Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH:22]=[CH:23][C:24]#[N:25])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]3)([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@:10]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:36])([CH3:37])[O:32]3)([CH3:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC[C@@H](C=CC#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: CC[C@@H](CCC#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hex-2-enenitrile prepared above in Step E (208 mg, 0.384 mmol) in EtOH (12.8 mL) was added 10% palladium on activated carbon (40.9 mg, 0.038 mmol). Then the reaction mixture was subjected to regular hydrogenation with hydrogen (0.774 mg, 0.384 mmol). After being stirred at rt for 1.5 h, the catalyst was filtered using a short plug of silica-gel and washed (EtOAc). The combined organic solutions were concentrated under reduced pressure. Purification by combi flash (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) (SiO2, 24 g, 35% and 40% EtOAc/Hexanes) provided the title compound as a colorless film.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:41])=[C:19]([C:21]4[NH:25][C:24]([C:26]5([CH3:39])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35](C)(C)C)=[O:33])[CH2:28][CH2:27]5)=[N:23][C:22]=4[CH3:40])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2CN(C(C3C=CC(C)=C(C4N=C(C5CCN(C(OC(C)(C)C)=O)CC5)NC=4C)C=3)=O)C2)=CC=1)#N.Cl.[F:83]C1(C2C=CC(C#N)=CC=2)CNC1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:83])[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:41])=[C:19]([C:21]4[NH:25][C:24]([C:26]5([CH3:39])[CH2:31][CH2:30][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]5)=[N:23][C:22]=4[CH3:40])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(C)CCN(C(=O)OC(C)(C)C)CC2)nc1C
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Agent: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: COC(=O)N1CCC(C)(c2nc(C)c(-c3cc(C(=O)N4CC(F)(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 184, except tert-butyl 4-(5-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-4-methyl-1H-imidazol-2-yl)-4-methylpiperidine-1-carboxylate (compound 185.3) was used in place of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 530 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].[H-].[Na+].Cl[C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:31]2[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1>CN(C)C=O>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([O:13][C:28]2[N:32]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@H](O)C[C@@H]2Cc2ccccc2)c1
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](Oc3nc4ccccc4n3Cc3ccc(F)cc3)C[C@@H]2Cc2ccccc2)c1
Yield: 64.7 %

Procedure:
(±)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinol (2.6 g) dissolved in N,N-dimethylformamide (100 ml) was stirred under N2. Sodium hydride (60%) (0.36 g) was added and the mixture was stirred at 40° C. for 1 hour. 2-Chloro-1-[(4-fluorophenyl)-methyl]-1H-benzimidazole (2.6 g) was added and the mixture was stirred at 60° C. for 20 hours. The solvent was evaporated and the residue was taken up in water and CH2Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding 2.85 g (65%) of (±)-cis-1-(3,5-dimethylbenzoyl)-4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-2-(phenylmethyl)piperidine (comp. 70; mp. 154.1° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[I:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[C:21]=1[CH:28]=O>CO>[I:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[C:21]=1[C:28]1[NH:1][C:2]2[CH:3]=[C:4]([N:10]3[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]3)[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Reactant: COc1nccc(I)c1C=O
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(C)=O)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66 %

Procedure:
To a solution of 1-[4-(3,4-diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone (4.00 g, 16.18 mmol) in methanol (100 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (4.25 g, 16.18 mmol). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (5.25 g, 66%). 1H NMR (400 MHz, CD3OD) δ 7.81 (1H, d, J=5.4 Hz), 7.48 (1H, d, J=5.4 Hz), 7.26 (1H, s), 6.85 (1H, s), 3.85 (3H, s), 3.78 (2H, t, J=5.0 Hz), 3.64 (2H, t, J=5.0 Hz), 3.16 (2H, t, J=5.2 Hz), 3.11 (2H, t, J=5.2 Hz), 2.62 (3H, s), 2.13 (3H, s). LCMS (M+H)+ m/z 492 (t=1.71 min.).
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][C:6]2([C:19]([O:21][CH3:22])=[O:20])[N:8](C(OCC3C=CC=CC=3)=O)[CH:3]1[CH2:4][CH2:5]2>CO.[Pd]>[F:23][C:2]1([F:1])[CH2:7][C:6]2([C:19]([O:21][CH3:22])=[O:20])[NH:8][CH:3]1[CH2:4][CH2:5]2
Reactant: COC(=O)C12CCC(N1C(=O)OCc1ccccc1)C(F)(F)C2
Agent: [Pd]
Solvent: CO
Product: COC(=O)C12CCC(N1)C(F)(F)C2
Reaction time: 12 h
Yield: 69.3 %

