Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](/[CH:8]=[CH:9]/[CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3](OC)[O:4]C.C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O>[CH3:1][CH:2]([CH:8]=[CH:9][CH:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH:3]=[O:4]
Reactant: COC(OC)C(C)/C=C/C=C(C)CCC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC=CC(C)C=O
Reaction time: 24 h
Yield: 101.8 %

Procedure:
To a 250 mL four-neck reaction flask protected from atmospheric moisture by nitrogen gas throughout the course of the reaction a mixture of 12.6 g of (E)-2,6,10-trimethyl-1,1-dimethoxy-3,5,9-undecatriene (0.05 mol) of formula (2A), 100 mL THF and 1.2 g of PTSA was added. After stirred until homogeneous, 22 g of water was added, and additional 24 h of stirring at 20˜25° C. was needed until the reaction completed according to GC. Then a solution of 2 g of NaHCO3 and 20 mL water was added for neutralization. After removal of THF by vacuum distillation, 100 mL of cyclohexane was added and then stratification. The organic layer was washed with 30 mL water, dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 10.5 g of crude 2,6,10-trimethyl-3,5,9-undecatriene-1-aldehyde of formula (12).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH:8]([N:11]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:12](=[O:28])[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:10])[CH3:9]>C1COCC1>[O:6]=[C:1]1[N:14]([CH2:13][C:12]([N:11]([CH:8]([CH3:10])[CH3:9])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[O:28])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:3](=[O:4])[CH2:2]1
Reactant: COc1ccccc1N(C(=O)CNc1ccccc1Nc1ccccc1)C(C)C
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccccc1N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)C(C)C
Reaction time: 8 h

Procedure:
Malonyl dichloride (0.50 mL) in THF (22 mL) is added dropwise over 35 min to a 0° C. solution of N-Isopropyl-N-(2-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Part C, (1.90 g, 4.87 mmol) in THF (45 mL) and the resultant mixture allowed to attain RT overnight. The solvents were removed in vacuo and the residue purified by silica gel flash column chromatography using 2% methanol in methylene chlorideas eluent to afford 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(2-methoxy-phenyl) acetamide (770 mg) as a cream foam, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ7.60-6.90 (m, 13H), 5.05 (m, 1H, J=6.9), 4.60-3.40 (m, 7H), 1.12 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH2:21]1
Reactant: COc1cc2nccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nccc(CN3CCC(N)CC3)c2cc1OC
Yield: 71887552 %

Procedure:
tert-Butyl 1-((6,7-dimethoxyquinolin-4-yl)methyl)piperidin-4-ylcarbamate (1 g, 2.49 nmol) was dissolved in DCM (25 mL). While stirring, TFA (1.9 mL, 25 mmol) was added dropwise at rt, and the reaction was allowed to stir for 15 hours. The solvent was removed and the crude compound was taken up in EtOAc (150 mL) and washed with sat. sodium bicarbonate (20 mL). The organics were washed with brine, dried with sodium sulfate, and concentrated. The mixture was columned using 100% DCM to 7% MeOH to give the desired product 1-((6,7-dimethoxyquinolin-4-yl)methyl)piperidin-4-amine (0.54 g, 1.79 mmol, 72% yield). MS (ESI pos. ion) m/z: 302.2 (MH+). Calc'd exact mass for C17H23N3O2: 301. 1HNMR (400 MHz, CDCl3): 8.63-8.64 (d, J=4.4 Hz, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.22-7.23 (d, J=4.4 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.83 (s, 2H), 2.84-2.87 (bd, J=12.0 Hz, 2H), 2.70-2.73 (m, 1H), 2.11-2.16 (bt, J=11.2 Hz, 2H), 1.78-1.82 (bd, J=12.8 Hz, 2 H), 1.37-1.41 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:19]>C(O)C.O>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1cccc(F)c1F
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cnccc1Nc1cccc(F)c1F
Yield: 77.9 %

