Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13](=[O:22])[CH2:14][C:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:11][O:12][C:13](=[O:22])[CH2:14][C:15]1([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CC1(N)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CC1(Nc2ccccc2[N+](=O)[O-])CCCCC1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
To a mixture of 1-fluoro-2-nitrobenzene (450 □L, 4.3 mmol) and (1-amino-cyclohexyl)-acetic acid methyl ester (880 mg, 5.2 mmol) in DMF (5 mL) was added DIPEA (1.0 mL, 5.7 mmol). The mixture was heated at 90° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desired [1-(2-nitro-phenylamino)-cyclohexyl]-acetic acid methyl ester (230 mg, 19%).
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:40]([CH:43](C)C)CC)(C)C.C(Cl)(Cl)=[O:47].[OH-].[NH4+]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=1)[CH2:12][N:11]([CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36])[C:43]([NH2:40])=[O:47]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cl
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O)C1CCCCC1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 20 mg, 0.038 mmol) in dichloromethane (1 ml) was added diisopropylethyl amine (6 mg, 0.045 mmol) followed by phosgene (18.8 mg, 0.038 mmol) at room temperature and stirred for 1 hour. Reaction mixture was then treated with concentrated ammonium hydroxide (0.5 ml) and stirred at room temperature for overnight. The reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulphate and concentrated in vacuo. The product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1CV), 2-20% (10CV), 20% (2CV) to yield the title compound (7 mg, 30%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 6H) 1.4 (m, 1H) 1.59 (m, 4H) 1.67 (s, 1H) 1.94 (d, J=12.4 Hz, 1H) 3.1 (s, 3H) 3.92 (d, J=7.8 Hz, 1H) 4.6 (m, 4H) 7.36 (s, 1H) 7.45 (d, J=7.9 Hz, 1H) 7.53 (d, J=8.3 Hz, 1H) 7.68 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 570.2, Found: 615.6 (M+45).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1.[NH4+].[Cl-]>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1CCC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: OC1(c2ccc(Br)cc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 1,4-dibromobenzene (1.00 g, 4.24 mmol) at −78° C. in ether (20 ml) was added n-BuLi (2.65 ml, 1.6 M solution in hexane, 4.24 mmol) and the reaction mixture was stirred at −78° C. for 30 min. Cyclobutanone (348 μl, 4.66 mmol) was then added and the reaction mixture was stirred at −78° C. for 15 min. The reaction mixture was then slowly (over 2 h) warmed to 0° C. and stirred for a further 1 h. Water was added followed by sat. NH4Cl and the reaction mixture was extracted with ether. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:4 ether/pentane) to give 1-(4-bromophenyl)-cyclobutanol (330 mg, 34%) as a colourless oil. 1H NMR (CDCl3, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 2.57-2.48 (m, 2H), 2.41-2.31 (m, 2H), 2.02 (m, 1H), 1.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[CH2:17][O:16]1.I[Si](C)(C)C.Cl>C(Cl)(Cl)Cl>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:14][N:15]2[C:19](=[O:20])[C:18]([CH3:21])([CH3:22])[CH2:17][O:16]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Temperature: 60 °C
Yield: 26.2 %

Procedure:
A mixture of 2.0 grams (0.006 mole) of 2-[[2-chloro-4-(ethoxycarbonylamino)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone in 20 mL of chloroform was stirred under an argon atmosphere, and 1.1 mL (0.007 mole) of iodotrimethylsilane was added via syringe. The reaction mixture was heated to 60° C. where it was stirred for two hours. After this time the reaction mixture was warmed to 70° C. where it was stirred for 16 hours. The reaction mixture was cooled to ambient temperature, and 10 mL of methanolic 2N hydrochloric acid was added. The resultant clear solution was concentrated under reduced pressure, and the residue was slurried in 50 mL of water. An insoluble material was removed by filtration, and the filtrate was neutralized with an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with methylene chloride, and the combined extracts were dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a solid residue. The solid was recrystallized from hexane-ethyl acetate to yield 0.4 gram of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 105°-107° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH3:2].[CH:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1)([CH3:35])[CH3:32]
