Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.I([O-])(=O)(=O)=O.[Na+].[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH3:10]>OS(O)(=O)=O>[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[I:1])[CH3:10]
Reactant: II
Reactant: CCc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CCc1ccc(C=O)cc1I
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
Iodine (0.245 mL, 4.73 mmol) and sodium metaperiodate (0.340 g, 1.59 mmol) were added slowly portionwise successively to stirred 95% H2SO4 (30.0 mL) at 25° C. and the mixture was stirred for 30 min to afford a dark brown iodinating solution. The iodinating solution was added dropwise to a stirred suspension of 4-ethylbenzaldehyde (1.34 g, 10 mmol) in 95% H2SO4 (10.0 mL) over 45 min while maintaining the temperature at 25-30° C. Stirring was continued for a further 15 min and the reaction was quenched by slowly pouring into stirred ice-water (300 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to afford 4-ethyl-3-iodobenzaldehyde, as a colorless solid. 1H NMR (600 MHz, CDCl3): δ 9.87 (s, 1H); 8.28 (d, J=1.7 Hz, 1H); 7.77 (dd, J=7.8, 1.6 Hz, 1H); 7.36 (d, J=7.8 Hz, 1H); 2.78 (q, J=7.6 Hz, 2H); 1.23 (t, J=7.6 Hz, 4H).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:24])=O)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:47]([O:49][C:50](=[O:53])[CH2:51][NH2:52])[CH3:48]>CN(C)C=O.ClCCl>[CH2:47]([O:49][C:50](=[O:53])[CH2:51][NH:52][C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:24])[CH3:48]
Reactant: CCOC(=O)CN
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cc(C(=O)N[C@H](CC)c2ccccc2)c2n1CCOC2
Temperature: 40 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (50 mg, 0.168 mmol) in dimethylformamide (1.7 ml) was added 1-hydroxybenzotriazole (23 mg, 0.168 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.168 mmol). The mixture was stirred for 1 h at 40° C., then amino-acetic acid ethyl ester (17 mg, 0.168 mmol) was added and the mixture was stirred at 25° C. overnight. Excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The residue was dissolved in a small amount of acetonitrile, excess water was added and the solution was freeze-dried to give 52 mg (82%) of {[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-acetic acid ethyl ester. LC/MS (method 4): Rt=1.19 min; m/z=414.2 (M+H+). 1H-NMR: δ (ppm)=8.46 (1H, t), 8.21 (1H, d), 7.35-7.36 (3H, m), 7.30 (2H, t), 7.21 (1H, t), 4.91 (2H, dd), 4.82 (1H, q), 4.19 (2H, t), 4.11 (2H, q), 3.90-3.92 (4H, m), 1.71-1.83 (2H, m), 1.21 (3H, t), 0.88 (3H, t).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:24].[CH:25](/B(O)O)=[CH:26]\[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][S:11][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH3:24])=[C:2](/[CH:25]=[CH:26]/[CH3:27])[N:10]=2)=[CH:14][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: C/C=C/B(O)O
Reactant: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
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: COCCOC
Solvent: O
Product: C/C=C/c1nc(SCc2ccc(OC)c([N+](=O)[O-])c2)nc2c1ncn2C
Yield: 86.3 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine (100 mg, 0.273 mmol) was dissolved in dimethoxyethane (4 ml), then trans-propenylboronic acid (70 mg, 0.815 mmol) and tetrakis(triphenylphosphine)palladium (0) (30 mg, 0.025 mmol) were added. Then 106 mg (1.0 mmol) of sodium carbonate dissolved in water (2 ml) was added, and the mixture was heated to reflux for 2 hours. After cooling it, the insolubles were filtered off with Celite, the filtrate was distilled away under reduced pressure, ethyl acetate (20 ml) and water (20 ml) were added to the residue and extraction was performed. After washing with water, drying was carried out with anhydrous magnesium sulfate, the insolubles were filtered off, the filtrate was distilled away under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: methanol=50:1) to obtain 2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-6-(1-trans-propenyl)-9H-purine (87.5 mg, 86%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=O)[CH2:8][CH2:7]1.S(Cl)(Cl)=O.[CH3:37][N:38]([CH:40]=O)[CH3:39]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([NH:6][C:12]2[CH:13]=[CH:14][C:15]([CH2:40][N:38]([CH3:37])[CH:39]3[CH2:25][CH2:24][O:23][CH2:20][CH2:19]3)=[CH:16][CH:11]=2)=[O:32])[CH2:8][CH2:7]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCCOC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (250 mg) in THF (10 ml) were added thionyl chloride (0.083 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1.5 hours. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (15 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (138 mg) and triethylamine (0.48 ml) in THF (3 ml) at 0° C. The mixture was stirred at room temperature for 3 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:4→1:3→1:2), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 1-(3-methoxypropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 103) (264 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[C@H:3]([OH:6])[CH2:4]Cl.[OH-].[K+].O>C(O)C>[F:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH2:1])[C@H:3]2[CH2:4][O:6]2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 0.5 h

