Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.N#N>CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 113 %

Procedure:
To a nitrogen purged flask containing 4-trifluoromethylphenyl boronic acid (76.6 g, 403 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.07 g, 9.31 mmol), and potassium carbonate (83.6 g, 605 mmol) were added 4-bromobenzylamine (75.0 g, 403 mmol), N2 sparged 2-methyltetrahydrofuran (750 mL) and N2 sparged water (750 mL). The mixture was then warmed to 80° Celsius for 15 h. The mixture was cooled to RT, the layers were separated and the organic layer was washed with brine, dried over magnesium sulfate and filtered through celite. The filtrate was concentrated to dryness to afford the title compound (114.37 g, 85% purity, 96%). MS (ESI): mass calcd. for C14H12F3N, 251.10; m/z found, 252.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 4H), 7.58 (d, J=7.9, 2H), 7.42 (d, J=7.9, 2H) 3.94 (s, 2H). Absolute stereochemistry was determined by alternative synthesis starting with the product of Example 2.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7].[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])/[CH:7]=[CH:6]/[CH2:5][C:4]([CH:3]([O:2][CH3:1])[O:17][CH3:18])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(O[Si](C)(C)C)C(OC)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(O[Si](C)(C)C)C(OC)OC

Procedure:
A mixture of 10.0 g. (36.7 mmoles) of 4-dimethoxymethyl-4-trimethylsiloxy-1-octyne, 12.82 g. (44 mmoles) of tri-n-butylstannyl hydride 100 mg. of azobisisobutyronitrile is heated to 140° C. under argon for 2 hours. The excess hydride is distilled off and the residue is purified by molecular distillation (bath temperature=170°-175° C., 0.2mm.) to give 20.5 g. of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:30][NH:31][O:32][CH3:33].Cl>C(Cl)Cl>[CH3:33][O:32][N:31]([CH3:30])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:4]=1
Reactant: C[Si](C)(C)c1cccc(C(=O)O)c1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of 3-trimethylsilylbenzoic acid in methylene chloride (12 ml) was cooled to -22° C. and N-methylmorpholine (2.0 ml) was added. To the mixture isobutylchloroformate (0.88 ml) was added. The mixture was stirred for 25 min. followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.9 g). The mixture was stirred at -22° C. for 1 hr., allowed to warm to room temperature and stirred for 1.5 hr. The reaction mixture was poured into dil HCl and the aqueous phase was extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with dil NaHCO3 and dried over Na2 SO4. The solvent was removed in vacuo and the crude product purified by flash chromatography (10% EtOAc in hexane) to yield 600 mg of the desired product. HRMS calc. 238.1263. Found: 238.1268.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1.[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([O:28][CH3:29])[CH:21]=1.CN1CCCC1=O>C(=O)([O-])O.[Na+]>[Cl:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=3[N:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: CCC(CC)c1ccc(C#N)c2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C#N)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 130 °C
Yield: 44.2 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (1.00 g, 3.82 mmol), 4-chloro-2-methoxy-6-methylaniline (1.97 g, 11.50 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was heated at 130° C. for 48 h. After cooling, the reaction mixture was diluted with aqueous saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a white powder (670 mg, 44%).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:11]([O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(O)(C)(C)C>[CH2:11]([O:18][C:19]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:25])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCN1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 79 %

Procedure:
Tert-butyl acrylate (5.00 mL) was added to a solution of L-proline benzyl ester hydrochloride salt (1.10 g, 4.54 mmol) and Et3N (632 μL, 4.54 mmol) in tert-butanol (5.00 mL). The reaction was heated to 80° C. for 3 h then and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (1.20 g, 79%). 1H NMR (300 MHz, CDCl3): 1.43 (9H, s), 1.72-2.00 (3H, m), 2.08 (1H, m), 2.39-2.48 (3H, m), 2.72 (1H, ddd, J 12.2, 8.4, 6.7), 3.00 (1H, dt, J 12.3, 7.8), 3.13 (1H, m), 3.28 (1H, dd, J 8.6, 5.4), 5.13 (1H, d, J 12.3), 5.18 (1H, d, J 12.3), 7.29-7.39 (5H, m).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13](Cl)=[O:14]>>[CH3:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: CCCCCCCC[C@H](C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Product: CCCCCCCC[C@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Yield: 32.6 %