Reactant: CC(Nc1cc(-n2nc(N3CC4CC3CN4)c3ccccc32)ccn1)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1nn(-c2ccnc(N[C@@H](C)c3ccccc3)c2)c2ccccc12
Product: N
Temperature: 70 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of {4-[3-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-indazol-1-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine (0.03 g, 0.074 mmol) in chloroform (1 mL) were added acetone (0.5 mL) and sodium triacetoxyborohydride (0.039 g, 0.18 mmol) and the solution was stirred at 70° C. for 1 h. After cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate. The aqueous layer was back-extracted with methylene chloride (2×). The combined organic extracts were dried (K2CO3), filtered, and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% 2M NH3 in MeOH/CHCl3 gave the title compound as an off-white glass. MS (ES+): 453.3 [M+H]+, 451.4 [M−H]−.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH2:50]([O:52][C:53]([CH:55]1[CH2:60][CH2:59][N:58]([C:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]([CH:55]1[CH2:56][CH2:57][N:58]([C:61]2[CH:66]=[CH:65][C:64]([NH:67][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:63][CH:62]=2)[CH2:59][CH2:60]1)=[O:54])[CH3:51]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (926 mg, 3.6 mmol), triethylamine (910 mg, 1.25 mL, 9.0 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 2.51 g, 5.4 mmol) and 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester (3.6 mmol, prepared above) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with. EtOAc, and washed twice with water. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes) to provide 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid ethyl ester. HRMS calcd for C25H24F3N3O4 (M+H) 488.1792, obsd 488.1792.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:3][CH:2]=1.[Li]C(C)(C)C.CCCCC.CN(C)[CH:33]=[O:34].C(=O)=O>C1COCC1.C(OC(=O)C)C>[C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:33]=[O:34])[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cc1
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)cc1
Temperature: 25 °C

Procedure:
To a cold (-78° C.), stirred solution of 1-(tol-4-yl)3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound B 1 g, 3.2 mmol), in THF (17 mL) was added t-BuLi in pentane (1.7M solution, 3 mL, 5.1 mmol). After 10 minutes dry dimethylformamide (DMF) (600 mg, 8 mmol) was added and the dry-ice cooling was replaced with ice-water bath. The mixture was gradually warmed to ambient temperature and diluted with ethylacetate (150 mL), washed with water (15 mL). The organic layer was dried with MgSO4 and solvent was removed under reduced pressure. The crude material was purified by silicagel chromatography to afford the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[O:15][CH3:16].[N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)=O)=[CH:26][C:21]=2[NH:20][CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.O=P(Cl)(Cl)Cl>>[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]3[S:39][C:4]([CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=4[O:15][CH3:16])=[CH:3][N:2]=3)=[CH:26][C:21]=2[N:20]=[CH:19]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: COc1cccc(CCC(=O)CN)c1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc(CCc2cnc(-c3ccc4[nH]cnc4c3)s2)c1OC

Procedure:
The compound was synthesized starting from amino-4-(2,3-dimethoxyphenyl)butan-2-on-hydrochloride (223 mg; 1 mmol), benzimidazol-5-carboxylic acid (248 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol), TEA (0.22 ml, 3 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described above; yield: 0.019 g (5.2%); MS m/z: 366.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 2.94 (t, 2H, 3J=7.5 Hz); 3.14 (t, 2H, 3J=7.5 Hz); 3.72 (s, 3H); 3.78 (s, 3H); 6.81-6.83 (m, 1H); 6.89-6.91 (m, 1H); 6.96-7.00 (m, 1H); 7.62 (s, 1H); 7.79 (d, 1H, 3J=8.7 Hz); 7.90 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.16 (br s, 1H); 8.97 (s, 1H); HPLC (METHOD [A]): rt 13.59 min (97.7%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)CC=1.C(#N)C.I([O-])(=O)(=O)=[O:23].[Na+].F[C:29](F)(F)[C:30]([OH:32])=[O:31]>O.[Ru](Cl)(Cl)Cl.O.CCCCCC>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:29][C:30]([OH:32])=[O:31])=[C:17]([C:9](=[O:23])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=1
