Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc2[nH]cnc2c1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1cnc2ccccc21

Procedure:
Using general procedure 2 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.125 g, 0.48 mmol) and benzimidazole (0.067 g, 0.57 mmol) gives the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](Cl)[C:12]#[CH:13].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:12]#[CH:11]
Reactant: C#CCCl
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C#CCNc1ccc(C(C)=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 25 g (0.185 mol) of 4-aminoacetophenone, 12.7 ml (0.176 mol) of propargyl chloride, and 35 ml of diisopropylethylamine in 500 ml of dry toluene is stirred at 60° C. for eight hours then at 90° C. for twenty-four hours. The reaction is cooled to room temperature and poured into a saturated sodium bicarbonate solution. The organic portion is separated and concentrated in vacuo to an orange oil. The oil is chromatographed on silica gel eluting with a gradient of 20-50% ethyl acetate in hexane. The appropriate fractions are concentrated to leave a pale yellow solid. The solid is recrystallized from ethanol to give two crops of the desired product, 14.99 g (49% yield); mp 97°-100° C.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:19](=[O:35])[NH:20][CH:21]([CH:24]([C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1)[OH:25])[CH2:22][CH3:23])[CH2:12][C:13]1([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]1)C1C=CC=CC=1>[Pd]>[NH2:10][C@@H:11]([CH2:12][C:13]1([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:19]([NH:20][C@H:21]([CH:24]([C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1)[OH:25])[CH2:22][CH3:23])=[O:35]
Reactant: CCC(NC(=O)C(CC1(C)CCCC1)NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Agent: [Pd]
Product: CC[C@H](NC(=O)[C@@H](N)CC1(C)CCCC1)C(O)c1nc2ccccc2o1

Procedure:
Pd/C (5%) (60 mg) was added to a solution of of [1-[1-(benzoxazol-2-ylhydroxymethyl)propylcarbamoyl]-2-(1-methylcyclopentyl)ethyl]-carbamic acid benzyl ester
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)=[O:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1

Procedure:
Using an analogous procedure to that described in Example 33, 6-chloropyrid-3-ylcarbonyl chloride was reacted with 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide to give the title compound; NMR Spectrum: (DMSOd6) 2.3 (s, 3H), 3.05 (t, 4H), 3.75 (t, 4H), 6.65-6.75 (m, 1H), 7.18 (t, 1H), 7.25-7.3 (m, 1H), 7.3-7.5 (m, 2H), 7.7 (d, 1H), 7.75-7.85 (m, 1H), 7.97 (s, 1H), 8.35-8.45 (m, 1H), 9.0 (d, 1H), 10.0-10.04 (s, 1H), 10.26-10.29 (s, 1H); Mass Spectrum: M+H+ 451.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:27]>CO>[C:1]1([S:7]([CH2:8][CH2:9][NH:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:15][CH2:16]2)=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCSc4ccccc4)CC3)cc2o1
Solvent: CO
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCS(=O)c4ccccc4)CC3)cc2o1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a stirred, ice—Cold, suspension of NaIO4 (0.13 g, 0.62 mmol) in H2O (1.2 mL) was added 6-[trans-4-(2-phenylsulfanylethylamino)cyclohexyl]-3H-benzoxazol-2-one (0.25 g, 0.62 mmol). The viscous reaction mixture was diluted with H2O (1.5 mL), warmed to room temperature, and then further diluted with MeOH (15 mL). After 21 hours, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) gave the free base of 6-[trans-4-(2-benzenesulfinylethylamino)cyclohexyl]-3H-benzoxazol-2-one, which was converted to the HCl salt (0.13 g, 49%): mp 107-110° C.; IR (KBr): 2936, 2783, 1768, cm−1; 1H NMR (500 MHz, DMSO-d6): δ 9.03 (br s, 2H), 7.74-7.60 (m, 5H), 7.16 (s, 1H), 6.99-6.97 (m, 2H), 3.48-3.43 (m, 1H), 3.33-3.29 (m, 1H), 3.18-3.04 (m, 4H), 2.54-2.52 (m, 2H), 1.86-1.84 (m, 2H), 1.51-1.44 (m, 4H); API-MS (m/z): 385 [M+H]+; HPLC: method A, 7.01 minutes (98.1%); method B, 12.83 minutes (99.2%); Anal. Calcd for C21H24N2O3S.HCl.1.25H2O: C, 56.88; H, 6.25; N, 6.32. Found: C, 56.86; H, 6.18; N, 6.22.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH:5]=[N:4][C:3]=1[C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][N:6]1[C:2]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[C:3]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[N:4]=[CH:5]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccnc(-c2ncn(Cc3ccccc3Cl)c2Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ccnc(-c2ncn(Cc3ccccc3Cl)c2-c2ccc(F)cc2)c1
Yield: 88.6 %

