Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([N:38]=[C:39]=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([NH:38][C:39]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)NC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 49 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.28 g, 1.9 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitnile (50 ml). After stirring for 1 hour, t-butylisocyanate (0.21 g, 2 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 ml) and washed with 0.1 N HCl (20 ml), water (20 ml), brine (20 ml) and dried. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol/isopropyl ether to give 0.36 g (51%) of the product: mp 186-188° C.; 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 7.77-7.59 (m, 3H), 6.17 (t, J=6.2 Hz, 1H), 5.86 (s, 1H), 5.08-5.01 (dd, J=5.4 and 12.4 Hz, 1H), 4.49 (d, J=6.0 Hz, 2H), 2.82-2.73 (m, 1H), 2.54-2.40 (m, 2H), 1.98-1.94 (m, 1H), 1.12 (s, 9H); 13C NMR (DMSO-d6) δ 172.33, 169.39, 167.11, 166.59, 156.85, 140.72, 134.20, 132.99, 131.06, 126.54, 121.20, 48.69, 48.37, 37.89, 30.46, 28.88, 21.53; Anal. Calcd. For C19H22N4O5+0.2 water: C, 58.51; H, 5.79; N, 14.37. Found: C, 58.86; H, 6.15; N, 14.24.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](OC)=[O:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>O1CCCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][OH:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
To 0.80 g (2.4 mmol) of methyl 1-benzyl-5-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate in 50 mL of tetrahydrofuran at −78° C. was added 7.3 mL (7.3 mmol) of DIBAL (1M in tetrahydrofuran). The mixture was allowed to warm to room temperature and stirred for 6 h. The reaction was quenched with 1N HCl and concentrated to a slurry. The slurry was dissolved in dichloromethane and was concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 4% methanol/dichloromethane mixture to give 0.44 g (60%) of the title compound as a light yellow powder.
Reaction SMILES: [CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=3[OH:40])[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].[OH-].[Na+].Br[CH2:48][CH:49]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:50][CH3:51]>COCCO>[CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:48][CH:49]([CH2:50][CH3:51])[CH2:52][CH2:53][CH2:54][CH3:55])=[CH:35][C:34]=3[OH:40])[N:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCCCC(CC)COc1ccc(-c2nc(-c3ccc(OCC(CC)CCCC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reactant: CCCCC(CC)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(-c2nc(-c3ccc(OCC(CC)CCCC)cc3)nc(-c3ccc(OCC(CC)CCCC)cc3O)n2)cc1
Reaction time: 0.25 h
Yield: 101.5 %

Procedure:
83.7 g (0.14 mol) of 4-{4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazin-2-yl}-1,3-dihydroxy-benzene together with 500 ml of Methylcellosolve are placed at 80 C. in a 1 l sulfonating flask fitted with stirrer, condenser, internal thermometer and dropping funnel. 18.1 g of a 30% sodium hydroxide solution (0.16 mol) are added, the mixture is stirred for 15 minutes and then a solution of 31.4 g (0.16 mol) of 3-bromomethylheptane and 30 ml of Methylcellosolve are added dropwise over 30 minutes. After stirring at 110 C. for 24 hours, alkylation is complete (thin-layer chromatogram). The mixture is evaporated to dryness under vacuum, the residue is dissolved in 500 ml of toluene and filtered, and the filtrate is subjected to extraction by shaking with water. Drying of the extracts over sodium sulfate and removal of the solvent by distillation give 100.9 g of a red-brown oil. The crude product is dissolved in 200 ml of toluene/ethyl acetate (97.5/2.5) and, for purification, is chromatographed over silica gel (10 cm×40 cm), giving 79.4 g (80% of theory) of the compound of the formula ##STR26## as a honeylike red-brown resin.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:34])=[O:2])[CH:8]=2)[N:12]([CH3:16])[CH:11]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1c(-c2cn(C)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1c(-c2cn(C)c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 115.1 %