Reactant: COc1ccccc1C1=CCc2ccc(Cl)cc21
Reactant: O=C(O)C(F)(F)F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CC#N
Product: COc1ccccc1C(=O)c1cc(Cl)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12.02 g of the compound from Example 17A (44.76 mol) are mixed with 120 ml of acetonitrile, 120 ml of hexane and 180 ml of water. 39.25 g of sodium periodate (183.51 mol) and 0.18 g of ruthenium(III) chloride hydrate (0.81 mol) are added, and the mixture is stirred at room temperature for 48 h. For working up, the reaction mixture is acidified with a 5% aqueous trifluoroacetic acid solution and extracted three times with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is removed in a rotary evaporator. The residue is taken up in ethyl acetate, and the solution is stored at 5° C. for 16 h. The deposited crystals are filtered off and dried under high vacuum. 5.12 g (38% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:21])=[C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:16]=2)[C:10]#[N:11])[C:4]([C:22]([F:25])([F:24])[F:23])=[N:3]1.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[CH3:1][N:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:21][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:16]=2)[C:10]#[N:11])[C:4]([C:22]([F:25])([F:23])[F:24])=[N:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1nc(C(F)(F)F)c(C(O)=C(C#N)c2nc(C(C)(C)C)cs2)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)c(C(OC(=O)C(C)(C)C)=C(C#N)c2nc(C(C)(C)C)cs2)c1Cl
Temperature: 0 °C
Yield: 26.3 %

Procedure:
0.5 g of 3-(1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl)-2-(4-tert-butylthiazol-2-yl)-3-hydroxyacrylonitrile and 0.14 g of triethylamine were added to 15 ml of THF at room temperature and stirred to give a uniform solution. 0.16 g of pivaloyl chloride was dropwise added to the solution with cooling with ice, then gradually heated, and stirred at room temperature for 8 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed thrice with saturated saline. After having been dried over sodium sulfate, the resulting product was passed through a short column filled with silica gel. The solvent was distilled off under reduced pressure, and the residual product was applied to silica gel thin-layer chromatography (developer solvent: chloroform) to obtain 0.16 g of 3-(1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl)-2-(4-tert-butylthiazol-2-yl)-3-pivaloyloxyacrylonitrile (III-6) and 0.35 g of its geometric isomer (III-15).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:34].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:34])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(Oc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(Oc2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-phenoxypiperidin-1-yl)quinolin-7-yl]ethanone (0.0236 g, 0.0620 mmol) and ammonium acetate (0.0478 g, 0.620 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.15 mL, 0.15 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H25ClN3O (M+H)+: m/z=382.2; Found: 382.2.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:19](I)[CH3:20]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:19][CH3:20])[CH2:12][C@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
1.72 g of 60% sodium hydride in oil are added, under a nitrogen atmosphere, to a solution of 5 g of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid in 100 ml of THF, and the mixture is stirred for 45 minutes at RT. 3.27 g of ethyl iodide are then added, the mixture is refluxed for 3 hours and stirred for 18 hours while allowing the temperature to return to RT. The reaction mixture is concentrated under vacuum, the residue is taken up in 5% KHSO4 solution and extracted with EtOAc, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 4.5 g of the expected product are obtained in the form of an oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[NH:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>O.CC(C)=O>[Cl:19][CH2:20][C:21]([N:6]1[CH2:11][CH2:10][CH2:9][C:8]2([CH2:16][CH:15]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH2:14]3)[CH2:7]1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: C1CNCC2(C1)CC1CCC2CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)N1CCCC2(CC3CCC2CC3)C1

Procedure:
