Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.CCOC(C)=O>[N:20]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-Chloro-5,6-diphenylpyrazine (45 mg, 0.17 mmol) in 500 μL DMF at room temperature under nitrogen was added sodium azide (11 mg, 0.17 mmol) and the reaction was warmed to 100° C. After stirring overnight, the reaction was cooled to room temperature, diluted with EtOAc (30 mL) and washed 4×30 mL with H2O and 1×30 mL with saturated NaCl. The organics were isolated, dried (MgSO4), filtered and concentrated to the 2-azidopyrazine, which exists as a yellow solid (45 mg, quantitative). 1H-NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.58-7.42 (m, 6H), 7.36-7.23 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: Cc1ccc(Br)cc1C=O
Reactant: CC#N
Product: Cc1ccc(Br)cc1C(O)CC#N

Procedure:
Addition of 5-bromo-2-methylbenzaldehyde to acetonitrile gave 3-(5-bromo-2-methylphenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (3.33 g, 86%): 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.0, 2.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.96 (d, J=4.4 Hz, 1H), 5.04-5.00 (m, 1H), 2.88 (ABd, J=16.8, 4.4 Hz, 1H), 2.77 (ABd, J=16.8, 6.4 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]([F:28])([F:27])[CH:25]=[CH2:26].O>CN(C)C=O>[F:27][C:24]([F:28])=[CH:25][CH2:26][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: C=CC(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC=C(F)F)C1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (30.0 g) in N,N-dimethylformamide (300 ml) were added potassium carbonate (36.2 g) and 3-bromo-3,3-difluoropropene (16 ml), and the mixture was stirred at 60° C. for 4.5 hours. To the reaction mixture was added water, and the mixture was extracted with n-hexane/ethyl acetate (1/1) solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the titled compound (33.5 g).
Reaction SMILES: [OH:1][C:2]1([C:31](O)=[O:32])[CH2:7][CH2:6][CH:5]([N:8]2[C:16]([NH:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[F:26])=[N:15][C:14]3[C:9]2=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=3)[CH2:4][CH2:3]1.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(NC(C)C)(C)C>C1COCC1>[CH:34]1([NH:39][C:31]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:8]3[C:16]([NH:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=4[F:26])=[N:15][C:14]4[C:9]3=[N:10][C:11]([NH:27][CH:28]([CH3:30])[CH3:29])=[N:12][CH:13]=4)[CH2:4][CH2:3]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)O)CC3)c2n1
Reactant: NC1CCCC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Nc1ncc2nc(Nc3c(F)cc(F)cc3F)n(C3CCC(O)(C(=O)NC4CCCC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1-Hydroxy-4-{2-[(methylethyl)amino]-8-[(2,4,6-trifluorophenyl)amino]purin-9-yl}cyclohexanecarboxylic acid (0.200 g, 0.4 mmol) was dissolved in 4 mL of dry THF. Cyclopentyl amine (0.079 mL, 0.8 mmol) was added neat followed by di-isopropyl amine (0.105 mL, 0.6 mmol). Benzotriazol-1-yloxytris (dimethylamino)phosphponium hexafluorophosphate (BOP) was added last, as a solid in one portion at room temperature (0.177 g, 0.4 mmol). The reaction was complete within 10 min as confirmed by LC-MS. DMF was removed under reduced pressure. The residue was triturated in saturated aqueous sodium bicarbonate. The resulting beige solid was collected by filtration and washed with water. The crude product was re-crystallized from hot methanol-water. The crystals were dried in vacuum oven. (141 mg, 66% yield) M+1: 532.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[NH2:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([Cl:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[Cl:36][C:24]1[CH:23]=[C:22]([NH:21][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[CH:20][C:11]=3[O:10][C@@H:9]([CH3:37])[CH2:8][NH:7][C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: COCC(=O)O
Product: COCC(=O)NC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 53 %

Procedure:
The procedure described in Example 1 was repeated using methoxyacetic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 3.20 (s, 3H), 3.40 (m, 1H), 3.72 (m, 1H), 3.75 (s, 2H), 4.93 (m, 1H), 5.29 (s, 2H), 7.23 (m, 2H), 7.31 (d, 1H), 7.58 (m, 2H), 7.70 (t, 1H), 7.86 (dt, 1H), 7.95 (s, 1H), 8.12 (d, 1H), 8.19 (t, 1H), 8.47 (s, 1H), 8.58 (m, 1H), 9.97 (s, 1H); Mass Spectrum MH+ 508.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][OH:19])[CH2:4][CH2:3][CH2:2]1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=[CH:30]3)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=[CH:30]4)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Temperature: 100 °C
Yield: 24.6 %