Procedure:
3-[3-(2-Butoxy-3,5-diisopropylphenyl)-1-methyl-1H-indol-5-yl]-but-2-enoic acid methyl ester (119 mg, 0.26 mmol) was dissolved in methanol (2.5 mL)/dioxane (2.5 mL) and treated with 1N NaOH (2.5 mL) at 60° C. for 3 h. The reaction was diluted with 1N HCl (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic portions were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to provide 134 mg of residue. The material was purified using radial chromatography by elution with hexane:ethyl acetate gradient to provide 60 mg (52%) of a light yellow solid. 1H NMR (250 MHz, CDCl3): δ 8.05 (d, 1H, J=1.4), 7.49 (dd, 1H, J=1.6, 8.7), 7.44 (s, 1H), 7.38 (d, 1H, J=8.7), 7.07 (d, J=2.3), 7.30 (d, 1H, J=2.2), 7.10 (d, 1H, J=2.2), 3.89 (s, 3H), 3.47 (m, 3H), 2.97 (sep, 2H, J=6.9), 2.73 (s, 3H), 1.46 (m, 2H), 1.34-1.22 (m, 14H), 0.78 (t, 3H, J=7.3). MS [EI+] 448 (M+H)+[EI−] 446. Anal. Calcd for C29H37NO3: C, 77.82; H, 8.33; N, 3.13. Found: C, 77.50; H, 8.28; N, 3.15.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23]O)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].C(Br)(Br)(Br)[Br:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][Br:43])[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCO)c2)c2cccnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCBr)c2)c2cccnc21
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-hydroxy-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (90 mg, 0.16 mmol) in methylene chloride (1.5 ml) were added carbon tetrabromide (81 mg, 0.245 mmol) and triphenylphosphine (51 mg, 0.196 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane: 1:5) to give the title compound (53 mg, 0.086 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K2CO3 (anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H)+283.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1.N12CCCN=C1CCCCC2.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:61]([CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1)=[N+:62]=[N-:63]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(Cc1cccc(CN=[N+]=[N-])c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 9-{2-[2-(3-hydroxymethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (230 mg, 0.49 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL, 0.88 mmol), and tetrahydrofuran (12 mL) at 0° C. under an atmosphere of nitrogen was added diphenylphosphoryl azide (0.19 mL, 0.88 mmol). Mixture stirred overnight warming to room temperature. Solvent removed under vacuum and product isolated as a white solid after purification on silica. M+1=494.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH2:10])[CH:7]([CH3:9])[CH3:8]>CCOCC>[CH2:6]([NH:10][C:3](=[O:4])[CH2:2][Cl:1])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CN
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Product: CC(C)CNC(=O)CCl

Procedure:
Chloroacetyl chloride (ex. Aldrich) (50 g) was added dropwise, with stirring to isobutylamine (ex. Aldrich) (70 ml) in dry ether (250 ml) at 0° C. When the mixture had reached room temperature it was worked up in conventional fashion to give N-isobutyl 2-chloroacetamide. The latter (20 g) was heated for 3 hours at 120° C. with triethylphosphite (23 g). The mixture was subjected to distillation in vacuo to give N-isobutyl diethylphosphono acetamide (22.5 g, bp. 140-142.5° C. at 0.1 mm).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].Br>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Br
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Yield: 152.3 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose, 143 mg of cuprous oxide and 173 mg of 47% hydrobromic acid, and the mixture was refluxed in a warm-water bath at 60° C. for 8 hours. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, the same post-treatment as in Example 5 was carried out, thus giving 11.0 g (76.2%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11](CC2C=CC=CC=2)[CH2:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:11][CH2:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCC2)N(Cc2ccccc2)CC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CCCC2)NCC1(C)C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To 7.58 g of 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane-9-carboxylic acid tert-butyl ester in 140 ml of methanol was added 1.13 g Palladium on charcoal (10%) and the mixture was hydrogenated at r.t. and ambient pressure for 16 h. The catalyst was removed by filtration over celite and the filtrate was concentrated in vacuo to yield 5.38 g (95%) of the title compound, which was used without further purification.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].[OH-].[Na+:18]>O>[Na+:18].[C:10]([N:2]([OH:1])[CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[O-:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=P(O)(O)CCCNO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(O)CCCP(=O)([O-])O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3.8 g (0.02 mol) 3-(N-hydroxyamino)-propylphosphonic acid is introduced into 20 ml water and 4.51 g (0.044 mol) acetic anhydride are added drop by drop at room temperature. After the solution has been stirred for 1.5 hours at room temperature a pH of 2.5 is adjusted with 0.2 n NaOH, the solution is concentrated in the entire diaphragm pump vacuum, taken up twice in 40 ml water in each case, which are again removed by concentration and the oil is washed twice with 30 ml ether in each case, taken up in 50 ml water and a pH of 6.5 is adjusted with 1.6 g NaHCO3. After removal of volatile constituents under vacuum, 20 ml n-butanol are added to remove the residual water and are also removed under reduced pressure. The oil is boiled up twice with isopropanol, the isopropanol phase is discarded and the remaining glassy resin is pulverised with a spatula to a yellow solid (5.65 g). In order to recrystallise it, it is taken up in only a little methanol, filtered from the undissolved component and acetone is added dropwise to the filtrate. A first filtering results in 1 g product with a melting point of 175° C. Recrystallisation as described above is carried out again for further purification. (DE-A-27 33 658)
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21]C2CCSS2)=[CH:12][CH:11]=1)=[NH:8].C1[C@@H](CC(O)=O)[S:31][S:30]C1.S1CCC(CC(O)=O)S1.C1[C@@H](CCCCC(O)=O)SSC1>>[NH2:8][C:7](=[N:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][CH:19]2[CH2:20][CH2:21][S:31][S:30]2)=[CH:14][CH:15]=1)[C:3]1[S:2][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C[C@@H]1CCSS1
Reactant: N=C(Nc1ccc(NC(=O)CCCCC2CCSS2)cc1)c1cccs1
Agent: Cl
Agent: O=C(O)CC1CCSS1
Agent: O=C(O)CCCC[C@@H]1CCSS1
Product: NC(=Nc1ccc(NC(=O)CC2CCSS2)cc1)c1cccs1

