Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][CH2:17][C@H:18]([CH:31]([CH3:33])[CH3:32])[CH2:19][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:21]=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][CH2:17][C@H:18]([CH:31]([CH3:33])[CH3:32])[CH2:19][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:21]1[CH2:4][O:22]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)[C@@H](COCc1ccccc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@@H](COCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A flame dried 250-mL, round-bottom flask was charged with sodium hydride (2.4 g, 60.0 mmol) and trimethyloxosulfonium iodide (13.2 g, 60 mmol). The flask was evacuated and refilled with N2, and dry DMSO (100 mL) was added. The mixture was stirred at rt for 1 h to afford a solution. A second 500-mL, round-bottom flask was charged with tert-butyl (2S,4S)-4-(benzyloxymethyl)-5-methyl-1-oxohexan-2-ylcarbamate (14 g, 40 mmol) and THF (150 mL). The flask was evacuated and refilled with N2, and the sulfur ylid solution prepared above was added through a cannula. The resulting mixture was stirred for 1 h at rt. The reaction mixture was quenched with brine and extracted with EtOAc (3×200 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl (1S,3S)-3-(benzyloxymethyl)-4-methyl-1-((R)-oxiran-2-yl)pentylcarbamate (7.2 g, 50%). 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.55 (m, 1H), 7.17 (m, 1H), 4.50 (m, 2H), 3.84-3.68 (m, 2H), 3.45 (m, 1H), 3.27 (s, 3H), 3.25-3.18 (m, 3H), 2.13 (m, 2H), 1.89-1.72 (m, 2H), 1.55 (m, 3H), 1.32-1.11 (m, 9H), 0.99-0.80 (m, 12H); MS: 364 (M++1)
Reaction SMILES: [Cl:1][C:2]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2=[CH:6][N:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:4]2[C:3]=1[C:19](O)=[O:20].[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:31]([O:30][C:28]([N:22]1[CH2:27][CH2:26][N:25]([C:19]([C:3]2[C:4]3[C:5](=[CH:6][N:7]=[C:8]([O:10][CH3:11])[CH:9]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]=2[Cl:1])=[O:20])[CH2:24][CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc2c(C(=O)O)c(Cl)n(-c3ccccc3)c2cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude compound of step 4, tert-butyl 1-piperazinecarboxylate (565 mg, 3.03 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (581 mg, 3.03 mmol) and 1-hydroxybenzotriazole hydrate (312 mg, 2.29 mmol) in DMF (20 ml) was added NMM (911 μl, 8.27 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[C:14]1([NH:28][C:29](=[O:31])[CH3:30])[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:24]([O-])=O)[C:15]1=[O:27].Cl>C(O)C.O.[Fe]>[CH3:33][N:2]([CH3:1])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[C:14]1([NH:28][C:29](=[O:31])[CH3:30])[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[C:15]1=[O:27]
Reactant: CC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)N(C)C)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)N(C)C)C(=O)c2cccc(N)c2C1=O
Yield: 53.1 %

Procedure:
2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate (0.20 g, 0.4 mmol) was dissolved in anhydrous ethanol (10 ml) and water (1 ml). This solution was added with iron (0.18 g, 3.2 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs under reflux. After filtrating and washing with MeOH, the remainder was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (90 mg, 50%).
Reaction SMILES: [C:1](=[O:12])([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH2:3]Cl.[I-:13].[Na+]>C(#N)C>[C:1](=[O:12])([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH2:3][I:13]
Reactant: [I-]
Reactant: O=C(OCCl)OCC1CCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCI)OCC1CCCO1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (3.4 g) and sodium iodide (10.46 g) were added to acetonitrile (70 ml), and then the mixture was heated with stirring at 60° C. for 90 minutes. After the reaction solution was cooled, the solvent was distilled off under reduced pressure, and the residue was partitioned between ether (70 ml) and a saturated sodium chloride aqueous solution (50 ml). The organic layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml), water (50 ml) and a saturated sodium chloride aqueous solution (50 ml) successively, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain iodomethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (4.8 g) as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CN([CH:30]=[O:31])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([CH:30]=[O:31])[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (5.1 g, 0.02 mol) was suspended in THF (200 mL) and the resulting solution was cooled to −78° C. whereupon the starting material precipitated from solution. LiHMDS (1M in THF, 25 mL, 1.25 equiv) was added dropwise to the stirred suspension. After addition was complete, the mixture was stirred for 30 min, then DMF (9 mL, 6 equiv) was added and the resulting solution was stirred for 15 min at −78° C. and then warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and then cannulated (via a wide-bore double-ended needle) into a stirred solution of ˜0.5M HCl (600 mL). The product precipitated from solution as a pale yellow powder. This was isolated by filtration through a sintered glass funnel, washed with water and dried in vacuo overnight to give 5 g of 5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (87.7%). 1H NMR (400 MHz, CDCl3): δ 3.83-3.88 (m, 4 H), 4.06-4.15 (m, 2 H), 4.72 (m, 2 H) and 9.95 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:7]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Reaction time: 0.08 h
Yield: 74.3 %