Procedure:
To a solution of 4-chloro-3-nitropyridine (3.0 g, 18.9 mmol) in dry ethanol as added 2,3-difluorobenzenamine (3.66 g, 28.3 mmol). The reaction mixture was refluxed for 30 min. After cooling and concentration in vacuo to give a brown solid, the crude product was taken up in water and the aqueous solution adjusted to a pH of 8-9 and the solution extracted with EtOAc (3×100 mL). The combined organics were washed with water (3×100 mL) and brine solution (1×100 mL), respectively, dried over Na2SO4, and evaporated in vacuo to give a light brown solid. The crude product was triturated with petroleum ether (3×30 mL) to afford N-(2,3-difluorophenyl)-3-nitropyridin-4-amine (3.7 g, 79% yield) as light yellow solid.
Reaction SMILES: [CH2:1]([S:7]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([CH3:19])=[N:16][C:15]=2[CH:20]=1)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([O:30]CC)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[CH2:34](OCC)[CH3:35]>CO>[C:21]1([CH3:33])[CH:22]=[CH:23][C:24]([S:27]([O-:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:34]([N+:16]1[C:15]2[CH:20]=[C:11]([NH:10][S:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:9])=[O:8])[CH:12]=[CH:13][C:14]=2[O:18][C:17]=1[CH3:19])[CH3:35]
Reactant: CCCCCCS(=O)(=O)Nc1ccc2oc(C)nc2c1
Reactant: CCOCC
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: CCCCCCS(=O)(=O)Nc1ccc2oc(C)[n+](CC)c2c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A mixture of 60 grams (0.2 Mol) 5-hexylsulfonamido-2-methylbenzoxazole and 44 grams (0.22 Mol) ethyl p-toluenesulfonate was heated in a round bottom flask at 150° C. for 5 minutes. Upon cooling to room temperature the crude brown mass almost solidified. The product was dissolved in 25 mL methanol and poured into 300 mL diethyl ether with rapid stirring for one hour. The solid precipitate was chilled at 2° C. for 12 hours, then filtered. The tan powder was thoroughly washed with ether and recrystallized from 200 mL hot isopropyl alcohol to yield 23.4 grams (47 mMol, 23% yield) of white crystalline product, m.p.=159°-161° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[N:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][C:17]([F:18])([F:19])[F:20])[CH:13]=[CH:12][C:11]=1[N:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: COc1cc(OC(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC(F)(F)F)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Trifluoroacetic acid (90 mL) was added to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-[2-methoxy-4-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate (Description 17, 3.4 g) in dichloromethane (135 mL) and the mixture was stirred at room temperature for 1 h. The mixture was allowed to warm to room temperature, saturated aqueous sodium bicarbonate solution (380 mL) was added and the mixture was extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale brown solid (1.84 g, 74%). 1H NMR (250 MHz, CDCl3) δ3.28-3.58 (8H, m), 3.87 (3H, s), 6.77 (1H, d, J 1.9 Hz), 6.84 (1H, d, J 8.9 Hz), and 6.91-6.95 (1H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12]O)[CH:7]=2)[CH2:3][CH2:2]1.O=S(Cl)[Cl:16].C(O)(C)C>C(Cl)Cl>[ClH:16].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][Cl:16])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: OCc1cc(OCC2CC2)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Cl
Product: ClCc1cc(OCC2CC2)ccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
4-cyclopropylmethoxy-2-hydroxymethylpyridine (93% pure) (0.9 g 0.0046 mol) was dissolved in methylene chloride (10 ml) and cooled to 0° C. SOCl2 (0.5 ml, 0.0069 mol) in methylene chloride (5 ml) was added dropwise at 0° C. and the reaction mixture was stirred 15 min at room temperature. Isopropanol (0.5 ml) was added and the mixture was evaporated giving the desired product (0.68 g, 78%). NMR data is given below.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1CC[CH2:12][CH2:11][CH2:10]1.C#CC>[Cu]I.O>[C:10]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)#[C:11][CH3:12]
Reactant: Nc1ccc(I)cc1
Reactant: C1CCNCC1
Agent: [Cu]I
Agent: C#CC
Solvent: O
Product: CC#Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.47 g (25 mmol) of 4-iodoaniline, 0.878 g (1.25 mmol) of bis-triphenylphosphine palladium dichloride, 0.47 g (2.5 mmol) of copper (I) iodide, and 20 mL of piperidine are placed in a pressure apparatus. Then 6.1 bar gaseous propyne are piped into the pressure apparatus, while the temperature rises to 39° C. It is therefore cooled with water. The mixture is stirred for 2 hours at ambient temperature and the reaction mixture is then extracted with ethyl acetate and water. The organic phase is dried over sodium sulfate, evaporated down, and the residue purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (4:1)). Yield: 2.1 g (64% of theory); C9H9N (M=131.17); calc.: molecular ion peak (M+H)+: 132; found: molecular ion peak (M+H)+: 132.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7]O.C(O[CH:12]=[C:13]([C:30]([C:32]1([CH3:35])[CH2:34][CH2:33]1)=[O:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[C:26]([F:29])([F:28])[F:27])=[O:15])C>>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[CH:12]=[N:7][O:31][C:30]=2[C:32]2([CH3:35])[CH2:34][CH2:33]2)=[O:15])=[C:17]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)(=[O:24])=[O:23]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1C(F)(F)F)C(=O)C1(C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC1(c2oncc2C(=O)c2ccc(S(C)(=O)=O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
Sodium acetate (1.0 g) was added to a stirring mixture of hydroxylamine hydrochloride (0.85 g) and 2-ethoxymethylene-1-(4-methylsulphonyl-2-trifluoromethylphenyl)-3-(1-methylcyclopropyl)propane-1,3-dione (4.2 g) in industrial methylated spirit (200 ml). The mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness and then suspended in ethyl acetate (100 ml). The resultant suspension was washed with water (100 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-(4-methylsulphonyl-2-trifluoromethylbenzoyl)-5-(1-methylcyclopropyl)isoxazole (compound 99, 3.5 g) as a white solid, m.p. 141°-142° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccc(F)c2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 3-fluorobenzenesulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 522 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[C:32]([OH:35])[CH:33]=3)[CH2:28][CH2:27][N:26]2[CH3:37])[CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.O>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([F:36])=[C:32]([O:35][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:33]=3)[CH2:28][CH2:27][N:26]2[CH3:37])[CH2:24][CH2:23][CH2:22]1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CN1CCc2cc(F)c(O)cc2C1C1(c2ccccc2Cl)CCC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1cc2c(cc1F)CCN(C)C2C1(c2ccccc2Cl)CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Decanoyl chloride (0.66 g) in dichloromethane (5 ml) was added to a stirring mixture of (+)-1-[1-(2-chlorophenyl)cyclobutyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (1.5 g, prepared in a similar manner to that described in Example 64), triethylamine (1.06 g) and dichloromethane (25 ml). The mixture was stirred at ambient temperature for 20 minutes, then water (20 ml) was added and stirring continued for 1 hour. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried over magnesium sulphate, filtered and concentrated in vacuo to yield (-)-1-[1-(2-chlorophenyl)cyclobutyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.31 g). This had a specific optical rotation αD of -5.59°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([OH:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].CC1C=[CH:19][C:20](S(O)(=O)=O)=[CH:21][CH:22]=1.C1(=O)CCC1>C1(C)C=CC=CC=1>[C:19]12([O:14][C:11]3[CH:12]=[CH:13][C:8]([C:5]4([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]4)=[CH:9][C:10]=3[O:15]1)[CH2:20][CH2:21][CH2:22]2
Reactant: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ccc3c(c2)OC2(CCC2)O3)CC1
Yield: 461 %