An amount of 20 g (0.244 mole) of sodium acetate and 18 g (0.100 mole) of spiro[bicyclo[2.2.2]octane2,3'-piperidine] is dissolved in 100 ml of water and 300 ml of acetone. A two-phase system is formed, to which is added dropwise at 0° to 5° an amount of 10.2 ml (14.4 g, 0.13 mole) of chloroacetyl chloride. An addition is then made to the mixture, at 0° to 5°, of 700 ml of water, whereupon the reaction product precipitates in flake form. Stirring is maintained for a further hour and the reaction product subsequently filtered off. After washing and then drying of the product over phosphorus pentoxide in a desiccator, there is obtained 1'-chloroacetyl-spiro [bicyclo[2.2.2]octane-2,3'-piperidine], M.P. 63° (with decomposition).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.[C:15](=O)([O-])[O-].[K+].[K+].S([O:26][CH3:27])(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[CH3:15][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:26][CH3:27])=[O:14]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1ccc2ccccc2c1OC
Yield: 90.4 %

Procedure:
To a solution of 1-hydroxy-naphthalene-2-carboxylic acid (5 g, 26.6 mmol) in acetone (100 mL) was added potassium carbonate (11 g, 79.72 mmol) followed by dimethyl sulfate (7.38 g, 58.46 mmol). The reaction mixture was refluxed overnight and then diluted with ethyl acetate (200 mL) and washed with water. The organic layer was dried (MgSO4), and the solvent was removed to give an oil (5.2 g): 1H NMR (CDCl3) δ 3.98 (s, 3H, CH3), 4.06 (s, 3H, CH3), 7.59 (m, 3H, Ar—H), 7.85 (m, 2H, Ar—H), 8.25 (m, 1H, Ar—H); MS 217 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.[CH2:17]([O:21][C:22](=[O:39])[CH:23](OC(=O)C)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[CH2:17]([O:21][C:22](=[O:39])[CH:23]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.73 g. (0.010 mol.) of phenol and 0.2 ml. of boron trifluoride etherate in 20 ml. of methylene chloride was added dropwise with stirring over a 15 minute interval 3.37 g. (0.011 mol.) of N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester. After three hours the reaction mixture was cooled and the precipitate collected by filtration to give N-benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester, m.p. 143°-144°.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4OCC4C=CC=CC=4)[C:19]3=[O:36])[N:13]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:44])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:45]([O:49][C:50]([C:52]1[C:60]2[CH2:59][CH2:58][N:57]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH:56]([CH2:68][N:69]3[C:77](=[O:78])[C:76]4[C:71](=[CH:72][CH:73]=[CH:74][C:75]=4OCC4C=CC=CC=4)[C:70]3=[O:87])[C:55]=2[S:54][C:53]=1[NH2:88])=[O:51])([CH3:48])([CH3:47])[CH3:46].C(OC(=O)C(N1C=CN=C1)=O)(C)(C)C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:36])[N:13]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:44])=[O:7])([CH3:3])([CH3:4])[CH3:2].[C:45]([O:49][C:50]([C:52]1[C:60]2[CH2:59][CH2:58][N:57]([C:61]([O:63][C:64]([CH3:66])([CH3:67])[CH3:65])=[O:62])[CH:56]([CH2:68][N:69]3[C:70](=[O:87])[C:71]4[C:76](=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:77]3=[O:78])[C:55]=2[S:54][C:53]=1[NH2:88])=[O:51])([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCN(C(=O)OC(C)(C)C)C2CN1C(=O)c2cccc(OCc3ccccc3)c2C1=O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3cccc(OCc4ccccc4)c3C1=O)N(C(=O)OC(C)(C)C)C2
Agent: CC(C)(C)OC(=O)C(=O)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCN(C(=O)OC(C)(C)C)C2CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above mixture of 2-amino-5-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester and 2-amino-7-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (0.15 g, 0.24 mmol) in distilled dichloromethane (4 ml) under nitrogen was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.14 g, 0.72 mmol) and the reaction mixture was stirred at ambient temperature for 1.5 hour. The volatiles were evaporated in vacuo and the crude residue was purified by silica gel chromatography using dichloromethane as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 50 mg of 2-(tert-butoxyoxalyl-amino)-5-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (A) and 50 mg of 2-(tert-butoxyoxalyl-amino)-7-(4-benzyloxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (B). Another 50 mg remained as a mixture of the two isomers (A) and (B).