Procedure:
The mixture of O7-benzyl O4-methyl 2,2-difluoro-7-azabicyclo[2.2.1]heptane-4,7-dicarboxylate (0.24 g, 0.74 mmol), 10% Pd/C (0.3 g) in methanol (20 mL) was stirred for 12 hours under 1 atm H2. Removal of the catalyst solid and solvent gave methyl 2,2-difluoro-7-azabicyclo[2.2.1]heptane-4-carboxylate 148a. This crude product was used in next step without purification. Yield: 69.3%. MS: calc'd (MH +) 192, measured (MH +) 192.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][Cl:35])(=O)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)C>[Cl:35][CH2:34][CH2:33][O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(OCCCl)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-(3-Hydroxyphenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (5.0 g, 14.5 mmol), tetrabutylammonium iodide (536 mg, 1.5 mmol) and sodium hydroxide (9.8 g, 41.7 mmol) were dissolved in anhydrous ethanol and heated to reflux for 15 min. 2-Chloroethyl tosylate (581 mg, 41.67 mmol, 7.6 mL) was then added and the mixture allowed to stir at 80° C. for 18 h. After this time, the reaction mixture was concentrated in vacuo and the crude product purified by chromatography over silica gel eluting with 50% ethyl acetate/hexanes to 10% methanol in ethyl acetate to give 1-[3-(2-chloroethoxy)phenyl]-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([CH3:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:21])=O>>[CH:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:21])=[O:8])([CH3:3])[CH3:2]
Reactant: Cc1c(C(=O)O)cccc1C(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)cccc1C(C)C

Procedure:
3-Isopropyl-2-methyl-benzoic acid (0.75 g) was refluxed in ca. 3 mL of thionyl chloride with a drop of DMF fro several hours and thionyl chloride was removed in vacuo to yield 3-isopropyl-2-methyl-benzoyl chloride. The acid chloride was dissolved in 5 mL of CH2Cl2 and added slowly and simultaneously but separately with 5 mL of aqueous NaOH (0.265 g, 6.6 mmol) to a solution of 3,5-dimethyl-benzoic acid N-tert-butyl-hydrazide (0.973 g, 4.4 mmol) dissolved in 10 mL of CH2Cl2 prechilled to −5° C. During the addition, the temperature was kept below 5° C. The mixture was allowed to warm slowly to room temperature and was stirred overnight. The organic layer was removed and the aqueous layer was extracted with CH2Cl2. The organic extracts were combined, dried, and solvent was removed in vacuo to give 1.61 g of crude product as a yellow oil. This material was chromatographed on silica gel using 4:1 hexanes:ethyl acetate as eluant, and subsequently triturated from 1:1 hexane:ether, yielding 3,5-dimethyl-benzoic acid N-tert-butyl-N′-(3-isopropyl-2-methyl-benzoyl)-hydrazide, after arduous removal of ether in a vacuum oven at 60° C. (0.35 g, m.p. 182.5° C. 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.6 (s, 1H), 7.25 (d, 1H), 7.1 (s, 2H), 7.05 (s, 1H), 7.0 (m, 1H), 6.3 (d, 1H), 3.1 (m, 1H), 2.3 (s, 6H), 1.95 (s, 3H), 1.6 (s, 9H), 1.18 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2.Cl[C:19]1[C:24]([NH:25][C:26](=O)[O:27]C(C)(C)C)=[CH:23][CH:22]=[CH:21][N:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(O)C.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[O:27]=[C:26]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]3)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[NH:25]1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(-n3c(=O)[nH]c4cccnc43)ccc21
Temperature: 90 °C
Reaction time: 40 h
Yield: 26.6 %

Procedure:
A mixture of tert-butyl 5-amino-2,3-dihydro-1H-indole-1-carboxylate (4.10 g), tert-butyl 2-chloropyridin-3-ylcarbamate (4.20 g), Pd2(dba)3 (0.48 g), Xantphos (0.608 g), sodium tert-butoxide (2.52 g) in 2-propanol (64 ml) and toluene (12 mL) was stirred at 90° C. for 40 h, and treated with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in CH3CN and the precipitate was collected by filtration to give tert-butyl 5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (1.64 g). The filtrate was evaporated and then the residue was chromatographed on silica gel eluting with AcOEt/Hexane=2/1 to afford second crop (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[F:8][C:7]1[C:2]([NH:1][C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])=[N:3][C:4]([OH:9])=[N:5][CH:6]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1nc(O)ncc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a suspension of 4-amino-5-fluoropyrimidin-2-ol (0.200 g, 1.5 mmol) in anhydrous DMF (3 mL) was added phenylisocyanate (0.251 g, 2.1 mmol) and the mixture was stirred at 23° C. for 1 h and then at 60° C. for 16 h. The reaction mixture was cooled to room temperature, and the residual solid was collected by filtration. The filter cake was washed with diethyl ether (Et2O) and dried in a vacuum oven at 40° C. for 3 h to give 1-(5-fluoro-2-hydroxypyrimidin-4-yl)-3-phenylurea as a white solid (0.210 g, 55%), which was used immediately in the next step.
Reaction SMILES: CC1C=CN=CC=1N1C=CC2NC3C=CC=CC=3C=2C1=O.[C:22]1(=[O:35])[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:27][C:26]=2[CH:25]=[CH:24][NH:23]1.Br[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][C:42]=1[C:43]([F:46])([F:45])[F:44].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>[Cu](I)I.CS(C)=O>[F:44][C:43]([F:46])([F:45])[C:42]1[CH:41]=[CH:40][N:39]=[CH:38][C:37]=1[N:23]1[CH:24]=[CH:25][C:26]2[NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[C:34]=2[C:22]1=[O:35]
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=c1[nH]ccc2[nH]c3ccccc3c12
Agent: I[Cu]I
Agent: Cc1ccncc1-n1ccc2[nH]c3ccccc3c2c1=O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=c1c2c(ccn1-c1cnccc1C(F)(F)F)[nH]c1ccccc12
Yield: 1.4 %

