Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][CH2:21]1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])=[O:6].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41]1>C(Cl)Cl>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)=[C:2]([NH:1][C:45]([C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)=[O:46])[CH:3]=1)=[O:6]
Reactant: O=C(O)c1ccsc1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccsc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 272.1 %

Procedure:
To a suspension of 3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.1 g, 0.229 mmol) in methylene dichloride (5 ml), triethylamine (0.069 g, 0.489 mmol), thiophene-3-carboxylic acid (0.044 g, 0.344 mmol) and 1-propane phosphonic cyclic anhydride (0.21 g, 0.489 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulphate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.34 g, 34%) of the titled compound as a brown solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][C:16](Cl)([CH3:19])[C:17]#[CH:18]>CC#N>[CH3:15][C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:19])[C:17]#[CH:18]
Reactant: Oc1ccc(I)cc1
Reactant: C#CC(C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(I)cc1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 4-iodophenol (5.01 g, 22.8 mmol) in CH3CN (100 mL) containing K2CO3 (15.7 g, 0.114 mol) was added KI (4.91 g, 29.6 mmol) followed by 3-methyl-3-chlorobutyne (7.01 g, 68.3 mmol) at room temperature. The reaction was heated to 80° C. for 60 hours. The reaction was cooled to room temperature, quenched with 2.5N NaOH and extracted with ether. The combined organic extracts were washed with 2.5N NaOH (2X eq. vol.), dried over anhydrous K2CO3 and concentrated. The residue was taken up in a minimal amount of 10% ether/petroleum ether and filtered through a 2" silica gel pad, using 10% ether/petroleum ether elution. The filtrate was concentrated to give 6.04 g, (93%) of product.
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:39]([O:42][C:43](Cl)=[O:44])([CH3:41])[CH3:40]>C(Cl)Cl>[CH:39]([O:42][C:43]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:24])([F:25])[F:23])=[O:16])=[CH:12][N:13]=2)[CH2:3][CH2:4]1)=[O:44])([CH3:41])[CH3:40]
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt (50 mg, 0.102 mmol) in methylene chloride (6 mL) was added triethylamine (0.1 mL). The clear solution was cooled in an ice bath and isopropylchloroformate (1M in toluene, 0.2 mL) was added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hr. The solvents were evaporated and the residue was triturated with methanol. The precipitate was filtered and dried to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid isopropyl ester (32.4 mg). LC-MS calcd for C24H24F3N5O4 (m/e) 503.2, obsd 503.8 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([O-:23])=[O:22].[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:30][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
To a solution of N-(2- dimethylaminoethyl)-N-methyl-4- chloro-3-nitrobenzenesulfonamide (2.2 g, 6.84 mmol) and 4- nitrophenol (0.97 g, 7.0 mmol) in dimethylformamide (30 mL) was added 60% sodium hydride-mineral oil suspension (0.28 g, 7.0 mmol). The resulting solution was stirred at 60° for 20 hours under N2. After concentrating under reduced pressure at 50° , the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed over silica gel and 2.8 g of the nitrophenyl ether eluted with 3% methanol-97% chloroform.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][Cl:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3](=[O:9])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: CC(C)(CCl)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1
Reaction time: 15 h
Yield: 80.4 %

Procedure:
213 g (1 mol) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one were added dropwise to a boiling suspension of 128.5 g (1 mol) of 4-chlorophenol and 140 g (1 mol) of potassium carbonate in 1,000 ml of absolute acetone. The mixture was stirred for 15 hours under reflux and was then allowed to cool, and the inorganic residue was filtered off and rinsed with acetone. The filtrate was concentrated by distilling off the solvent in vacuo and the residue was taken up in 1,000 ml of methylene chloride, washed three times with 250 ml of water at a time, dried over sodium sulphate and distilled. 210 g (80.7% of theory) of 4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 125°-127° C./0.1 mm Hg were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:2]1=2.[CH3:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14]>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([O:10][C:13](=[O:14])[C:12]([CH3:17])([CH3:16])[CH3:11])=[CH:9][C:2]1=2
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc2ccsc2c1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2ccsc2c1
Yield: 95.5 %

Procedure:
Dissolve benzo[b]thiophen-6-ol (10 g, 67 mmol) in pyridine (300 mL). Add 2,2-dimethyl-propionyl chloride (38 mL, 308 mmol) dropwise, and stir at room temperature for 8 hours. Concentrate in vacuo to ¼ volume, partition between ethyl acetate (250 mL) and water (250 mL). Separate layers, wash organic layer with water (250 mL) and brine (200 mL). Dry with magnesium sulfate, filter, and concentrate in vacuo to give 15 g of 2,2-dimethyl-propionic acid benzo[b]thiophen-6-yl ester (98%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29]>C1COCC1.CO>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccccn4)c3C2=O)C(=O)N1
Yield: 39.6 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pyridine-2-carbonyl chloride hydrochloride (0.71 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in a biphasic mixture of diethyl ether (20 ml)/20% NH4OH (20 ml) and filtered to give an off-white solid. The solid was re-slurried in methanol (20 ml) and filtered to give 0.30 g (40%) of product: mp 336–338° C.; 1H NMR (DMSO-d6) δ 11.83 (s, 1H), 11.20 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 8.15 (t, J=7.4 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.77–7.72 (m, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.22 (dd, J=5.2 and 12.5 Hz, 1H), 3.00–2.86 (m, 1H), 2.69–2.52(m, 2H), 2.15–2.11 (m, 1H); 13C NMR (DMSO-d6) δ 172.67, 169.67, 168.20, 166.61, 162.69, 148.83, 148.19, 138.45, 136.50, 136.16, 131.39, 127.72, 124.23, 122.46, 118.29, 116.32, 48.96, 30.91, 21.98; Anal. Calcd. For C19H14N4O5: C, 60.32; H, 3.73; N, 14.81. Found: C, 60.05; H, 3.57; N, 14.45.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)=[O:4].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCNC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCN1CC=C(c2ccc(Cl)cc2)CC1)C(F)(F)F
Yield: 44.9 %

