Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]5[O:21][C:20]([NH:22][CH2:23][C:24]6[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=6)=[N:19][N:18]=5)[CH:15]=4)[N:10]([S:32]([C:35]4[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=4)(=[O:34])=[O:33])[CH:9]=3)[CH:5]=[N:4][CH:3]=2)=[CH:45][CH:44]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(-c5ccc(F)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Yield: 36.3 %

Procedure:
To a solution of 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.853 mmol) and 4-fluorophenylboronic acid (143.5 mg, 1.02 mmol) in 1,4-dioxane/H2O (3:1, 15 mL), was added K2CO3 (235.5 mg, 1.71 mmol) and Pd(PPh3)4 (49 mg, 0.0427 mmol). The reaction was heated at reflux for 24 h then quenched with H2O and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 50% EtOAc in Hex) to give 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (200 mg, 36.5%). MS (ESI, pos. ion) m/z: 647.1 (M+1); 1H-NMR (400 MHz DMSO-d6): δ 12.11 (s, 1H), 9.18 (s, 1H), 9.08-8.98 (m, 2H), 8.52 (d, J=2.8 Hz, 1H), 8.36-8.33 (m, 2H), 8.14-8.03 (m, 1H), 7.74 (d, J=8 Hz, 1H), 7.65-7.55 (m, 2H), 7.46-7.7.28 (m, 4H), 6.92-6.88 (m, 2H), 4.41 (m, 2H), 3.73 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:9]/[C:10](/[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11]\[OH:12])[CH:3]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O/N=C(\CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2cccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)c2)c1

Procedure:
In analogy to example 22, from (E)-3-(3-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 12) and (3-methylsulfonylphenyl)boronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=457.2 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10]I.Cl>C1COCC1.CCOCC.[Zn]>[ClH:7].[Cl:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCCCI
Reactant: C1COCCN1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
Step 1. To a solution of morpholine (1.0 g, 11.47 mmol) and 1-chloro-3-iodopropane (2.35 g, 11.5 mmol) in dry THF (30 ml) was added activated zinc powder (0.75 g, 11.47 mmol). After the mixture was stirred at rt overnight, it was filtered, washed with EtOAc (20 ml), and concentrated. The residue was dissolved in EtOAc (50 ml), washed with 10% aq. NaHCO3 (10 ml), water (2×10 ml), dried over MgSO4, and concentrated. The residue was dissolved in ether (20 ml) before a 1 M ethereal HCl solution (11.5 ml, 11.5 mmol) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (2×10 ml), and dried to afford 4-(3-chloropropyl)morpholine hydrochloride (0.70 g, 31%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 2.17-2.28 (m, 2H), 3.01-3.09 (m, 2H), 3.15-3.19 (m, 2H), 3.39-3.42 (m, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.81-3.86 (m, 2H), 3.92-3.96 (m, 2H), 11.46 (brs, 1H). Step 2. To a solution of OZ288 (0.50 g, 1.40 mmol) in dry acetonitrile (50 ml) were added powdered NaOH (0.225 g, 5.61 mmol) and tetrabutylammonium hydrogensulfate (0.1 g, 0.28 mmol). After the reaction mixture was stirred at rt for 30 min, 4-(3-chloropropyl)morpholine hydrochloride (0.25 g, 1.26 mmol) was added. The mixture was stirred at 60° C. overnight before the inorganic solid was filtered off and washed with EtOAc (2×25 ml). After removal of the solvents in vacuo, the residue was dissolved in EtOAc (50 ml). The organic layer was washed with water, brine, dried over MgSO4, and concentrated. After the residue was dissolved in EtOAc (20 ml), a solution of methanesulfonic acid (0.14 g, 1.40 mmol) in ether (10 ml) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ461 (0.475 g, 58%) as a colorless solid. mp 158-160° C.; 1H NMR (500 MHz, CDCl3) δ 1.61-2.07 (m, 22H), 2.32-2.40 (m, 2H), 2.44-2.55 (m, 1H), 2.79 (s, 3H), 2.88-2.98 (m, 2H), 3.22-3.31 (m, 2H), 3.57 (d, J=12.2 Hz, 2H), 3.97-4.18 (m, 6H), 6.79 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 11.39 (brs, 1H); 13C NMR (125.7 MHz, CDCl3) δ 23.63, 26.41, 26.80, 31.54, 34.63, 34.73, 36.34, 36.72, 39.37, 41.93, 52.23, 55.81, 63.69, 64.51, 108.29, 111.32, 114.20, 127.71, 139.10, 156.40. Anal. Calcd for C30H45NO8S: C, 62.15; H, 7.82; N, 2.42. Found: C, 62.05; H, 7.63; N, 2.51.
Reaction SMILES: [CH2:1]([C@H:8]1COC(=O)N1)[C:2]1[CH:7]=CC=C[CH:3]=1.[Li]CCCC.CCCCCC.[C:25](Cl)(=[O:29])/[CH:26]=[CH:27]/[CH3:28].C1C[O:34]CC1>>[CH3:28][C@H:27]1[CH2:3][C@@H:2]([CH3:7])[CH2:1][CH2:8][C@@H:26]1[C:25]([OH:29])=[O:34]
Reactant: C/C=C/C(=O)Cl
Reactant: C1CCOC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[C@H]1CC[C@H](C(=O)O)[C@@H](C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
(S)-4-Benzyloxazolidin-2-one (35 g, 0.2 mol) was dissolved in THF (500 mL) and cooled to −78° C. A solution of nBuLi in hexane (80 mL, 0.2 mol) was added dropwise. The solution was stirred at this temperature for 30 min and then (E)-but-2-enoyl chloride (19 mL, 0.2 mol) was added slowly. The cold bath was removed and the reaction was allowed to stir at room temperature for 1 h, whereupon saturated NH4Cl solution (200 mL) was added. Most of the THF was removed under vacuum and the mixture was partitioned between ether and brine. After drying over Na2SO4, the organic layer was concentrated and the residue purified by silica gel chromatography (20% EtOAc in hexanes) to give the desired product (39 g, 79% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:4][CH:3]=1.O1CCC[CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:8]2[CH:24]([CH3:33])[C:25]([OH:27])=[O:26])=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cc1c(Sc2ccccc2)c2cc(F)ccc2n1Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Product: CC(C(=O)O)c1c(Sc2ccccc2)c2cc(F)ccc2n1Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 6, but using ethyl 1-(p-chlorobenzyl)-5-fluoro-3-phenylthioindole-2-acetate (Example 8, Step 1) as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 80°-82°.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([F:15])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1F
Product: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1F
Temperature: 50 °C