Procedure:
To a solution of 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (1.0 g, 4.8 mmol) in toluene (30 mL) was added TsOH (0.10 g, 0.50 mmol) and cyclobutanone (0.70 g, 10 mmol). The reaction mixture was heated at reflux for 2 h before being concentrated under vacuum. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 15:1) to give methyl 1-(spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-5-yl)cyclopropanecarboxylate (0.6 g, 50%). 1H NMR (CDCl3 300 MHz) δ 6.78-6.65 (m, 3 H), 3.62 (s, 3 H), 2.64-2.58 (m, 4 H), 1.89-1.78 (m, 2 H), 1.56-1.54 (m, 2 H), 1.53-1.12 (m, 2 H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])=[CH:16][CH:15]=1.[NH2:26][C:27]1[CH:51]=[CH:50][C:30]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]3[CH:38]=[C:39]([C:41]4[CH2:46][CH2:45][N:44]([C:47](=O)C)[CH2:43][CH:42]=4)[S:40][C:33]=23)=[C:29]([F:52])[CH:28]=1.CCN(C(C)C)C(C)C>C1COCC1.CO>[F:52][C:29]1[CH:28]=[C:27]([NH:26][C:2]([N:22]2[CH2:23][CH2:24][N:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[C:21]2=[O:25])=[O:4])[CH:51]=[CH:50][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[CH:38]=[C:39]([C:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH:42]=3)[S:40][C:33]=12
Reactant: O=C1NCCN1c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CN1CC=C(c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
Triphosgene (209.2, 0.47 mmol) was added to a solution of 1-(4-fluorophenyl)imidazolidin-2-one (209.2 mg, 0.71 mmol) in THF (4.7 mL) and the mixture was heated to reflux for 6 h. 1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone 270 (120.0 mg, 0.31 mmol) and DIPEA (0.1 mL, 0.5 mmol) were added and the mixture was stirred for 1 h at room temperature. The reaction mixture was transferred to a silica gel flash chromatography column and eluted with 3% MeOH in DCM affording 264 (97.6 mg, 0.16 mmol, 52% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.47 (d, 5.5 Hz, 1H), 7.84 (dd, J=2.4 Hz, 13.1 Hz, 1H), 7.71-7.63 (m, 2H), 7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.27 (m, 2H), 6.63 (m, 1H), 6.42 (m, 1H), 4.21 (br, 1H), 4.15 (br, 1H), 3.96-3.93 (m, 4H), 3.71-3.65 (m, 2H), 2.70 (br, 1H), 2.59 (br, 1H), 2.09 (s, 1.5H), 2.05 (s, 1.5H). MS (m/z): (M+1) 590.2 (100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>C1C=CC=CC=1.[Ag]=O>[CH3:23][O:22][C:20]([CH2:19][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:21]
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)C1CCCCNC1
Agent: O=[Ag]
Solvent: c1ccccc1
Product: COC(=O)CN1CCCCC(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of 1.46 g 3-benzyloxycarbonylperhydroazepine and 1.06 g methvl bromoacetate in 30 ml benzene add 1.06 g silver oxide. Stir the reaction in the dark for 24 hr., filter and concentrate the filtrate in vacuo. Dissolve the residue in HCl (pH 1.5) and wash the solution with ether. Make the aqueous phase to pH 12 and extract with ethyl acetate. Dry and concentrate the extracts to obtain 1-methoxycarbonylmethyl-3-benzyloxycarbonylperhydroazepine. NMR (CDCl3, TMS)-δ 1.8 ;(m, 6H); δ 2.8 (m, 2H); δ 3.1 (d, 2H); δ 3.45 (s, 2H); δ 3.65 (s, 3H); δ 5.15 (s, 2H); δ 7.3 (s, 5H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH:16]([NH:31][C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:50])[CH2:36][CH2:35]2)=[O:33])[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[O:18])[C:11](=[O:51])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[N:25]1([CH:22]2[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH:16]([NH:31][C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[NH:42][C:41]4=[O:50])[CH2:38][CH2:39]3)=[O:33])[CH2:15][N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:51])[CH2:20][CH2:21]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(NC(Cn1ccc(OCc2ccccc2)cc1=O)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Pd]
Solvent: CO
Product: O=C(NC(Cn1ccc(O)cc1=O)C(=O)N1CCC(N2CCCCC2)CC1)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 1 h

