Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16]2[N:17]=[C:18](Cl)[N:19]=[CH:20][C:15]=2[C:14](=[O:22])[C:13]([C:23](=[O:25])[NH2:24])=[C:12]1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[NH2:26][C:12]1[N:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:27])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:16]2[N:17]=[C:18]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:39][CH:38]=3)[N:19]=[CH:20][C:15]=2[C:14](=[O:22])[C:13]=1[C:23](=[O:25])[NH2:24]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Cl)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Temperature: 120 °C
Yield: 19.6 %

Procedure:
A mixture of 0.60 g (1.51 mmol) of the product prepared in step 11.3 and 0.53 g (3.02 mmol) of 4-morpholin-4-ylphenylamine in 6.5 mL of NMP is placed in a 10 mL microwave tube. The sealed tube is placed in the microwave oven (CEM machine, Discovery model) and the mixture is heated under pressure at 120°C. for 60 minutes at a power of 75 W, and then cooled to room temperature. 15 mL of water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained by suction and then dried in an oven. The crude solid is triturated in methanol, drained by suction and dried in an oven under vacuum. 0.159 g of the expected product is obtained in solid form. Yield=20%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[O:9][C:5]=2[CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:22][C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:14]=[CH:13][C:6]=3[CH:7]=2)=[O:12])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2o1
Product: O=C(c1cc2ccc(C(F)(F)F)cc2o1)N1CCC[C@H]1CN1CCCCC1

Procedure:
71 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using 6-(trifluoromethyl)benzofuran-2-carboxylic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[C:23](O)(=[O:27])[C@H:24]([CH3:26])[OH:25].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:25][C@@H:24]([CH3:26])[C:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:12])[F:13])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2)=[O:27]
Reactant: C[C@H](O)C(=O)O
Reactant: N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
A solution of 0.26 g (0.85 mmol) (S)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one in 18 ml tetrahydrofurane was treated at 0° C. with 0.08 g (0.94 mmol) L-lactic acid, 0.13 g (0.85 mmol) 1-hydroxybenzotriazole hydrate, 297 μl (1.70 mmol) N-ethyldiisopropylamine and 0.17 g (0.85 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/heptane (0-100/100-0) yielded 0.22 g (68%) (S)-2-hydroxy-N—[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-propionamide as grey solid, MS: m/e: 379.4 (M+H+), [α] 589=−23° (1.1% in CHCl3).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH2:11][C:10](=[O:16])[CH2:9][C:8]=2[CH:7]=1)(=[O:5])=[O:4].N(C)[CH3:18]>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH2:11][C:10](=[O:16])[CH2:9][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)CC2
Reactant: CNC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonyl chloride (see Preparative Example 3, 1.0 g, 4.1 mmol) in CH2Cl2 (10 mL) at 15° C. (using a water bath) was added Me2NH (2M in THF, 8 mL, 16 mmol, 4 eq) dropwise. After stirring at room temperature for 30 minutes, the mixture was diluted with CH2Cl2 (30 mL), washed with H2O (20 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica using 20% EtOAc/hexanes to give 0.46 g (45%) of 7-oxo-5,6,7,8-tetrahydro-naphthalene-2-sulfonic acid dimethylamide as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, 1H, J=8.1 Hz), 7.53 (s, 1H), 7.41 (d, 1H, J=8.1 Hz), 3.65 (s, 2H), 3.14 (t, 2H, J=6.6 Hz), 2.71 (s, 6H), 2.58 (t, 2H, J=6.6 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[Br:13]Br.O>CC(O)=O>[Br:13][C:7]1[C:8]([OH:11])=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:12])[CH:1]=2
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2cc(Br)c(O)cc2c1
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of naphthalene-2,7-diol (5.00 g, 31.3 mmol) in AcOH (25 mL) was added Br2 (3.3 mL, 62.6 mmol) in AcOH (25 mL) dropwise over 15 minutes at 10-15° C., then mixture was stirred at 10-15° C. for 1 hour. Sn powder (7.75 g, 64.6 mmol) and H2O (20 mL) was added and the mixture was heated to 80° C. for 1 hour. The mixture was diluted with ice-water (50 mL), the extracted with EtOAc (30 mL×3), organic was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (PE/EtOAc=15/1) and further prep-HPLC (0.1% TFA as additive) gave the product (2.0 g, yield 27%) as a solid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:46])[CH2:7][N:8]([CH2:40][C:41]([O:43]CC)=[O:42])[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=[CH:12][C:11]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)C>>[C:41]([CH2:40][N:8]([C:9](=[O:39])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:13]=[CH:12][C:11]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:7][C:6]([OH:46])=[O:5])([OH:43])=[O:42]
Reactant: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 91 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[5-(tetradecyloxy)-2-(phenylmethoxy)benzoyl]glycine ethyl ester under conditions described in Example 81 gave N-(carboxymethyl)-N-[5-(tetradecyloxy)-2-(phenylmethoxy)benzoyl]glycine (91% yield, mp 71°-74°).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[CH:6]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:50]([CH:47]2[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]2)=[O:51])[CH:6]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3cccc(CC(=O)OC)c3)c2n1
