2:33][O:34][C@@H:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:19]=[C:18]([CH3:17])[O:22][N:21]=3)=[CH:24][CH:25]=2)[CH2:30]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: Cc1nc(-c2ccc([C@H]3CNCCO3)cc2)no1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc([C@H]3CN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (9.80 g, 44.0 mmol) and (2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholine hydrochloride (13.3 g, 47.2 mmol) was added triethylamine (13.4 g, 132 mmol) at room temperature, and the solution was stirred at room temperature for 4 hours. After the solution was concentrated under reduced pressure, the resulting crude product was washed with water, dried under reduced pressure to afford 3-methyl-2-((2S)-2-(4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)morpholino)-6-(pyrimidin-4-yl)pyrimidin-4 (3 H)-one (the compound of the present invention, 18.0 g, 89%).
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[C:14]1([N:20]2[C:24]([SH:25])=[N:23][N:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].O>CN(C)C(=O)C>[C:7]1(=[O:8])[N:3]([CH2:2][S:25][C:24]2[N:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=[N:22][N:23]=2)[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CSc1nnnn1-c1ccccc1
Yield: 72 %

Procedure:
A solution of 2.40 g N-(bromomethyl)phthalimide (0.010 mol) and 2.00 g 1-phenyl-1H-tetrazole-5-thiol, sodium salt (0.010 mol) in 20 ml N,N-dimethylacetamide was stirred 0.5 hours. The slurry was then poured into water extracted with ethyl acetate, dried and concentrated in vacuo. The solid obtained was recrystallized from ethyl acetate/hexane to give 2.43 g (72.0%) of a colorless solid, m.p. 146°-7° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([O:21][CH3:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:37]([Si:41]([CH3:52])([CH3:51])[O:42][CH2:43][CH2:44][N:45]1[CH:49]=[CH:48][C:47]([NH2:50])=[N:46]1)([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C)C=O>[C:37]([Si:41]([CH3:52])([CH3:51])[O:42][CH2:43][CH2:44][N:45]1[CH:49]=[CH:48][C:47]([NH:50][C:8](=[O:9])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:46]1)([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
In a round bottom flask under argon was placed (R)-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionic acid (prepared in Example 100, 61 mg, 0.19 mmol) which was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (2 drops). To this solution was then added a solution of oxalyl chloride in methylene chloride (2.0 M solution, 100 μL, 0.20 mmol). Upon addition there was gas evolution. The reaction was stirred for 30 min at 25° C. After such time the reaction was cooled to 0° C. in an ice bath and 2,6-lutidine (47 μL, 0.38 mmol) and the reaction was stirred for 30 min at 0° C. To the solution was then added 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 45 mg, 0.19 mmol). The reaction was then warmed to 25° C. and stirred for 2 h. After this time, the reaction was quenched with a small amount of methanol and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes) to afford (R)—N-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (15 mg, 15%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][C:8](N)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N([O-])=O.[Na+].[ClH:19]>O.[Cu]Cl>[Cl:19][C:8]1[S:9][C:10]2[C:2]([CH3:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Cl
Reactant: Cc1c([N+](=O)[O-])ccc2nc(N)sc12
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Suspend 7-methyl-6-nitro-benzothiazol-2-ylamine (5.17 g, 24.7 mmol) in conc. HCl (70 mL) and water (70 mL). Add copper (1) chloride (542 mg, 5.47 mmol) followed by slow addition of sodium nitrite (17.4 g, 252 mmol). Stir at rt for 2 h and then add water (100 mL). Filter the solid and dry in a vacuum oven at 40° C. overnight to yield 4.45 g (79%) of the title compound: 1H NMR δH (400 MHz, DMSO) 8.16 (d, J=9.2 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 2.71 (s, 3H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCCc1ccccc1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCCc2ccccc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 3-phenyl-propylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 1.93 (p, 2, J=7), 2.64 (t, 2, J=7), 2.99 (s, 3), 3.53 (t, 2, J=2), 4.10 (s, 2), 4.60 (s, 2), 7.02–7.28 (overlapping m, 9). 13C (125 MHz, CDCl3) δ: 29.77, 33.05, 34.56, 42.81, 48.79, 51.47, 109.25, 115.66, 115.83, 126.14, 128.30, 128.49, 129.34, 129.40, 132.16, 132.79, 140.88, 152.46, 161.39, 163.34, 165.02, 166.08.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH2:13][NH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:26]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:14][CH2:13][CH2:12][C:11]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(-c2ccccc2)cc1)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 22 h