Procedure:
(1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylamine (EXAMPLE 17, 33 mg, 0.14 mmol) and absolute ethanol (1.5 mL) are mixed. Potassium hydroxide (9.8 mg, 0.175 mmol) in absolute ethanol (0.5 mL) is added to this mixture and the resulting mixture is stirred at 20-25 deg for 30 min. At this time ESMS indicates formation of the product (MH+=200.1). Water (2 mL) is added and mixture is concentrated under reduced pressure to half the volume and then diluted with ethyl acetate (15 mL). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (2×10 mL). The organic phases are combined, washed with saline and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to give the title compound, MH+=200.1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:21])=[O:15])[CH:9]=[CH:10][C:11]=1[Cl:12])(=O)C.[OH-].[K+]>O>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:21])=[O:15])=[CH:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1cc(NC(=O)c2ccoc2C)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1occc1C(=O)Nc1ccc(Cl)c(CO)c1
Temperature: 70 °C
Yield: 94.5 %

Procedure:
A solution of 29 g of the N-(3-acetoxymethyl-4-chlorophenyl)-2-methyl-3-furancarboxamide prepared in Step 4 above and 14.5 g potassium hydroxide in 110 ml water, was prepared. The solution was then heated at 70° C. for 16 hours and then acidified with 2N hydrochloric. The solid so produced collected, washed with water, and dried, producing 23.65 g of N-(4-chloro-3-hydroxymethylphenyl)-2-methyl-3-furancarboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C@@H:15]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:16]([NH:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20]1)=[O:17]>>[CH2:24]([N:21]1[CH2:22][CH2:23][C@H:19]([NH:18][C:16](=[O:17])[C@@H:15]([NH:14][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)=[O:11])[C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)[C@H](N)C(=O)N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CC(C)(C)[C@H](NC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)N[C@H]1CCN(Cc2ccccc2)C1

Procedure:
Compound 3b was prepared from 3-(trifluoromethyl)phenyl isocyanate and compound 2b, using the method described in Example 9. MS (EI)=476 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]#[N:16])[CH:10]=[N:11][CH:12]=1.[H][H]>[Ni].N.CO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1c1cncc(CCC#N)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1CCC[C@H]1c1cncc(CCCN)c1
Yield: 88.4 %