Procedure:
Using analogous reaction conditions and work up as described for the preparation of 62A above, 2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (I-62a: 200 mg, 1.08 mmol) was reacted with 3-bromo-4-trifluoromethylpyridine (368.4 mg, 1.63 mmol), 8-hydroxy quinoline (31.3 mg, 0.216 mmol), K2CO3 (223.5 mg, 1.62 mmol), copper iodide (41.14 mg, 0.216 mmol) and DMSO (5 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM), followed by preparative HPLC afforded 5 mg of the product (1.5% yield).
Reaction SMILES: [CH2:1]([Si:4]([CH2:18][CH:19]=[CH2:20])([CH2:15][CH:16]=[CH2:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([Mg]Cl)(C)C.[Li]CCCC.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:1]([Si:4]([CH2:18][CH:19]=[CH2:20])([CH2:15][CH:16]=[CH2:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:33]=[O:34])=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CC[Si](CC=C)(CC=C)CCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[Si](CC=C)(CC=C)CCCc1ccc(C=O)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Under a nitrogen atmosphere, to 4-{3-(triallylsilyl)propyl}phenyl bromide (3) (14.2 g, 40.6 mmol), tetrahydrofuran (THF) (50 ml) was added, cooled to −10° C. using salt ice. 2M of iPrMgCl solution (0.70 equiv., 14.2 ml) and 1.67M of nBuLi solution (1.4 equiv., 34.0 ml) were each added dropwise, then stirred at around −10° C. for 2 hours. N,N-dimethylformamide (DMF) (2 equiv., 6.3 ml) was added and stirred at room temperature for 14 hours. To the reacted mixture, diethyl ether was added and then neutralized with saturated ammonium chloride aqueous solution. The obtained water layer was extracted with diethyl ether, the collected organic layer was washed with saturated saline solution then dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure, obtaining a crude product. The crude product was separated and purified using silica gel column chromatography (eluent: hexane/ethyl acetate=20/1), obtaining 4-{3-(triallylsilyl)propyl}benzaldehyde (4) represented by the following chemical formula (yield: 11.0 g, yield (%): 89%).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@:25]1([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[CH:19]=[CH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([O:13][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C@:25]3([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]3)[CH:19]=[CH:18]4)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1

Procedure:
The mixture of trans-4-phenyl-cyclohexanol (86.9 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 100.0 mg, 0.0004111 mol) and triphenylphosphine (129 mg, 0.000493 mol) in tetrahydrofuran (4 mL, 0.05 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred and refluxed for 3 hours. TLC monitoring showed the reaction to be complete. The mixture was taken up into DCM and subjected to chromatographic purification with EtOAc/hexane (10:90 to 80:20) to give (R)-4-(6-(trans-4-phenylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (160 mg, 97% yield). LCMS 402.28 ([M+1]+, 100%).
Reaction SMILES: CCN(CC)CC.[CH:8](=[C:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH2:9][CH3:10]>C(Cl)Cl>[CH2:8]([CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH2:9][CH3:10]
Reactant: CCC=C1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CCCC1=O
Temperature: 50 °C
Reaction time: 28 h
Yield: 95.1 %