Procedure:
Under nitrogen, a mixture of intermediate 45, 5-fluoro-2,N,N-trimethyl-benzenesulfonamide, (435 mg, 2.0 mmol) and N-bromosuccinimide (391 mg, 2.2 mmol) in CCl4 (20 mL) was stirred at 80–90° C. for 5 min. To this mixture was added 2,2′-azobisisobutyronitrile (AIBN, 100 mg) and stirring continued at 80–90° C. for 30 min. After cooling, the insoluble precipitates were filtered and the filtrate concentrated and purified by column chromatography (SiO2, CH2Cl2) to provide 440 mg (Yield 74%) of the title compound; 1H NMR (500 MHz, CDCl3) δ ppm: 2.87 (6H, s) 4.86 (2H, s) 7.28 (1H, dd, J=8.55, 2.75 Hz) 7.61–7.65 (2H, m); LC/MC m/z 296/298 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc(OCc2ccccc2)cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OCc2ccccc2)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 38A, 183 mg, 0.63 mmol) in methylene chloride (6.37 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.35 mL, 0.7 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and then at 25° C. for 30 min. The reaction mixture was then treated with 5-benzyloxy-pyridin-2-ylamine (281 mg, 1.4 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol). The reaction mixture was stirred at 25° C. for 16 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded N-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (150 mg, 50.0%) as a yellow solid: mp 47-49° C.; EI-HRMS m/e calcd for C26H26Cl2N2O2 (M+) 469.1449, found 469.1455.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([SiH:24]2[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:27]2[CH2:28][CH2:29][Si@H:24]([CH:21]3[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:19][CH2:20]3)[CH2:25][CH2:26]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COCCCCCC1CCC([SiH]2CCC(O)CC2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Product: COCCCCCC1CCC([Si@H]2CC[C@H](OC(=O)c3ccc(F)cc3)CC2)CC1

Procedure:
The general procedure of Example 31 was repeated using 4-fluorobenzoic acid and 4-(4-(5-methoxypentyl)cyclohexyl)-4-silacyclohexanol, thereby obtaining the intended product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1.CCN(CC)CC>C(OCC)C>[C:1]([O:5][C:6](=[O:28])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:37](=[O:38])[NH:36][C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3ccc(F)cc3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 57 %

Procedure:
2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.74 mmol, 1 equiv.) was dissolved in diethyl ether (7.5 mL), followed by the addition of 4-fluorophenylisocyanate (101 mg, 0.74 mmol, 1 equiv.) and Et3N (1 mL). The reaction mixture was stirred at room temperature for 50 min. Solid precipitated from the reaction mixture. Solid was collected by filtration and washed with ether to yield 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 57% yield (228 mg).
Reaction SMILES: [C:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[CH:10]=1)(=O)[CH2:2][CH2:3][CH3:4].NN.C(O)COCCO.[OH-].[K+]>O>[CH2:1]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=2[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc2cc(Cl)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCc1cc2cc(Cl)ccc2o1