Procedure:
19.3 g (0.085 mol) of 2,4-difluoro-3-trifluoromethylbenzoic acid are added in portions at room temperature to 130 ml of thionyl chloride. After metering has ended, the mixture is heated at 50° C. until the evolution of gas has ceased. The excess thionyl chloride is then removed by distillation and the crude product is reacted further directly.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([O:34]COC)[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([OH:34])[CH2:31][CH2:32][CH2:33]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[C:13]([F:24])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)c(F)c5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: CN(C)CC(=O)Nc1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)cc1F

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-fluorophenyl)-2-(dimethylamino)acetamide (Example 64C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (400 MHz, DMSO-d6) ppm 12.57 (s, 1H) 9.63 (s, 1H) 8.34 (s, 1H) 8.27 (s, 1H) 8.10 (t, 1H) 8.01 (dd, 1H) 7.85 (dd, 1H) 7.15 (s, 1H) 6.68 (s, 1H) 3.14 (s, 2H) 2.64 (m, 2H) 2.42 (m, 2H) 2.32 (s, 6H) 198 (m, 2H); MS ESI(+) m/z 500.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH:11]2[CH2:13][CH2:12]2)=C([CH:9]=1)C#N.[OH-:14].[K+].Cl.C1(C)C=CC=CC=1.[CH3:24][CH2:25][OH:26]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH:11]2[CH2:13][CH2:12]2)=[C:24]([CH:9]=1)[C:25]([OH:14])=[O:26]
Reactant: N#Cc1cc(Cl)ccc1NC1CC1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Cl)ccc1NC1CC1
Yield: 92 %