Procedure:
In a 100 ml-volume three-way-cocked eggplant type flask whose atmosphere had been displaced with nitrogen was charged 845 mg (0.5 mmole) of Ru2Cl4 ((+)-BINAP)2 (NEt3), and 12.4 g (100 mmole) of 2-propylidenecyclopentanone and 50 ml of methylene chloride were added thereto to form a solution. The solution was put in a 100 ml autoclave having been displaced with nitrogen and stirred at 50° C. under a hydrogen pressure of 90 kg/cm2 for 28 hours to conduct a hydrogenation reaction. The solvent was removed from the reaction mixture by distillation, and the residue was purified by silica gel column chromatography using a mixed solvent of diethyl ether and hexane (1:4 by volume) as an eluent to obtain 12 g (percent yield: 97%) of 2-propylcyclopentanone as a clear yellow liquid. 1H-NMR (CDCl3)δ(ppm): 1.50 (t, 3H, J=7 Hz), 1.42 (m, 4H), 1.50-2.80 (m, 7H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([SH:27])=[N:25][N:26]=3)[CH:23]=2)[CH:15]=[N:14]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([S:27][C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[N:8]=[CH:7][CH:6]=[CH:5]5)=[N:25][N:26]=3)[CH:23]=2)[CH:15]=[N:14]1
Reactant: Cn1cc(-c2ccc3nnc(S)n3c2)cn1
Reactant: Brc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3c2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
A mixture of 6-bromoquinoline (72.0 mg, 0.346 mmol), Intermediate E (80 mg, 0.346 mmol), Pd2(dba)3 (31.7 mg, 0.035 mmol), xantphos (40.0 mg, 0.069 mmol) and DIPEA (0.242 ml, 1.384 mmol) in DMF (10 ml) was bubbled with N2 for 15 min. The reaction was stirred at 100° C. for 2 h under MW radiation. The mixture was concentrated and the residue obtained was purified by silica gel chromatography eluted with DCM/MeOH (from 100% to 90%) to afford the title compound as yellow solid (63 mg, 45.7% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, 1H), 8.59 (s, 1H), 8.28 (m, 2H), 7.98 (m, 3H), 7.89 (s, 1H), 7.81 (d, 1H), 7.59 (d, 1H), 7.50 (m, 1H), 3.84 (s, 3H). LCMS (method B): [M+H]+=359, tR=2.0 min.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH3:3][C:4]([C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([Cl:15])[CH:21]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 7 h

Procedure:
The starting material can also be prepared as follows: 4.8 g 50% sodium hydride in mineral oil are added to 100 ml hexamethylphosphoramide while stirring under nitrogen. Hereupon 17.1 g diethyl α-methylmalonate are added and the mixture slowly heated to 100°. The solution of 19.2 g 2,4-dichloro-nitrobenzene in 20 ml hexamethylphosphoramide is added dropwise during 1/2 hour and the temperature kept at 100° for 7 hours. After cooling, the mixture is diluted with water, concentrated in vacuo, the residue taken up in water and extracted with benzene. The extract is washed with water, dried, filtered, evaporated, the residue distilled and the fraction boiling at 147°-148°/0.25 mm Hg collected, to yield the diethyl α-methyl-α-(3-chloro-4-nitrophenyl)-malonate. (The analogously prepared diethyl α-ethyl-α-(3-chloro-4-nitrophenyl)-malonate boils at 170°-174°/1 mm Hg.)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[Cl:17])=[C:4]([CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[O:21][C:20]2=[O:39])[CH:3]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:48]>ClCCl>[F:37][C:35]([F:36])([F:38])[C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:39])[N:19]([CH2:18][C:4]3[CH:3]=[C:2]([Br:48])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=3[Cl:17])[C@H:23]2[CH3:24])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1
Reactant: CC(C)c1ccc(Cl)c(-c2ccc(N)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CC(C)c1ccc(Cl)c(-c2ccc(Br)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-3-[(4-amino-2′-chloro-5′-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.175 mmol) in bromoform (0.5 mL) and dichloromethane (1 mL) was added t-butyl nitrite (23 μL, d=0.867, 90% pure, 0.193 mmol). The resulting mixture was stirred at 50° C. for 1 h. An aliquot indicated completion of the reaction. The reaction crude was deposited on 2 prep-TLC plates eluted by dichloromethane to afford the title compound. LC-MS: 635.80 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 6:4 mixture of rotamers δ 7.84-7.88 (m, 1H), 7.67-7.74 (m, 2 H), 7.60-7.63 (m, 1 H), 7.51-7.57 (m, 1 H), 7.38-7.42 (m, 1 H), 7.19-7.23 (m, 1 H), 7.11-7.16 (m, 1 H), 7.09 (d, J=2.3 Hz, 0.6 H), 7.03 (d, J=2.3 Hz, 0.4 H), 5.66 (d, J=8.0 Hz, 0.4 H), 5.55 (d, J=8.0 Hz, 0.6 H), 4.86 (d, J=15.6 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H), 3.77-4.00 (m, 2 H), 2.87-2.95 (m, 1 H), 1.20-1.28 (m, 6 H), 0.53 (d, J=6.6 Hz, 1.2H), 0.45 (d, J=6.4 Hz, 1.8 H).