Procedure:
To a solution of [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (150 mg, 0.503 mmol), methyl 6-(4-hydroxyphenyl)-1-naphthalenecarboxylate (140 mg, 0.503 mmol), triphenylphosphine (145 mg, 0.553 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.553 mmol) dropwise. The solution was heated in a microwave reactor at 100° C. for 10 minutes. The product was purified by chromatography (silica gel, 0-15% ethyl acetate in hexanes gradient elution) to afford a white solid (0.069 g, 25%). 1H-NMR (DMSO-d6,) 8.77 (d, J=9 Hz, 1H), 8.23-8.20 (m, 2H), 8.09 (d, J=9 Hz, 1H), 7.93 (d, J=11 Hz, 1H), 7.70-7.51 (m, 6H), 6.90 (d, J=9 Hz, 2H), 4.83 (s, 2H), 4.00 (quintet, J=9 Hz, 1H), 3.92 (s, 3H), 2.43-2.31 (m, 4H), 2.10-1.92 (m, 2H). APCI-LCMS m/z 558 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[O:27]([NH2:29])[CH3:28]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([NH:29][O:27][CH3:28])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CON
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C(=O)O)cc1OCC2
Agent: Cl
Solvent: C1CCOC1
Product: CONC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with Methoxylamine hydrochloride (9.8 mg, 0.12 mmol) in THF to provide 168. LC/MS (ESI+): m/z 369 (M+H). 1H NMR (400 MHz, DMSO) δ 8.45 (t, J=16.8, 1H), 7.95 (d, J=26.9, 2H), 7.49 (dd, J=20.1, 18.6, 2H), 5.86 (dt, J=13.1, 6.4, 1H), 4.56 (d, J=2.8, 4H), 3.72 (s, 2H), 1.61-1.32 (m, 5H)
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH:15]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Temperature: 0 °C
Yield: 82.3 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 1.00 g, 8.84 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL) and a 60% dispersion of sodium hydride in mineral oil (423 mg, 10.61 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and the 3-bromomethyl-benzoic acid methyl ester (2.11 g, 9.20 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The reaction was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 10% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-(3-nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.90 g, 82%) as a white waxy solid: H1-NMR (400 MHz, CDCl3) δ 3.93 (3H, s), 5.42 (2H, s), 6.91 (1H, d, J=2.0 Hz), 7.42-7.48 (3H, m), 7.97 (1H, s), 8.03-8.04 (1H, m).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:40])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH:39]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:40])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(C(C)OCCOC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn(C(C)OCCOC)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:4][C:3]=1[CH3:19].[NH2:20][NH2:21]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:21][N:20]=2)=[CH:4][C:3]=1[CH3:19]
Reactant: Cc1cc(C(=O)CC(=O)c2ccccc2)ccc1F
Reactant: NN
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(-c3ccccc3)[nH]n2)ccc1F
Temperature: 75 °C
Reaction time: 3 h

Procedure:
1.7 g 1-(4-fluoro-3-methyl-phenyl)-3-phenyl-1,3-propanedione was dissolved in 20 mL of a solution of 1 N hydrazine in THF and stirred for 3 h at 75° C. The solvent was removed and the residue was crystallized to give 1.7 g of the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:14][N:13]=[C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[CH:11]=3)=[N:7][C:6]=2[CH:27]=1.[CH2:28](I)[CH3:29]>>[CH2:28]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:14][N:13]=[C:12]([O:15][CH2:16][C@@H:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH3:18])[CH:11]=3)=[N:7][C:6]=2[CH:27]=1)[CH3:29]
Reactant: CCI
Reactant: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Product: CCOc1ccc2oc(-c3cc(OC[C@H](C)NC(=O)OC(C)(C)C)no3)nc2c1

Procedure:
Using tert-butyl [(1S)-2-{[5-(5-hydroxy-1,3-benzoxazol-2-yl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate and ethyl iodide, and in the same manner as in Example 2, step E, the title compound was obtained.
Reaction SMILES: [CH2:1]([CH:3]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:4][O:5][C:6]([CH:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])=[O:7])[CH3:2].[S:29]([O-:32])([OH:31])=[O:30].[Na+:33].N(C(C)(C)C#N)=NC(C)(C)C#N>C(O)(C)C>[CH2:23]([CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][O:16][C:14]([CH:9]1[CH:8]([C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:7])[CH2:13][CH2:12][CH:11]([S:29]([O-:32])(=[O:31])=[O:30])[CH2:10]1)=[O:15])[CH3:24].[Na+:33]
Reactant: O=S([O-])O
Reactant: CCCCC(CC)COC(=O)C1CC=CCC1C(=O)OCC(CC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCC(CC)COC(=O)C1CCC(S(=O)(=O)[O-])CC1C(=O)OCC(CC)CCCC
Temperature: 81.5 °C
Reaction time: 16 h