Procedure:
The experimental protocol used is the same as that described for compound 1, with trisnorlipoic acid [or 2-(1,2-dithiolan-3-yl)acetic acid] (prepared according to Tetrahedron Letters, (1997), 38, 33, 5785) replacing lipoic acid. Yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][S:15](=[O:34])(=[O:33])[NH:16][C:17](=[O:32])[C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15](=[O:33])(=[O:34])[NH:16][C:17](=[O:32])[C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=CS(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
A solution of 880 mg of 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methylene]-piperidine-1carboxylic acid tert.-butyl ester in 100 ml of MeOH is hydrogenated (10% Pd/C as a catalyst). From the mixture obtained the catalyst is filtrated off and solvent is evaporated.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH2:60][CH2:61][C:62]#[N:63])[C:57](=[O:64])[CH2:56][O:55][C:54]=4[N:65]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH2:60][CH2:61][C:62]#[N:63])[C:57](=[O:64])[CH2:56][O:55][C:54]=4[N:65]=3)=[CH:48][CH:49]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCC#N)C(=O)CO4)cc2)CCC1
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: N#CCCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 98.2 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(3-cyanopropyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (35 mg, 0.065 mmol) was reacted to afford the title compound (28 mg). 1H NMR (500 MHz, CH3OD) 7.62 (1H, s), 7.41 (2H, d), 7.39 (2H, d), 7.3 (3H, m), 7.25 (2H, m), 4.98 (2H, s), 4.19 (2H, t), 2.73-2.79 (2H, m), 2.55-2.61 (4H, m), 2.22-2.25 (1H, m), 2.10-2.25 (2H, m), 1.95-1.99 (1H, m). LCMS (Method A): RT=4.01 min, M+H+=440.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH2:42]1[O:50][C:49]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][C:44]=2[O:43]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC.C(Cl)(Cl)Cl.CO.C(#N)C>[O:43]1[C:44]2[CH:45]=[CH:46][C:47]([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:18]5[C:23]([CH:24]=4)=[CH:22][C:21]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:20][CH:19]=5)=[C:12]4[C:8]=3[CH2:9][NH:10][C:11]4=[O:39])=[CH:48][C:49]=2[O:50][CH2:42]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc4c(c3)OCO4)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 46.6 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (50.0 mg, 0.0842 mmol) was dissolved in dimethoxyethane (4 mL), and the solution was treated with 3,4-methylenedioxybenzeneboronic acid (70.0 mg, 0.421 mmol). [bis(diphenylphosphino)ferrocene]dichloropalladium (13.7 mg, 0.0168 mmol), potassium carbonate (116 mg, 0.842 mmol) and water (0.060 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol/acetonitrile=8/0.5/0.5 to 0.4/0.5/0.5) to obtain 4-(benzo[1,3]dioxol-5-yl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (22.2 mg, yield 47%).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[C:10]([N:14]1[CH2:8][CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: COC(=O)C(Br)CCBr
Solvent: CC#N
Product: COC(=O)C1CCN1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The procedure of Cromwell described in J. Heterocyclic Chem. 6: 435 (1969) and 5: 309 (1968) was followed for the preparation of this ester. To a 200 ml round bottom flask was added 5.20 g (0.02 mol) methyl 2,4-dibromobutyrate, 80 ml acetonitrile and 4.69 g (0.06 mol) of t-butylamine. After stirring at room temperature for 5 minutes, heat was applied and the temperature raised to and maintained at reflux for 24 hours. The yellowish mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, giving a yellow liquid to which dry ether was added. The pot was vigorously shaken and the ether solution decanted. This was repeated three times. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to give a pale yellow liquid. Kugelrohr distillation at 65° (1.8 mm) afforded 2.3 g (70%) of a water-white liquid: IR (liquid film) cm-1 1750, 1725, 1275, 1230, 1200, 1175, 1130, 1060; NMR (CDCl3) delta 3.70 (3H, s), 3.93 (1H, t, J=8 Hz), 3.15 (2H, m), 2.13 (2H, m), 0.93 (9H, s).
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:5][C:6]([O:8]C)=O)#[N:2].[H-].[Na+]>COCCOC>[C:1]([C:3]1([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc([N+](=O)[O-])cc2)CCC1=O
Yield: 102.2 %

Procedure:
To a solution of 2 (88.96 g, 0.27 mol) in DME (1 L) at RT under N2 was added (carefully) NaH (60% in mineral oil, 31.92 g, 0.80 mol) to give a dark violet solution. The reaction was heated at reflux for 4 h, was cooled and quenched carefully with H2O, acidified with 2N HCl and extracted with 2×EtOAc. The combined organics were washed with saturated NaCl solution, dried over a mixture of activated charcoal and Na2SO4, filtered through Celite and evaporated to give crude product 3 as a brown solid (83.42 g, >100%). 1H-NMR (500 MHz, dmso-d6) 12.1 (s, 1H), 8.31 (d, 2H), 7.88 (d, 2H), 3.75 (s, 3H), 2.86 (AB quartet, 2H), 2.65 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H), 2.35 (m, 1H) ppm.