Procedure:
Using p-hydroxybenzoic acid (3.25 g, 23.5 mmol) and (S)-2-methyldecanoylchloride (4.83 g, 23.6 mmol), the reaction was carried out in the same manner as described in Example 4, (1}, to give 2.35 g of the title compound as white crystals; mp. 92.5°-96.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].C([O-])(=O)C.[Na+].O=[CH:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:24]([O:23][C:22]([NH:21][CH2:20][CH2:19][NH:5][C@@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[C:3]([O:2][CH3:1])=[O:12])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 79 %

Procedure:
L-Histidine methyl ester (7.93 g, 32.8 mmol) and sodium acetate (10.75 g, 131 mmol) were added to a stirred solution of tert-butyl N-(2-oxoethyl)carbamate (5.22 g, 32.8 mmol) in methanol (100 ml). 4 Å molecular sieves and sodium cyanoborohydride (4.12 g, 65.6 mmol) were added and the mixture was stirred at room temperature for 17 hours. Aqueous hydrochloric acid (2N, 4 ml) was added and the mixture was then basified with saturated aqueous sodium carbonate solution to pH=10. The mixture was filtered to remove solid which was washed with methanol. Methanol was removed by evaporation under reduced pressure and the residual aqueous solution was extracted with ethyl acetate (2×300 ml). The combined organic extracts were then dried (MgSO4), filtered, and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel, eluting with a solvent gradient of dichloromethane:methanol (96:4 to 92:8), to afford the title compound as a colorless oil, 8.07 g, 79% yield.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:17][CH2:18][CH2:19][CH2:20][C:21]([NH:8][CH:5]1[CH2:6][CH2:7][C:2]([F:9])([F:1])[CH2:3][CH2:4]1)=[O:22]
Reactant: O=C(Cl)CCCCl
Reactant: NC1CCC(F)(F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCl)NC1CCC(F)(F)CC1
Reaction time: 4 h
Yield: 78.4 %

Procedure:
To a solution of 4,4-difluoro-cyclohexylamine (295 mg) and Et3N (0.91 mL) in 22 mL of CH2Cl2, add 4-chloro-butyryl chloride (0.42 g). Allow the resulting mixture to stand at room temp for 4 hr. Remove the organic solvent under vacuum. Dissolve the residue in Et2O. Wash the organic layer with 1N HCl, then brine, and then H2O, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 0.41 g of the title compound: mass spectrum (m/z): 240 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:6][C:5]1[N:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:16]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CC(C)(C)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C(C)(C)C)n1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A mixture of 12.5 g of 4,4-dimethyl-3-oxopentanenitrile, 25 g of tert-butylhydrazine hydrochloride, and 27.6 g of potassium carbonate in 400 mL of ethanol was refluxed for 24 h. The mixture was cooled to 25° C. and then it was filtered. The solvent was evaporated from the filtrate and the residue was partitioned between ethyl acetate and distilled water. The organic phase washed with brine and dried (MgSO4). The solvent was evaporated at reduced pressure and the residue was dissolved in a small volume of ether. The mixture was diluted with an equal volume of hexanes and then the volume of the solution was reduced by one half by evaporation at reduced pressure. The white solid which precipitated was collected by filtration to give 8.7 g of 5-Amino-1,3-di(tert-butyl)pyrazole 17. 1H-NMR (CDCl3): δ 5.43 (s, 1H), 1.62 (s, 9H), 1.25 (s, 9H).
Reaction SMILES: FC1C(F)=CC=C(F)C=1C(=N)NC1C=CC(F)=CC=1.[CH3:20][C:21]([CH3:34])([CH2:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=1[F:33])[C:22]#[N:23].[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C[Al](C)C>C1(C)C=CC=CC=1>[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:22](=[NH:23])[C:21]([CH3:20])([CH3:34])[CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[C:27]([F:32])[C:26]=2[F:33])=[CH:38][CH:37]=1
Reactant: CC(C)(C#N)Cc1c(F)ccc(F)c1F
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Agent: N=C(Nc1ccc(F)cc1)c1c(F)ccc(F)c1F
Solvent: Cc1ccccc1
Product: CC(C)(Cc1c(F)ccc(F)c1F)C(=N)Nc1ccc(F)cc1