Procedure:
Methanesulfonic acid 3-(2,2,2-trifluoroacetylamino)-propyl ester (4.51 g, 18.10 mmol), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (4.20 g, 18.25 mmol) and triethylamine (5.6 mL, 40.2 mmol) in ethanol (100 mL) were refluxed for 18 hours. The mixture was concentrated, redissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated on to silica gel. Flash chromatography using first an ethyl acetate/hexanes gradient followed by 3% methanol/ethyl acetate gave N-{3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-2,2,2-trifluoro-acetamide (2.82 g, 45%) as a white solid. Mp. 105-107° C.; NMR CDCl3 δ 9.58 (br s, 1H), 7.27-7.24 (m, 4H), 6.01-5.98 (m, 1H), 3.49 (g, J=5.3 Hz, 2H), 3.20-3.17 (m, 2H), 2.77 (t, J=5.7 Hz, 2H), 2.73-2.69 (m, 2H), 2.55-2.51 (m, 2H), 1.80 (p, J=3.6 Hz, 2H); 13C NMR CDCl3 δ 138.80, 134.41, 133.15, 128.52, 126.22, 120.99, 57.72, 52.80, 50.15, 40.96, 27.61, 23.23; IR (KBr) 3300, 3099, 2981, 2953, 2925, 2907, 2810, 2758, 2734, 1695, 1558, 1494, 1469, 1444, 1352, 1184, 1137, 1118, 1097,801,722,692.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[S:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]1
Reactant: NCc1ccsc1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCc1ccsc1
Yield: 93.1 %

Procedure:
Using the same reaction conditions as those of Example 4, 3-(aminomethyl)thiophene hydrochloride (4 mmol), triethylamine (4.4 mmol) and dodecanoyl chloride (4.0 mmol) were reacted to give N-(3-thienylmethyl)dodecanamide (1.1 g, 92%) M.p. 83°-84° C. (Found: C, 68.9; H, 10.2; N, 4.8; S, 10.8. Calculated for C17H29NOS: C, 69.1; H, 9.8; N, 4.7; S, 10.9%); EI m/e Intensity (%): 295 (18, M+), 97 (46, C4H3S.CH2+); δH(CDCl3) 7.01-7.30 (3H, m), 5.80 (1H, br,s), 4.46 (2H, d), 2.20 (2H, t), 1.80 (2H, m), 1.25 (16H, m), 0.87 (3H, t);
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>CN(C)C1C=CC=CC=1>[Cl:19][C:6]1[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:16])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCOC(=O)CCc1c(C)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)CCc1c(C)nc(C)nc1Cl
Yield: 72 %