Procedure:
5-Chloro-2-(cyclopropylamino)benzonitrile (4.66 g) was dissolved in a solution of KOH (4.75 g, 3.5 eq) in EtOH (12 mL) and water (2.5 mL). The solution was refluxed for 24 h, cooled, and acidified with concentrated HCl. The precipitate was filtered, washed with water, and dried by multiple concentrations from toluene delivering pure product (4.70 g, 92% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.88 (bs, 1H), 7.70 (d, 1H), 7.42 (dd, 1H), 7.09 (d, 1H), 2.47 (m, 1H), 0.78 (m, 2H), 0.45 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[F:22][C:23]([F:33])([F:34])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(OC(F)(F)F)c2)cc1
Temperature: 100 °C
Yield: 65.9 %

Procedure:
A mixture of methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-(trifluoromethoxy)benzaldehyde (0.025 ml, 0.20 mmol), NaBH(OAc)3 (109 mg, 0.52 mmol) and catalytic CH3COOH in DCM (12 ml) was heated at 100° C. (2 cycles of 5 min each) under microwave irradiation. The resulting mixture was purified by SPE-Si (2 g) eluting with a mixture DCM/AcOEt from 100/0 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D25) (52 mg).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].O[Li].O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[Pd](Cl)Cl.O.CN(C)C(=O)C>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Li]O
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (1.0 g), 3-formylphenylboronic acid (0.49 g, 1.05 eq), LiOH.H2O (0.26 g, 2.0 eq), palladium chloride (11 mg, 2 mol %) and 2-(dicyclohexylphosphino)biphenyl (44 mg, 4 mol %) were charged in a reaction container, and N,N-dimethylacetamide (10 mL) and water (5 mL) were added thereto. After nitrogen substitution, the mixture was stirred at 60° C. for 3 hr. The obtained reaction mixture was analyzed by high performance liquid chromatography to find the title compound (94.0% peak area).
Reaction SMILES: [H-].[Na+].[H][H].[OH:5][CH:6]1[CH:15]([OH:16])[CH2:14][C:13]2[C:12]([OH:17])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[OH:5][C@H:6]1[C@@H:15]([OH:16])[CH2:14][C:13]2[C:12]([O:17][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: Oc1cccc2c1CC(O)C(O)C2
Reactant: CCOC(=O)C(C)(C)Br
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc2c1C[C@H](O)[C@H](O)C2

Procedure:
Sodium hydride, 50% (0.75 mole) is added in portions with stirring to 50 ml. of cooled absolute ethyl alcohol. After the evolution of hydrogen has subsided, 0.075 mole of 6,7-dihydroxy-5,6,7,8-tetrahydro-1-naphthol is added, followed by the dropwise addition of 0.075 mole of ethyl α-bromoisobutyrate. The reaction mixture is refluxed with stirring for 16 hours. The solvent is evaporated in vacuo, the residue taken up in water and extracted with chloroform. The chloroform extract is washed with water, dried and freed of solvent to give the title compound in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:4][C:3]=1[CH3:18].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:43]2[C@H:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:15])=[CH:4][C:3]=1[CH3:18]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: Cc1cc(COCCCCCC(=O)O)ccc1F
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(COCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a cooled (−10° C.) solution of 6-(4-fluoro-3-methylbenzyloxy)hexanoic acid (0.565 g, 2.222 mmol) in 15 mL of THF, were added stepwise triethylamine (0.80 mL, 5.713 mmol) and pivaloyl chloride (0.27 mL, 2.179 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.092 g, 2.179 mmol) and (R)-4-benzyloxazolidin-2-one (0.375 g, 2.116 mmol) were added stepwise. After warmed slowly to room temperature with stirring overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.482 g, 52% yield). LC-MS: tR=11.2 min; m/z 414 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccc2ccccc2c1)c1nc(C)no1
Yield: 94.5 %