Procedure:
A mixture of 2-[5-bromo-1-[(2-chlorophenyl)methyl]imidazol-4-yl]pyridine-4-carbonitrile (270 mg, 0.726 mmol), 4-fluorophenylboronic acid (203 mg, 1.452 mmol), Pd(dppf)Cl2 (60 mg, 0.0726 mmol) and Na2CO3 (0.3 mL, 1.452 mmol, 2 M) in dioxane (10 mL) was refluxed overnight under N2, concentrated and purified by FCC (DCM/MeOH=20/1) to give the title compound (250 mg, 88%). [M+H] Calc'd for C22H14ClFN4, 389. Found, 389.
Reaction SMILES: C(Cl)CCl.ClC(Cl)C(O)=O.[NH2:11][C:12](=[O:40])[CH:13]([CH:15]([NH:20][C:21]([C:23]1[C:24]([N:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[N:30]2)=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[CH2:16][CH2:17][CH2:18][CH3:19])[OH:14].O>CS(C)=O>[NH2:11][C:12](=[O:40])[C:13]([CH:15]([NH:20][C:21](=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[N:29]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]=[N:30]1)[CH2:16][CH2:17][CH2:18][CH3:19])=[O:14]
Reactant: CCCCC(NC(=O)c1cccnc1-n1cc(-c2ccccc2)cn1)C(O)C(N)=O
Agent: O=C(O)C(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCCl
Product: CCCCC(NC(=O)c1cccnc1-n1cc(-c2ccccc2)cn1)C(=O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
0.47 g of EDC and 0.08 ml of dichloroacetic acid were added to 100 mg of N-[1-(2-amino-1-hydroxy-2-oxoethyl)pentyl]-2-(4-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide (0.25 mmol) in 4 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature overnight. For workup, the reaction mixture was poured into H2O, and the resulting precipitate was filtered off with suction and dried in a vacuum drying oven at 40° C. 77 mg of the title compound were obtained as an amorphous white solid. ESI-MS [M+H]+=406.2
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH3:23])[C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=1)#[N:2].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:34]([CH3:35])[C:33](=[O:36])[CH2:32][CH2:31][CH2:30][C:29]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:20][C:19]1[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:5]([CH2:4][CH2:3][C:1]#[N:2])[CH3:23])=[O:22])=[N:15][C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[N:34]([CH3:35])[C:33](=[O:36])[CH2:32][CH2:31][CH2:30][C:29]=3[CH:37]=2)=[N:17][CH:18]=1
Reactant: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Yield: 34.9 %

Procedure:
N-(2-Cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (101 mg, 0.288 mmol), 7-Amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (48 mg, 0.25 mmol), and 10-Camphorsulfonic acid (5.0 mg, 0.022 mmol) in Isopropyl alcohol (2.0 mL) were added into a microwave vial and irradiated at 120° C. for 30 min. The reaction was diluted with satd. sodium bicarbonate (5 mL) and cooled to aid in precipitate formation. The solids were collected and washed with 7 mL water. The solids contained product with starting chloropyrimidine and another impurity. The filtrate contained the aniline component, product and other impurities. The filtrate was extracted 3×10 mL DCM, dried and concentrated. The solids were chromatographed (ISCO, 12 g silica gel, 0-100% EtOAc:Hex) separately from the filtrate, and clean fractions were combined to give the product as a yellow foam (44 mg, 35%). LCMS: 504 (M+H), 1H-NMR (CDCl3): 8.93 (s, 1H), 8.34 (d, 1H, J=8.2 Hz), 8.10 (s, 1H), 7.44 (m, 3H), 7.37 (d, 1H, J=7.8 Hz), 7.18 (dd, 1H, J=7.4, 7.4 Hz), 7.07 (d, 1H, J=8.3 Hz), 6.95 (s, 1H), 3.81 (br s, 2H), 3.33 (s, 3H), 3.20 (s, 3H), 2.81 (br s, 2H), 2.64 (m, 2H), 2.32 (t, 2H, J=7.2 Hz), 2.15 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[N:15](OCCC(C)C)=[O:16].Cl>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9](=[N:15][OH:16])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC(=NO)C2=O
Temperature: 25 °C
Reaction time: 44 h
Yield: 137.7 %