Procedure:
N-(4-fluorophenyl)-2,2-dimethyl-3-(2,3,6-trifluorophenyl)propanimidamide (35) was prepared in a similar manner as that described for the synthesis of compound 25 using 2,2-dimethyl-3-(2,3,6-trifluorophenyl)propanenitrile (34) (500 mg, 2.35 mmol), 4-fluoroaniline (0.38 mL, 4.0 mmol), trimethyl aluminum (2M in heptanes, 1.99 mL, 3.99 mmol) and toluene (10 mL).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1conc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1conc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester (849 g, 208 mmol) in ethanol (215 mL) was added aqueous sodium hydroxide (2 N, 161 mL, 323 mmol) and the resulting mixture stirred overnight at room temperature. The mixture was then acidified with HCl solution (4 N, 85 mL) to pH 2-3. The precipitate was then filtered off and dissolved in THF (700 mL) and then washed with saturated sodium chloride solution. The aqueous phase was then extracted with ethyl acetate and THF (1:1, 300 mL) and the combined organic phases dried over sodium sulfate and evaporated to afford the title compound (40.8 g, 94%) which was obtained as an orange solid. MS: m/e=206.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.C(OCC)(=O)C.[C:40]1([CH3:50])[CH:45]=[CH:44][C:43]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:42][CH:41]=1>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:8]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]3)=[CH:4][CH:3]=1.[CH3:50][C:40]1[CH:41]=[CH:42][C:43]([S:46]([O-:49])(=[O:48])=[O:47])=[CH:44][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Place 6-(5-methylthiophen-2-yl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ol (103.4 mg, 0.22 mmol) in a vial. Add ethyl acetate (4 mL) and p-toluenesulfonic acid (52 mg, 0.30 mmol) and stir at ˜60° C. Add tetrahydrofuran to clarify the solution and sonicate for 15 minutes. Carefully decant the suspension from gum that forms on the flask. Filter the suspension to obtain a cake of very light pink solids. Wash the cake with pentane (2×2 mL) and dry in a 40° C. vacuum oven overnight to obtain the title compound. MP (DSC)=136.24° C.
Reaction SMILES: [CH3:1][C@H:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:25]([F:28])([F:27])[F:26])[CH2:3][CH3:4].C[N+]1([O-])CCOCC1>CC#N.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C@H:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][C:7]=1[C:25]([F:28])([F:26])[F:27])[CH2:3][CH3:4]
Reactant: CC[C@H](C)Oc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC[C@H](C)Oc1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A mixture of 510 mg (1.3 mmol) of 4-(5-(4-(2-(S)-methylpropyloxy)-3-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl)phenylmethanol (from Step C), 153 mg (1.3 mmol) of 4-methylmorpholine N-oxide and 510 mg of 4 A molecular sieves in 8 mL of CH3CN was treated with 13 mg (0.04 mmol) of tetrapropylammonium perruthnate and the resulting mixture was stirred ar rt for 2 h. The solids were filtered and the filtrate was concentrated. Chromatography on a Biotage 40 S cartridge using 9:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 330 mg of the title compound: 1H NMR (500 Mhz) δ 1.01 (t, J=7.3, 3H), 1.38 (d, J=5.9, 3H), 1.73–1.83 (m, 2H), 4.56 (sextet, 1H), 7.14 (d, J=8.9, 1H), 8.02 (d, J=8.2, 2H), 8.30 (d, J=8.2, 2H), 8.32 (d, J=8.9, 1H), 8.44 (s, 1H), 10.1 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:29])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:7]([CH:22]=[CH:23][CH2:24][CH2:25][CH3:26])=[C:6]([CH:27]([CH3:28])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared from the intermediate obtained in Step A by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.75 (t, J=7.5 Hz, 3 H), 1.10-1.40 (m, 15 H), 1.93 (tdd, J=7.0, 7.0, 1.0 Hz, 2 H) 3.30-3.50 (m, 2 ), 4.37 (d, J=12.0 Hz, 1 H), 4.43 (d, J=12.0 Hz, 1 H), 5.20-5.40 (m, 1 H), 5.9 (dt, J=16.0, 1.1 Hz, 1 H), 7.0-7.40 (m, 4 H). FAB-MS: calculated for C23H30NOCl 372; found 372 (M+H, 100%). Rf=0.26 (10% ethyl acetate/n-hexane). mp 101-104° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:30])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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+]