Procedure:
N-methyl-N-((1R)-1-{N-methyl-N-[(1R)-1(3-methyl[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)carbamic acid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 ml) and dichloromethane (40 ml) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from dichloromethane (80 ml). The residue was crystallised from ethyl acetate to give 1.9 g of (2R)-2-methylamino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([CH:19]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[F:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[N:11][CH:12]=1.[OH-].[Na+].Cl>CO>[Cl:6][C:7]1[C:8]([CH:19]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[F:40])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:9][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:11][CH:12]=1
Reactant: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a tetrahydrofuran (2 ml) solution of methyl 3-[5-chloro-4-[(2,5-difluorophenyl)(4-trifluoromethylphenylsulfonyl)methyl]pyridin-2-yl]propionate (92 mg, 0.17 mmol) were added methanol (2 ml) and a 1N aqueous solution of sodium hydroxide (2 ml) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid and the product thus obtained was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with ethanol and collected by filtration to give the title compound (61 mg, 0.12 mmol, 68%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[CH2:16][CH2:17][N:18]([C:21](OC(C)(C)C)=O)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[N:9][CH:10]=1)=[O:4].[C:30]1(=O)[CH2:34]C[CH2:32][CH2:31]1>>[CH:21]1([N:18]2[CH2:17][CH2:16][C:15]3[CH:28]=[CH:29][C:12]([O:11][C:8]4[N:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=4)=[CH:13][C:14]=3[CH2:20][CH2:19]2)[CH2:32][CH2:31][CH2:30][CH2:34]1
Reactant: O=C1CCCC1
Reactant: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)cn1

Procedure:
Example 254 (E254) was prepared from n-methyl-5-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)-2-pyrazinecarboxamide (D49) and cyclopentanone using the method described for Example 223; MS (ES+) m/e 367 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10](C4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]([F:44])([F:43])[O:31]C1C=C2C(=CC=1)NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:31][C:30]([F:44])([F:43])[F:29])[CH:13]=3)[N:8]=2)=[CH:27][CH:28]=1
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2ccc(OC(F)(F)F)cc12
Yield: 50 %

Procedure:
This compound was synthesized according to the procedure described above for Compound 2, reacting 5-trifluoromethoxyisatin (1.4 g, 6.06 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate, Intermediate 2 (1.72 g, 7.57 mmol). The crude acid was recrystallized from ethanol to give pure product as a yellow powder Compound 14 (1.2 g, 50% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 4.32 (s, 2H) 7.26-7.40 (m, 4H) 7.47 (d, J=9.09 Hz, 1H) 8.00 (d, J=8.84 Hz, 1H) 8.86 (s, 1H).
Reaction SMILES: [CH:1]([O:4][P:5]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=2)[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[CH3:48][Si:49]([CH3:54])([CH3:53])[CH2:50][CH2:51]O>C(Cl)Cl>[CH3:48][Si:49]([CH3:54])([CH3:53])[CH2:50][CH2:51][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=[C:16]([O:15][C:14]2[CH:29]=[CH:30][C:11]([P:5]([O:7][CH:8]([CH3:10])[CH3:9])([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])=[CH:12][CH:13]=2)[CH:17]=1
Reactant: C[Si](C)(C)CCO
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(Oc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid (Example 3, route 3, step E) (10 g, 22.9 mmol) in DCM (115 mL) was added DMF (0.09 mL, 1.15 mmol) and oxalyl chloride (4.0 mL, 45.8 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was concentrated. The resulting residue was azeotroped with 50 mL anhydrous toluene and then re-dissolved in DCM (40 mL), cooled to 0° C. A solution of pyridine (3.1 mL, 36.6 mmol) in DCM (10 mL) was added slowly to the reaction flask followed by 2-trimethylsilanylethanol (3.6 mL, 25.2 mmol). The resulting mixture was stirred at rt overnight. On second day solvents were removed and the residue was partitioned between EtOAc and saturated sodium bicarbonate. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel using an ethyl acetate-hexanes gradient to afford 5.0 g (41%) of 3-[4-(diisopropoxy-phosphoryl)-phenoxy]-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester. 1H NMR (500 MHz, DMSO-dc): δ 7.72 (dd, 13, 9 Hz, 2H), 7.26 (dd, J=3, 2 Hz, 1H), 7.16 (dd, J=9, 3 Hz, 2H), 7.06 (dd, J=3, 2 Hz, 1H), 6.99 (t, J=3 Hz, 1H), 4.69 (m, 1H). 4.54 (m, 2H), 3.48 (t, 2H), 1.28 (dd, J=8, 3 Hz, 12H), 1.18 (d, J=6 Hz, 6H), 1.04 (t, 2H), −0.16 (s, 9H).