Procedure:
A stirred solution of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [1-(4-benzyloxy-2-oxo-2H-pyridin-1-ylmethyl)-2-[1,4′]bipiperidinyl1′-yl-2-oxo-ethyl]-amide (29 mg) and 10% palladium on charcoal (5 mg) in methanol (1 mL) was placed under an atmosphere of hydrogen. After 1 h at room temperature, the reaction was flushed with nitrogen, filtered through celite, and concentrated to give the product. 1H-NMR (CD3OD, 500 MHz) δ 1.40–1.85 (m, 12H), 2.04 (dd, J=27.4, 17.0, 2H), 2.66 (dd, J=21.1, 11.0, 1H), 2.80–3.19 (m, 8H), 3.95 (ddd, J=49.8, 12.5, 7.9, 1H), 4.07–4.28 (m, 3H), 4.34 (bs, 2H), 4.36–4.59 (m, 2H), 4.63 (bd, J=12.8, 1H), 5.20 (m, 1H), 5.75 (dd, J=7.3, 2.1, 1H), 5.97 (dd, J=8.9, 7.6, 1H), 6.78 (d, J=7.6, 1H), 6.93 (dd, J=7.6, 7.3, 1H), 7.08–7.18 (m, 2H), 7.33 (dd, J=18.3, 11.0, 1H). Mass spec.: 606.32 (MH)+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([OH:30])=[C:25]([Br:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:33][C:34](=[O:45])[C@H:35](O)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[C:27]([Br:29])[C:26]([O:30][C@@H:35]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([OH:45])=[O:33])=[C:25]([Br:31])[CH:24]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: COC(=O)[C@H](O)CCc1ccccc1
Product: O=C(O)[C@H](CCc1ccccc1)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3,5-dibromo-biphenyl-4-ol, and (R)-(−)-2-hydroxy-4-phenylbutyric acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 85-87° C.; MS m/e 709 (M−H)+;
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:12][N:13]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:12][NH2:13])[CH2:9][CH2:10][CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCC[C@H](CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of [(R)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-butyl]-carbamic acid tert-butyl ester (1.2 g, 3.61 mmol) and hydrazine monohydrate (1.0 mL, 20.6 mmol) in EtOH (25 mL) and DCM (75 mL) is stirred at RT for 48 h. The precipitated solid is removed by filtration and washed with DCM. The filtrate is concentrated in vacuo to afford the title compound as white solid that is used without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]([CH:17]([NH:26][CH:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[NH:29][C:28]1=[O:38])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].O>O1CCCC1>[CH2:7]([O:14][C:15]([CH:17]([NH:26][CH:27]1[CH2:33][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:28]1=[O:38])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1Nc2ccccc2CCC1NC(CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21
Temperature: 25 °C

Procedure:
Potassium t-butoxide (1.2 g) was added to a solution of 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (3.0 g) and t-butyl bromoacetate (2.2 g) in tetrahydrofuran (100 ml) stirring at room temperature under an atmosphere of dry nitrogen. The reaction mixture was stirred for 20 hours at room temperature, then poured into water (250 ml) and extracted with dichloromethane (2×150 ml). The combined dichloromethane solutions were washed with water (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 3-(1-benzyloxycarbonyl-3-phenylpropylamino)-1-t-butyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one.