Reactant: CN1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3cccc(CC(=O)OC)c3)C(=O)C3CCN(C)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product from step (iii) (0.1 g), diisopropyl ethylamine (0.1 ml) and 1-methylpiperidine-4-carboxylic acid hydrochloride (45 mg) were dissolved in NMP (3 ml) then HATU (130 mg) added to the mixture. The mixture was stirred at rt for 5 h then purified by SCX and RPHPLC, which afforded the title compound. Yield 70 mg.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([O:25]CC)=[O:24])=[C:20]([CH3:28])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]([OH:25])=[O:24])=[C:20]([CH3:28])[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1[nH]c(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a solution (10 mL) of ethyl 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carboxylate (200 mg) in tetrahydrofuran was added an aqueous solution (2 mL) of lithium hydroxide monohydrate (65 mg), and the mixture was stirred at 50° C. overnight. The reaction mixture was slowly warmed to room temperature and stirred overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N hydrochloric acid. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4) and concentrated to give the title compound (165 mg, yield 89%) as white crystals. melting point 127° C.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]2[N:11]([CH:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:24][CH2:23]3)[N:12]=[C:13]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)[C:6]=12.C1(C)C=CC(S([CH2:44][N+:45]#[C-:46])(=O)=O)=CC=1.O>CO>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C@@H:25]2[CH2:26][CH2:27][C@H:22]([N:11]3[C:7]4=[N:8][CH:9]=[N:10][C:5]([NH2:4])=[C:6]4[C:13]([C:14]4[CH:21]=[CH:20][C:17]([C:18]5[O:19][CH:46]=[N:45][CH:44]=5)=[CH:16][CH:15]=4)=[N:12]3)[CH2:23][CH2:24]2)[CH2:33][CH2:32]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(-c5cnco5)cc4)c4c(N)ncnc43)CC2)CC1
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
Sodium methoxide (130 mg, 2.41 mmol) was added in portions to a mixture of 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (300 mg, 0.715 mmol) in methanol (20 mL). After 5 minutes, (p-tolylsulfonyl)methyl isocyanide (tosmic) (167 mg, 0.858 mmol) was added in portions. The solution was heated at reflux for 5 hours. Water (10 mL) was added while it was still hot. After cooling on ice for 5 minutes, the solid was filtered and washed with a mixture of methanol/water (50/50, 2 mL) then dried. The filtrate was evaporated to remove organic solvent and the solid was collected and washed with water. The combined solid was first purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase then re-crystallized twice from DMF to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(1,3-oxazol-5-yl)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 27%). 1H NMR (DMSO-d6) δ 1.61 (m, 2H), 1.71 (m, 2H), 2.10 (m, 2H), 2.15 (s, 3H), 2.44 (m, 1H), 4.82 (m, 1H), 7.78 (m, 3H), 7.79 (m, 2H), 8.24 (s, 1H), 8.51 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=459.2, Rt 0.72 nm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:9][C:8]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16]/[N:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:23][CH:24]=2)=[CH:9][C:8]=1[O:29][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([C:39]([F:38])([F:49])[F:50])=[CH:41][CH:42]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(OCCON=Cc2ccc(C(C)(C)C)cc2)cc1O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(OCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1OC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 4-[2-(4-tert-butyl-benzylideneaminooxy)-ethoxy]-2-hydroxy-benzoic acid tert-butyl ester (0.298 g, 0.72 mmol) in methylene chloride (10 mL) was added triethylamine (0.200 mL, 1.43 mmol) and 4-trifluoromethyl benzoyl chloride (0.200 mL, 1.42 mmol). The reaction was stirred at room temperature overnight, poured into brine and the aqueous layer extracted with ethyl acetate. The combined organics dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (8/92) to afford 4-{2-[({(E)-[4-(tert-butyl)phenyl]methylidene}amino)oxy]ethoxy}-2-{[4-(trifluoromethyl)benzoyl]oxy}benzoic acid tert-butyl ester (0.405 g, 96%) as a colorless oil. 1H NMR (300 MHz, CDCl3); δ 8.33 (d, 2H), 8.12 (s, 1H), 7.97 (d, 1H), 7.78 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 6.92 (dd, 1H), 6.76 (d, 1H), 4.50 (t, 2H), 4.33 (t, 2H), 1.40 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7](=[O:31])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[CH2:22][OH:23])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[O:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]1=[O:31])[CH3:2]
Reactant: CCOC(=O)C=CC(=O)N(CC(C)(C)C)c1ccc(Cl)cc1C(CO)c1ccccc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CC1OCC(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.1 %

Procedure:
To dichloromethane (70 ml) were added 3-[N-[2-[1-(2-chlorophenyl)-2-hydroxyethyl]-4-chlorophenyl]-N-neopentylcarbamoyl]acrylic acid ethyl ester (6.8 g), 18-crown-6 (3.78 g) and potassium carbonate. The mixture was stirred for 3 days at room temperature. Insolubles were filtered off, then the solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=5:1 v/v as an eluent) to give 1.64 g of a non-crystalline solid product.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[O:17])[CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH3:18])[C:6](=[O:8])[N:5]([CH2:9][CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[C:4](=[O:17])[CH:3]=1