Product: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 31 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (100 mg, 0.240 mmol), ethyl (4-bromophenyl)acetate (70.1 mg, 0.288 mmol), potassium carbonate (100 mg, 0.721 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.88 mg, 0.012 mmol) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 1 h before being cooled to room temperature and partitioned between AcOEt (60 mL) and water (30 mL). The layers were separated and the organic phase was washed with brine, dried on MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 5 to 25% AcOEt in hexanes) gave ethyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetate (33.9 mg, 0.075 mmol, 31%) as a colourless solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)([OH:3])=O.CN(C=O)C.C1(C)C=CC=CC=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>S(Cl)(Cl)=O.C1COCC1>[C:26]([NH:30][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Carboxyphthalid (36 g, 0.2 mole) is suspended in thionylchloride (100 mL). DMF (1.5 mL) is added and the mixture is refluxed for 1 hour. Toluene (200 mL) is added and the solvents are evaporated in vacuo. The residue is dissolved in THF (200 mL) and added to a solution of tert.butylamine (31 g, 0.42 mole) in THF (200 mL) at 5° C. The mixture is allowed to warm to room temperature and stirred overnight. The reaction is then poured into ice water (400 mL) and the precipitated crystals are filtered off. The crystals are washed with water (100 mL). Yield: 41 g, 87%. DSC onset: 189.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:21][N:22]=[C:23]=[S:24]>O1CCCC1>[CH3:21][NH:22][C:23]([C:8]1([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])=[S:24]
Reactant: O=C1CCCCC1c1ccc(Cl)nc1
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=S)C1(c2ccc(Cl)nc2)CCCCC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
A vigorously stirred solution of 2-(6-chloropyrid-3-yl)cyclohexanone (0.36 g 1.7 mmol) in anhydrous tetrahydrofuran (10 ml) under argon at -15° C. was treated with potassium t-butoxide (0.19 g, 1.7 mmol). The resulting mixture was stirred for 2 hours at room temperature before the addition of a solution of methyl isothiocyanate (0.12 g, 1.7 mmol) in dry tetrahydrofuran (2 ml). The mixture was stirred for a further 48 hours at room temperature, concentrated in vacuo and the residue treated with water (30 ml) and extracted with ethyl acetate (50 ml). The organic extract was dried over magnesium sulphate and then concentrated in vacuo (30° C.; 14 mmHg) to give a yellow oil which was purified by flash chromatography over silica gel eluting with ethyl acetate: hexane 4:6 to give (±)-N-methyl-2-oxo-1-(6-chloropyrid-3-yl) -cyclohexanecarbothioamide (0.25 g) m.p. 172°-3° C. NMR (CDCl3) 1.64-2.14(m 4H); 2.4-2.65(m 2H); 2.7-2.8(m 2H); 3.14-3.16(d,3H); 7.26-7.34 (ddd,1H); 7.6-7.66(dd,1H); 8.2(d,1H); 8.84-9.06 (broad singlet, 1H). Calculated for C13H15ClN2OS; C,55.2%; H,5.35%; N,9.91%, C1,12.5%; Found C,55.3%; H,5.3%; N,9.8%;C1,12.6%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)(O)=[O:2].C(=O)([O-])O.[NH4+:26].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>CN(C)C=O.N1C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:16]3[C:17]([OH:21])=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH:13]=2)=[CH:6][CH:5]=1)(=[O:2])[NH2:26]
Reactant: O=C(O)c1ccc(CCc2coc3cccc(O)c23)cc1
Reactant: [NH4+]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a mixture of 3-[2-(4-carboxyphenyl)ethyl]-4-hydroxybenzofuran (80 mg), ammonium hydrogen carbonate (90 mg) and pyridine (0.091 mL) in N,N-dimethylformamide (3 mL) was added ditert-butyl dicarbonate (0.25 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.1 mL), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was cooled to room temperature. To the mixture was added 1 mol/L hydrochloric acid (0.52 mL), and the resulting mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=30/1) and VARIAN BOND ELUT-SAX (eluent: methanol) successively to give the title compound (50 mg).