Procedure:
A mixture of ethyl 3-(2,6-dimethyl-3H-pyrimidin-4-on-5yl)propionate (3.87 g, 0.017 mol), phosphorus oxychloride (40 mL), and N,N-dimethylaniline (10 drops) was heated under reflux for 2 h. The mixture was concentrated, cooled, and ice water was added. Solid KOH was added to bring the pH to 6 and the mixture was extracted with ether. The extracts were dried (MgSO4) and concentrated to give 2.95 g (72%) of product as a brown oil.
Reaction SMILES: C[O-].[Na+].I.[CH2:5]([S:7][C:8](=[NH:10])[NH2:9])[CH3:6].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>CCO>[NH2:19][C:18]1[C:15]([C:16]#[N:17])=[CH:14][N:9]=[C:8]([S:7][CH2:5][CH3:6])[N:10]=1
Reactant: CCSC(=N)N
Reactant: CCOC=C(C#N)C#N
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: CCSc1ncc(C#N)c(N)n1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A suspension of NaOMe (2.7 g, 50 mmol) in EtOH (200 mL) is added to a mixture of S-ethylisothiourea hydroiodide (11.58 g, 50 mmol), ethoxymethylidenemalononitrile (6.1 g, 50 mmol) and ethanol (250 mL) at 25° C. The reaction mixture is refluxed under N2 for 2 h, and then the solution is concentrated on a hot plate until precipitation is observed. After cooling, the solid is collected by suction filtration and is stirred in water at 25° C. Filtration and vacuum oven drying affords 4-amino-5-cyano-2-ethylthiopyrimidine (4.02 g, 45%) as a brown solid. 1H NMR δ (DMSO) 8.45 (1H, s), 7.90 (2H, brs), 3.00 (2H, q, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH2:1]([C:3]([CH:5]=[CH2:6])=[O:4])[CH3:2].C[O-].[Na+].[N+:10]([CH3:13])([O-:12])=[O:11]>CO>[N+:10]([CH2:13][CH2:6][CH2:5][C:3](=[O:4])[CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: C=CC(=O)CC
Reactant: C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)CCC[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To ethylvinylketone (41.4 g, 493 mmol) in MeOH (150 mL) and nitromethane (160 mL) was added sodium methoxide (ca. 123 mmol; 27 mL of a 25% solution in MeOH). The mixture was warmed to −10° C. over 30 min. After 1.5 h at −10° C., the mixture was quenched with saturated NH4Cl (250 mL) and water (250 mL). The mixture was pured into a separatory funnel and the lower organic layer was removed. The aqueous portion was extracted with CH2Cl2 (2×250 mL) and the combined organic portions were dried with MgSO4 and concentrated. The resultant liquid was reconcentrated from toluene (2×250 mL) followed by methanol (1×250 mL) to yield the desired material.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:13])[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1.[C-:14]#[N:15].[K+].C(OCC)(=O)C>CN(C=O)C>[F:13][C:5]1[C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=[C:3]([CH2:2][C:14]#[N:15])[CH:4]=1
Reactant: Fc1cc(CCl)cc2c1OCCO2
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1cc(F)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 7-(chloromethyl)-5-fluoro-2,3-dihydro-1,4-benzodioxine (0.92 g, 4.55 mmol) and potassium cyanide (1.55 g, 23.8 mmol) in DMF (10 mL) was stirred at 60° C. for 18 h. After cooling to rt ethyl acetate (100 mL) was added and the mixture was washed with water (2×30 mL) then brine (30 mL) and dried over sodium sulfate. Filtration and concentration followed by column chromatography on silica (4:1 hexanes/ethyl acetate) afforded (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)acetonitrile (0.42 g, 46% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 6.61 (m, 2H), 4.30 (s, 4H), 3.62 (s, 2H)
Reaction SMILES: C1C=CC(COC([NH:11][C@@H:12]([C:19]([OH:21])=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=CC=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]2)[CH2:25][CH2:24]1.[H][H]>CO.[Pd]>[CH:16]1[CH:15]=[CH:14][C:13]([C@@H:12]([NH2:11])[C:19]([OH:21])=[O:20])=[CH:18][CH:17]=1.[CH3:22][N:23]1[CH2:24][CH2:25][CH:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([NH2:37])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:28]1
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CN1CCC(C2CCN(C(N)=O)CC2)CC1
Solvent: CO
Product: N[C@@H](C(=O)O)c1ccccc1

Procedure:
A vigorously stirred solution of CBz-D-phenylglycine-4-(1-methylpiperidin-4-yl)piperidinamide (1.1 g, 2.45 mmol) in methanol (120 ml), containing Palladium on carbon (200 mg) was treated with hydrogen gas (balloon) at atmospheric pressure overnight. The reaction mixture was filtered through celite and concentrated to yield the title compound as a colourless oil (585 mg, 76%).
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:17][NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21]>>[CH:1]1([C:6]2[C:15]3[C:10](=[C:11]([CH2:17][NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21])[CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2c(C3CCCC3)nccc2c1
Reactant: O=C(NCO)C(Cl)Cl
Product: O=C(NCc1cccc2c(C3CCCC3)nccc12)C(Cl)Cl

Procedure:
1-Cyclopentylisoquinoline (obtained from 1-cyano-2-benzoyl-1,2-dihydroisoquinoline and cyclopentyl bromide) and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to obtain 1-cyclopentyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 151.0° to 152.3° C. The product was successively reacted in the same way as in steps (c), (d), (e), and (f) of Example 18 to afford 1-cyclopentylisoquinoline-5-acetonitrile having a melting point of 99.4° to 100.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:33][CH2:34][C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[C:40](B1OC(C)(C)C(C)(C)O1)([CH3:42])=[CH2:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([C:40]([CH3:42])=[CH2:41])[CH:3]=[CH:4][C:5]=4[O:33][CH2:34][C:35]4([CH3:39])[CH2:38][O:37][CH2:36]4)[CH2:13][C:12](=[O:14])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Br)ccc2OCC2(C)COC2)C12C(=O)Nc1cc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OCC2(C)COC2)c(C2CC(=O)NC(c3cc(Cl)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 80 °C
Yield: 12.7 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(3-methyl-oxetan-3-ylmethoxy)-phenyl]-6-chloro-2′-(5-chloro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.08 mmol), isopropenylboronic acid pinacol ester (40 mg, 0.24 mmol) and K3PO4 (50 mg, 0.24 mmol) in THF was added Pd(PPh3)4 (15 mg). The mixture was heated at 80° C. for 8 h under an argon atmosphere, purified by prep-HPLC to give the title compound as a white solid (6 mg).