Reactant: CCCCC(CC)Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCC(CC)Cn1c(=O)cc(Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution containing 20 g of 6-chloro-3-(2-ethylhexyl)uracil thus obtained in 50 ml of dimethylformamide was added 11 g of potassium carbonate and then 12.1 g of methyl iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was poured into water and extracted twice with 100 ml of chloroform. The organic phase was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure to obtain 21 g of 6-chloro-3-(2-ethylhexyl)-1-methyluracil as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[CH:18]2[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:21][C:20](=[O:30])[NH:19]2)=[CH:5][CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([N:19]1[CH:18]([C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:32][CH:31]=2)[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:21][C:20]1=[O:30])(=[O:35])[CH3:34]
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1cc([N+](=O)[O-])ccc1SCc1ccc(OC)cc1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)C1=C(C)NC(=O)N(C(C)=O)C1c1cc([N+](=O)[O-])ccc1SCc1ccc(OC)cc1

Procedure:
The compound 2a is treated with excess acetic anhydride and is heated to reflux for 2 hours to yield the compound 2b.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2].Br[CH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1>>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: Cc1cc(CBr)no1
Product: COc1ccc2c(C=O)c(C(C)C)n(Cc3cc(C)on3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 137) and 3-(bromomethyl)-5-methylisoxazole by General Procedure J.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1>CC#N.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([OH:22])=[O:21])=[C:9]2[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: Cc1cc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-(7-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (71) was prepared by the method of Example 67 skipping step 7 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate. 1H-NMR: 400 MHz, (CD3OD) δ: 7.71 (m, 2H), 7.58 (m, 3H), 7.52 (dd, J=9, 2 Hz, 1H), 7.33 (m, 2H), 5.15 (s, 1H), 2.59 (s, 3H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 5 min run): tR (min)=3.67.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 42%. Melting point: 202-205° C. (Ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:4]=1[CH2:5][N:6]1[C@H:9]([CH2:10][C:11]#[CH:12])[C@H:8]([N:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]1=[O:33].C(O)(C)(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:58]([NH:65][CH2:66][CH2:67][N:68]=[N+:69]=[N-:70])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>CS(C)=O.CCOC(C)=O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:61]([O:60][C:58]([NH:65][CH2:66][CH2:67][N:68]1[CH:12]=[C:11]([CH2:10][C@@H:9]2[C@H:8]([N:13]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7](=[O:33])[N:6]2[CH2:5][C:4]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:3]=2[O:2][CH3:1])[N:70]=[N:69]1)=[O:59])([CH3:64])([CH3:62])[CH3:63]
Reactant: C#CC[C@@H]1[C@H](N(Cc2ccc(OC)cc2)C(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2Cc2cn(CCNC(=O)OC(C)(C)C)nn2)cc1
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To a solution of benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-(prop-2-yn-1-yl)azetidin-3-yl)(4-methoxybenzyl)carbamate (95.6 mg, 0.18 mmol) in a mixture of DMSO (1.2 mL), tert-butanol (1.2 mL) and water (1.2 mL), was added copper(II) sulfate pentahydrate (4.5 mg, 0.018 mmol), sodium L-ascorbate (35.8 mg, 0.18 mmol) and N-Boc-2-azidoethylamine (76 mg, 0.39 mmol). After stirring for 12 h, more copper(II) sulfate pentahydrate (10.6 mg, 0.23 equiv), sodium L-ascorbate (37.4 mg, 1.04 equiv) and N-Boc-2-azidoethylamine (82.1 mg, 2.44 equiv) were added. After stirring for 4 days total, the reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). Combined organic layers were washed with LiCl (5% aq), brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc-Hep, 0-40%) to afford the title compound (57.2 mg, 44%). LCMS: Rt=1.06 min, m/z=715.5 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])(=[O:3])[NH2:2].[C:13]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C>C(O)C.O=[Pt]=O>[C:13]([N:21]1[CH2:26][CH2:25][CH:24]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][C:1](=[O:3])[NH2:2])[CH2:23][CH2:22]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)CCc1ccccc1N
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)CCc1ccccc1NC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
2-(2-Carbamoylethyl)aniline (37 g) and 1-benzoyl-4-oxopiperidine (67.6 g) are dissolved in ethanol (500 ml) and to the solution is added acetic acid to adjust the pH of the solution to about 5.5. To the solution is further added PtO2 (1 g) and the mixture is stirred under 1 atm. at room temperature under H2 atmosphere. When H2 is absorbed up to 5 liters, the reaction is stopped and the catalyst is separated by filtration. The filtrate is concentrated to give N-(1-benzoyl-4-piperidinyl)-2-(2-carbamoylethyl)aniline.