Procedure:
The intermediate 2-biphenyl-4-yl-N-[2-(3,4-bis-benzyloxy-phenyl)-ethyl]-acetamide (1) was prepared as follows: To a stirred solution of 2.85 g (7.7 mmol) of 3,4-dibenzyloxyphenethyl amine and 1.49 g (7 mmol) of 4-biphenylacetic acid in 20 ml of anhydrous dimethylformamide at 0° C., 2.5 ml (17.7 mmoles) of triethyl amine was added dropwise and then 1.4 ml (7.7 mmol) of diethyl cyanophosphonate (90% purity) was added dropwise. The reaction mixture was stirred for 22 hours and allowed to reach room temperature, and then it was poured into 300 ml of water. The precipitated solid was separated on a glass filter funnel, washed with water (3×70 ml), and air-dried overnight. This solid was recrystallized using hexanes/ethanol mixture to provide 3.1 g (84%) of grayish crystals, mp 142-144° C.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH2:21]([N:23](CC)CC)C>C(Cl)Cl>[CH3:21][NH:23][C@@H:9]1[C:14]2[C:15](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C@H:8]1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O[C@@H]1Cc2ccccc2[C@H]1N1CCCC1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1

Procedure:
A solution of methanesulfonyl chloride (6 g) in methylene chloride (50 ml) was added dropwise rapidly to a stirred and cooled (0°-5°) solution of trans-2,3-dihydro-2-hydroxy-(pyrrolidin-1-yl)-1H-indene (5.5 g) and triethylamine (6 ml) in methylene chloride (200 ml). After the addition was complete, the mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was treated with a 33% solution of methylamine in ethanol (100 ml) and the mixture was stirred at reflux for 3 hours and evaporated under reduced pressure. The residue was treated with water and extracted twice with ether. The combined ether extracts were washed successively with 2N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated under reduced pressure to yield a liquid which was distilled under vacuum to give trans-2,3-dihydro-1-methylamino-2-(pyrrolidin-1-yl)-1H-indene (6.3 g) b.p. 118°-120°/0.25 torr.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: [H][H]
Reactant: O=C(NCCCCc1ccccc1OCC(O)CO)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccccc1OCC(O)CO
Yield: 67.2 %

Procedure:
Cbz-protected amine 31 (2.1 g, 5.6 mmol) was dissolved in methanol (50 mL) and Pd/C (0.46 g, 5% wet.) was added in methanol (20 mL). The reaction mixture was stirred for 3 h at 1 atmosphere of hydrogen, then the solution was filtered through a pad of silica gel. The solvent was then evaporated to give free amine 32 (0.9 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (m, 2H), 1.50 (m, 2H), 2.92 (m, 1H), 3.22–4.05 (br s, 4H), 3.43 (m, 2H), 3.93 (m, 1H) 6.82 (d, 2H), 7.07 (d, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:15]([O:14][C:12]([NH:11][C:5]1([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][N:8]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])(=[O:28])=[O:27])[CH2:7][CH2:6]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A mixture of 2 g (7.8 mmol) 4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester, 1.72 g (8.1 mmol) 2-chlorobenzenesulfonyl chloride and 2.36 g (23 mmol) NEt3 in 30 mL DCM was stirred at room temperature over night. DCM and NaHCO3 aq. was added and the organic phase was dried with MgSO4 and evaporated. The ester (MS (m/e): 433.3 [(M+H)+]) was used without further purification. 3 g of the crude product was dissolved in methanol and 2.7 mL KOH aq. (5M), 30 mL water and 10 mL THF was added and the mixture was stirred at 55° C. for 5 h. The organic solvents were removed under vacuum and acetic acid was added. The mixture was extracted with ethyl acetate and the combined organic phases were washed with water, dried with MgSO4 and evaporated to yield 2.87 g of the title compound as white foam. MS (m/e): 419.1 [(M+H)+]
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 72.3 %

Procedure:
Following the procedure of Example 1(c), but reacting 2.8 g (6.7 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 950 mg (4.4 mmol) of methyl 4-bromobenzoate, 1.6 g (72%) of the expected compound were obtained.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)OC(C)(C)C)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate (445 mg, 1.22 mmol, 1.00 equiv), tert-butyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (prepared according to PCT Application WO2010/048207A2) (378 mg, 1.46 mmol, 1.20 equiv), potassium carbonate (542 mg, 3.92 mmol, 3.22 equiv), N,N-dimethylformamide (10.0 mL). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×15 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 0.52 g (81%) of tert-butyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C21H17F5NOS3, 427.1 (M+H). found 427.1.