Procedure:
A mixture of 31.5 g. (0.14 mol.) of 2-butyryl-5-chlorobenzofuran and 35 ml. of 98% hydrazine in 70 ml. of diethylene glycol was warmed for a few minutes on a steam bath. Then 23.3 g. of potassium hydroxide was added and the reaction mixture was refluxed for two hours. After cooling, water was added to the mixture and the resulting aqueous solution was extracted with benzene. The extract was washed with water, 10% aqueous hydrochloric acid and water, dried (MgSO4) and concentrated in vacuo to yield 2-n-butyl-5-chlorobenzofuran, b.p. 70°-75° (10-15 mm.).
Reaction SMILES: [CH2:1]([O:15][CH2:16][C@H:17]([CH2:19][OH:20])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:1]([O:15][CH2:16][C@H:17]([CH2:19][O:20][C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCOC[C@@H](O)CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In 30 ml of dry pyridine, 2.82 g of 1-tetradecyl-sn-glycerol is allowed to react 3.27 g of triphenylchloromethane to give 1-tetradecyl-3-trityl-sn-glycerol. This compound is subjected to methylation with methyl iodide and deprotection to give 2 g of 1-tetradecyl-2-methyl-sn-glycerol.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2>>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[CH:40]=[C:41]([C:44]3([CH3:51])[NH:48][C:47](=[O:49])[N:46]([CH2:2][C:3]([N:5]4[CH2:11][CH2:10][CH2:9][N:8]([C:12]5[CH:17]=[CH:16][C:15]([C:18]([OH:27])([C:23]([F:25])([F:26])[F:24])[C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=5[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]4)=[O:4])[C:45]3=[O:50])[CH:42]=[CH:43][C:35]1=2
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Reactant: CC1(c2ccc3c(c2)OCCO3)NC(=O)NC1=O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc4c(c3)OCCO4)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[CH:15][C:10]3[C:11]([CH3:14])=[CH:12][O:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[CH:1]1([C:7]2[CH:16]=[CH:15][C:10]3[CH:11]([CH3:14])[CH2:12][O:13][C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1coc2cc(C3CCCCC3)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1COc2cc(C3CCCCC3)ccc21
Reaction time: 5 h

Procedure:
9.2 g of 6-cyclohexyl-3-methyl-benzofuran are dissolved in 140 ml of ethyl acetate and hydrogenated in the presence of palladium (10% on active charcoal). After 5 hours, the mixture is filtered and reduced in volume. 6-Cyclohexyl-2,3-dihydro-3-methyl-benzofuran is obtained as an oily product by distillation in a bulb tube at 120°/0.1 mm.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:65]=[C:66]([CH:69]=[CH:70][CH:71]=1)[C:67]#[N:68].CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:67]([C:66]1[CH:65]=[C:64]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])[CH:71]=[CH:70][CH:69]=1)#[N:68]
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2cccc(C#N)c2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 49.3 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (11.2 mg, 0.05 mmol, 10 mol % Pd), (S)-BINAP (46.6 mg, 0.075 mmol, 15 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)-cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 3-Bromobenzonitrile (182 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 78 mg (50%) of the title compound. The ee was determined to be 60% by chiral HPLC analysis.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-].[Na+].OO>C1COCC1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([CH2:1][CH2:2][CH3:3])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (0.2475 g, 0.57 mmol, 1.0 equiv) in 6 mL of dry THF was added 9-BBN (0.5 M solution in THF, 2.3 mL, 1.15 mmol, 2.0 equiv). The mixture was stirred for 3 h at rt. It was then subjected to oxidative workup by adding 3 N aqueous NaOH (6 mL) followed by careful and dropwise addition of 50% aq H2O2 (4 mL) with vigorous stirring. The reaction mixture was stirred for 1 h, extracted with CH2Cl2, and dried over Na2SO4. Surprisingly, the reductive product was observed instead of hydroboration-oxidation. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0902 g of (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-phenyl-6-propyl-1,3-oxazinan-2-one LC-MS Method 1 tR=2.22, min, m/z=436; 1H NMR (400 MHz, CD3OD) δ 7.33-7.14 (m, 8H), 6.96-6.87 (m, 4H), 5.48 (q, J=7.0 Hz, 1H), 3.01-2.96 (m, 1H), 2.41-2.36 (m, 1H), 2.29-2.21 (m, 1H), 2.14-2.07 (m, 1H), 1.81-1.72 (m, 2H), 1.46 (d, J=7.0 Hz, 3H), 1.39-1.29 (m, 1H), 1.08-0.98 (m, 1H), 0.76 (t, J=7.5 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −113.79 (m), −115.77 (m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J36) (360 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (302 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (430 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCC=O
Reactant: COc1ccc(N)cc1OC
Product: CCCCNc1ccc(OC)c(OC)c1
Yield: 87.9 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3,4-dimethoxyaniline (500 mg, 3.26 mmol) and butyraldehyde (290 μL, 3.26 mmol) were converted to the title compound (600 mg, 83%). 1H NMR (CDCl3) δ 6.81-6.70 (m, 1H), 6.27-6.21 (m, 1H), 6.16 (dd, J=8.5, 2.5 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.08 (t, J=7.0 Hz, 2H), 1.56-1.40 (m, 4H), 0.99-0.93 (m, 3H); MS(ESI+) m/z 210.2 (M+H)+.