Procedure:
5-tert-butyl-indan-1-one (9.39 g, 39 mmol) was dissolved in 150 ml methanol. Isoamyl nitrite (5 g, 43 mmol) and conc. HCl (5 ml) were added, and the reaction stirred at ambient temperature for 44 hours. The solvents were removed under vacuum to give 11.67 grams of crude product which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.82 (d, 1H), 7.51 (s, 1H), 7.49 (d, 1H), 3.83 (s, 2H), 3.50 (s, 1H, OH) 1.34 (s, 9H). MS (CSI) m/e 218 (M+H)+, 235 (M+NH4)+
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([NH2:16])([C:13]([OH:15])=[O:14])[CH2:8]2)[CH3:2].C(N(CC)CC)C.[C:24](=O)([O:40]N1C(=O)CCC1=O)[O:25][CH2:26][CH:27]1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(#N)C.O>[C:24]([CH:8]1[C:9]2[C:4](=[C:3]([CH2:1][CH3:2])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1([NH2:16])[C:13]([OH:15])=[O:14])([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CCc1cccc2c1CCC(N)(C(=O)O)C2
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.4 %

Procedure:
A mixture of racemic 5-ethyl-2-aminotetraline-2-carboxylic acid (765 mg, 3.49 mmole), triethylamine (1.0 ml, 7.17 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 1.79 g, 5.31 mmole) in acetonitrile (40 ml) and water (40 ml) was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH ˜3 with 10% aqueous citric acid solution, and the white emulsion extracted twice with methylene chloride, twice with ethyl acetate. The methylene chloride extracts were washed with water, brine and dried over magnesium sulfate. The ethyl acetate extracts were washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-ethyl-2-aminotetraline-2-carboxylic acid (330 mg, 21% yield) as a white solid. HRMS (FAB): C28H28NO4 (M+H) calc. 442.2018; observed: 442.2010.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH2:11][OH:12]>>[CH2:11]([O:12][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCO
Product: CCOC(=N)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
4-Bromo-benzonitrile (5 g) was suspended in absolute EtOH (100 ml) and cooled to 0-5° C. HCl gas was bubbled through, initially vigorously for several minutes and later slowly for 5 hours. The resulting solution was allowed to stir overnight. Most of solvent was removed and the precipitate was filtered, washed with EtOH twice and dried to afford compound 2BM (4.1 g) as white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]2[O:15][CH2:16][O:17][C:12]2=[CH:11][C:10]=1[CH:18]([CH3:23])[C:19](OC)=[O:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>COCCO>[CH3:23][CH:18]1[C:10]2[CH:11]=[C:12]3[O:17][CH2:16][O:15][C:13]3=[CH:14][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:26][NH:25][C:19]1=[O:20]
Reactant: NN
Reactant: COC(=O)C(C)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Solvent: O
Solvent: COCCO
Product: CC1C(=O)NN=C(c2ccccc2)c2cc3c(cc21)OCO3
Yield: 18 %