Procedure:
(S)-3-(5-(1-Methylpyrrolidin-2-yl)pyridin-3-yl)propanenitrile (preparation 3) (140 mg, 0.65 mmol) and Raney nickel (50 mg) in 20% ammonia in MeOH (50 mL) were stirred under 50 psi hydrogen at 50° C. for 4 hours. The reaction mixture was filtered through Celite then the solvent evaporated. The crude product was purified by flash chromatography (7% [20% ammonia in MeOH] in DCM) to give the title compound as a pale yellow oil (126 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CC(N(C)C)=O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Reaction time: 8 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (5.0 g) and dimethylaminopyridine (0.12 g) in dimethylacetamide (25 ml) was added dropwise phenyl chlorocarbonate (6.2 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5→3:7) to give phenyl (4-chloro-2-cyanophenyl)carbamate (7.04 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:34])([C:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:31])([F:30])[F:29])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:33])[C:19](=[O:32])[NH:20][N:21]=2)=[CH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:34])([CH:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([F:30])([F:29])[F:31])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:33])[C:19](=[O:32])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(c1cc2c(cc1C(F)(F)F)OCC1=NNC(=O)[C@@H](C)N12)C1(C)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(c1cc2c(cc1C(F)(F)F)OCC1=NNC(=O)[C@@H](C)N12)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 3-methyl-3-[1-((R)-4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-vinyl]-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, 0.089 g, 0.185 mmol) in MeOH (12 mL) was added 10% Pd/C (0.039 g, 0.037 mmol) and the reaction mixture was stirred under H2 at ambient temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 3-methyl-3-[1-((R)-4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (0.084 g, 94%). LC/MS (Table 1, Method 25) Rt=0.934 min; MS m/z: 427 [M+H−56]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:11][CH:9]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])=[CH:38][CH:39]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(N)CCc1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC(C)CCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-phenylbutan-2-amine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[NH2:19][C:20]1[C:21]([CH2:26][CH2:27][CH2:28][CH2:29]N)=[N:22][CH:23]=[CH:24][CH:25]=1>>[NH2:19][C:20]1[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][N:6]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Reactant: NCCCCc1ncccc1N
Product: Nc1cccnc1CCCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
Using a procedure similar to that of Example 16, 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone was reacted with 1.1 molar equivalents of 4-(3-amino-2-pyridyl)butylamine, to give 2-[4-(3-amino-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 130°-1.5°.
Reaction SMILES: [O:1]=[C:2]1[C@@H:5]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH2:14][O:15][Si](C)(C)C(C)(C)C)[N:3]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F.N1C=CC=CC=1.P(=O)(O)(O)O>C1COCC1.N1C=CC=CC=1>[OH:15][CH2:14][C@H:4]1[N:3]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:2](=[O:1])[C@H:5]1[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: F
Agent: O=P(O)(O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
N-{(3S,4S)-2-oxo-1-(phenylmethoxy)-4-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]azetidin-3-yl}(tert-butoxy)carboxamide (2.80 g, 6.41 mmol) was dissolved in THF (50 mL) and pyridine (5 mL). Pyridine-hydrofluoride complex (4.0 mL, 2.6 eq of pyridine, 24 eq of HF) was added at −20° C. After 10 min, the mixture was warmed up at room temperature and stirred for 3.5 h. Phosphoric acid buffer (0.025 M, KH2PO4/Na2HPO4; ratio 1/1, 400 mL) was added and the resulting solution was extracted with ethyl acetate (3×100 mL). The organic phase was dried over Na2SO4 and the solvent was evaporated in vacuo. 2.04 g of the desired product was obtained and used for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C@@H:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[NH2:6].C(N(C(C)C)CC)(C)C.[Br:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33]>ClCCl>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C@H:5]([NH:6][C:32](=[O:33])[C@H:31]([Br:30])[CH3:35])[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: C[C@@H](Br)C(=O)Cl
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](Br)C(=O)N[C@@H](Cc1ccccc1Br)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 25.7 g of benzyl (S)-2-bromophenylalaninate and 150 ml of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 20 ml of diisopropylethylamine followed by 13.2 g of (2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with dilute acetic acid solution, and evaporate off the solvents to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:20](=[O:21])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:22])=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(N)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: CCOC(=O)C(CC)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1

Procedure:
A mixture of ethyl-2-(p-aminobenzyl)-butyrate (4.4 g) and phthalic anhydride (3 g) is heat melted until ceasing of water evolution (5 minutes). After cooling, the solid as obtained is crystallized from ethanol. Yield: 4.8 g (68.6%); m.p. 86°-87° C. Analysis:
Reaction SMILES: [C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[C:22]([C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: NC(=O)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccc(C(N)=O)cc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-cyano-1,1-diphenylmethyl)piperidine (0.303 g), 4-carbamoylphenethyl bromide (0.275 g--see Preparation 5), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated inn vacuo to give the title compound as a gum, yield 0.065 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[F:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([N+:17]([O-:19])=[O:18])[CH:10]=3)[O:14][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c([N+](=O)[O-])c3)n2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 11 (12.46 g; 47.13 mmol) was dissolved in DCM (200 mL) and n,n′-dicyclohexylcarbodiimide (11.67 g; 56.56 mmol) was added. Then Intermediate 1 was added (10 g; 47.13 mmol) and the suspension was stirred at RT for 12 hours. The precipitate was filtered off and the solvent evaporated to give a yellow solid. The residue was dissolved in Toluene (300 mL) and Py (150 mL) and the solution was heated to 130° C. for 12 hours. The reaction mixture was concentrated to afford a yellow sticky oil which was precipitated from ACN affording the title compound as a yellow solid. LC/MS (Method B): 441.3 (M+H)+ HPLC: Rt 5.86 min (Purity: 95.1%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a solution of 5-phenyl-1-pentanol (3.28 g, 20 mmoles) and triethylamine (6.13 ml, 44 mmoles) in CH2Cl2 (35 ml) under N2, p-toluen-sulphonyl chloride (4.19 g, 22 mmoles) was added and then put under stirring up to room temperature for 1 night. The mixture was washed with water, NaHCO3 and 5% HCl, anhydrified and brought to dryness to give 6.55 g of the title compound (yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].I[CH2:30][CH2:31][CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH2:30][CH2:31][CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: COC(=O)C(C)(C)CCCI
Product: COC(=O)C(C)(C)CCCOc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Methyl 5-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2,2-dimethylpentanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and methyl 5-iodo-2,2-dimethylpentanoate according to general procedure D.