Procedure:
A mixture of methyl 2-(2-benzoyl-4,5-methylenedioxyphenyl)propionate, hydrazine hydrate (0.45 mL), and 2-methoxyethanol (6 mL) was heated to reflux for 20 h. The solvent was then removed in vacuo and the residue was purified by a flash chromatography (EtOAc:Hex=1:1.5) to yield the product as a white solid (62 mg, 18%), mp, 206°-209° C. 1H NMR (CDCl3) 8.45 (s, 1H), 7.62 (m, 2H), 7.45 (m, 3H), 6.88 (s, 1H), 6.63 (s, 1H), 6.05 (s, 1H), 6.00 (s, 1H), 3.29 (q,J=6.7, 1H), 1.62 (d,J=6.7, 3H).
Reaction SMILES: [C:1]1([PH+:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC[C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:29]([C:36]2[CH:41]=[CH:40][C:39](CBr)=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1.[C:50]1([P:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C1(C)C=CC=CC=1>CN(C=O)C>[C:25]1([C:28]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=1.[C:14]1([PH+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:63]1([PH+:56]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1ccc(C(=C(c2ccccc2)c2ccc(CBr)cc2)c2ccccc2)cc1
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(C(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
Triphenylphosphonium salt, TPE-TPP, was prepared from 3 (0.5 g, 1.0 mmol) and triphenylphosphine (1.0 g, 4.0 mmol) in DMF at 100° C. After stirring for 24 h, the solution was poured into large amount of toluene. The white precipitate was collected in 80% yield. 1H NMR (400 MHz, DMSO-d6), δ (TMS, ppm): 7.90-7.55 (m, 30H), 7.16-6.66 (m, 18H), 5.039 (d, 4H). 13C NMR (100 MHz, DMSO-d6), δ (TMS, ppm): 143.4, 142.5 140.1, 135.2, 134.0, 131.1, 130.6, 130.3, 130.1, 128.0, 127.0, 126.1, 118.1, 17.2, 40.21. m/z (MALDI-TOF) 882.49 [M−2Br)+]; calc. 882.35. Anal. Calcd. C64H52Br2P2: C, 73.7; H, 5.0. Found: C, 73.7; H, 4.9.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>CO.C1(C)C=CC=CC=1.ClCCl.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>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:7]=[O:8]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccccn1
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: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccccn2)c1
Yield: 88.8 %

Procedure:
2M aq. Na2CO3 (5 mL) and a solution of 3-formylphenylboronic acid (1.14 g, 7.60 mmol) in methanol (5 mL) were added to a solution of 2-bromopyridine (1.00 g, 6.33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) in toluene (10 mL) and the mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.03 g (89%) of the title compound. MS 184 (M+H)+.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:13]=[N:12][C:11]=1[C:22]([N:24]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1)=[O:23])(OCC)=O)C.[S:50]1[CH:54]=[CH:53][N:52]=[C:51]1[CH:55]=O.[H-].[Na+]>C1COCC1.C(=O)([O-])O.[Na+]>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10](/[CH:9]=[CH:55]/[C:51]2[S:50][CH:54]=[CH:53][N:52]=2)=[C:11]([C:22]([N:24]([CH2:46][CH:47]([CH3:48])[CH3:49])[C@H:25]2[CH2:30][C@@H:29]([C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:26]2)=[O:23])[N:12]=[N:13]1
Reactant: CCOP(=O)(Cc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F)OCC
Reactant: O=Cc1nccs1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1/C=C/c1nccs1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
tert-Butyl (3S,5R)-3-[({5-[(diethoxyphosphoryl)methyl]-1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (470 mg) and 1,3-thiazole-2-carbaldehyde (90 mg) were dissolved in THF (4 ml), sodium hydride (50% in oil, 50 mg) was added under ice-cooling and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (327 mg).
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCCCC(=O)O)CCc2ccc(C#N)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 798 mg (1.48 mmol) of ethyl 7E-8-[2-(4-tert-butylbenzyloxy)phenyl]-6-[2-(4-cyanophenyl)ethyl]oct-7-enoate in 20 ml of THF and 20 ml of water is mixed with 71 mg (2.97 mmol) of lithium hydroxide and stirred at 50° C. for 12 hours. Cooling is followed by dilution with water and diethyl ether and separation of the phases. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. 700 mg (1.4 mmol, 93% of theory) of the title compound are obtained.
Reaction SMILES: BrC1C=CC(C(NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)(C)C)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58]4(OCC(C)(C)C[O:59]4)[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])([CH3:49])[CH3:48])=[CH:43][CH:42]=1>>[Br:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:50]2[CH2:55][CH2:54][C:53]3([CH2:67][CH2:66][C:58](=[O:59])[CH2:57][CH2:56]3)[O:52][C:51]2=[O:68])([CH3:49])[CH3:48])=[CH:43][CH:42]=1
Reactant: CC1(C)COC2(CCC3(CCN(C(C)(C)c4ccc(Br)cc4)C(=O)O3)CC2)OC1
Agent: CC1(C)COC2(CCC(O)(CCNC(C)(C)c3ccc(Br)cc3)CC2)OC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC(C)(c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O

Procedure:
The title compound is prepared from 9-{2-[1-(4-bromo-phenyl)-1-methyl-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[1-(4-bromo-phenyl)-1-methyl-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained after that is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 37% of theory; LC (method 6): tR=1.28 min; Mass spectrum (ESI+): m/z=380/382 (Br) [m+H]+.