Procedure:
In the stream of an argon gas, 80 g of 4-cyclohexene-1,2-dicarboxylic di(2-ethylhexyl)ester (manufactured by Tokyo Chemical Industry Co., Ltd.) and 900 mL of isopropyl alcohol was placed. 660 mL of an aqueous solution of 42.3 g of sodium hydrogen sulfite (manufactured by Wako Pure Chemical Industries, Ltd.) was added. The resulting solution was heated to a reflux temperature, and stirred at 80 to 83° C. for 16 hours. During this stirring, every one hour from the start to 1 to 5 hours after the start of refluxing, as well as after 9 hours and 10 hours, 1.66 g of 2,2′-azobis(isobutyronitrile) (manufactured by Wako Pure Chemical Ltd.) was added. After cooling to room temperature, the reaction liquid was concentrated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:24])[N:17]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: Cc1cnc(C=O)c(C)c1
Product: Cc1cnc(CNCCCCN(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
Yellow oil prepared from 3,5-dimethyl-pyridine-2-carbaldehyde and (4-amino-butyl)-methyl-carbamic acid tert-butyl ester. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.53-1.57 (m, 4H), 2.27 (s, 6H), 2.69-2.73 (m, 2H), 2.82 (s, 3H), 3.18-3.23 (m, 2H), 3.83 (s, 2H), 7.24 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[CH3:20])(=[O:3])[CH3:2].[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1[NH:25][CH:22]([CH3:24])[CH3:23])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(C)c2[nH]c1=O
Product: CC(=O)c1c(NC(C)C)c2cccc(C)c2[nH]c1=O
Yield: 100.3 %

Procedure:
3-Acetyl-8-methyl-4-methylsulfoxy-2-quinolinone (2.63g, 0.01 mol) and isopropylamine (0.6g, 0.01 mol) were used, but the reaction was carded out as the above process of example 37 to obtain the desired product (2.59g, yield: 68%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33]C[C@H](C1C=CC=CC=1)O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:33])=[O:29])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (76 mg, 0.18 mmol) and (S)-2-amino-1-phenylethanol (30 mg, 0.22 mmol) in DMF (4 ml) was added 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol). After stirring the resulting mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1 elution) to give N-1(2S)-2-hydroxy-2-phenylethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (92.8 mg, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:13]=[C:14]=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][C:14]([NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)N=C=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)NC(=O)Nc1ccc(C#N)cc1
Reaction time: 168 h
Yield: 132.1 %

Procedure:
To a solution of 2-isocyanato-3-phenylpropionic acid ethyl ester (6 g, 27.37 mmol) in DMF (50 ml) was added a solution of 4-aminobenzonitrile (3.23 g, 27.37 mmol) in DMF (30 ml) at 3° C. during 20 min. Stirring was continued for 7 d at room temperature, and additional 2-isocyanato-3-phenylpropionic acid ethyl ester (2.86 g) was added successively. The solvent was removed and the residue dissolved in ethyl acetate (100 ml), washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml). The organic phase was dried (MgSO4), filtered and evaporated to give 12.20 g of the title compound which was used without further purification. MS 338.3 (M+1)+
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]=1[CH2:17][O:18][CH3:19])=[CH:13][C:12]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=3)(=[O:3])[CH3:2].C(O[CH:31](OCC)[N:32](C)C)C>>[CH2:21]([O:20][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH:6]=[N:5][C:4]([C:1]3[O:3][N:32]=[CH:31][CH:2]=3)=[C:16]([CH2:17][O:18][CH3:19])[C:15]2=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(OCC)N(C)C
Reactant: COCc1c(C(C)=O)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Product: COCc1c(-c2ccno2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At 100° C., 500 mg of 3-acetyl-6-benzyloxy-4-methoxymethyl-β-carboline is stirred overnight in 5 ml of N,N-dimethylformamide diethylacetal. After concentration by evaporation, the mixture, without further purification, is taken up in 20 ml of absolute ethanol, combined with 600 mg of hydroxylamine-O-sulfonic acid in 5 ml of methanol, and stirred for 5 hours at room temperature. After neutralization with triethylamine, the reaction mixture is stirred overnight, introduced into water, and extracted with ethyl acetate; the organic phase is dried over magnesium sulfate and concentrated under vacuum. After chromatography over silica gel with acetone:triethylamine in a ratio of 10:1 as the eluent, 130 mg of 6-benzyloxy-4-methoxymethyl-3-(5-isoxazolyl)-β-carboline is obtained, melting point 125°-126° C.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13].S([O-])([O-])=O.[Na+].[Na+].[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>>[OH:25][C:21]([CH3:24])([CH3:23])[CH2:22][O:3][N:4]1[C:9]([CH3:10])([CH3:11])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(=O)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one and ferrous chloride in tert-butyl alcohol at 30-60° C. Excess peroxide is decomposed with aqueous sodium sulfite. The organic layer is concentrated and the residue is purified by flash chromatography to afford the desired 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:33])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([Cl:33])=[O:30])=[CH:24][CH:23]=3)=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccccc2-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 1.6 g of 4-n-octyloxyterphenyl-4"-carboxylic acid was heated with an excess amount of thionyl chloride under reflux condition for 6 hours, unreacted thionyl chloride was distilled off to obtain 4-n-octyloxyterphenyl-4"-carboxylic acid chloride.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][NH:19][CH2:18][CH2:17][C:15]=2[N:16]=1.C(N(CC)CC)C>C1COCC1>[Cl:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[O:8])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: Clc1ncc2c(n1)CCNC2
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A solution of nicotinoyl chloride (0.230 g, 1.62 mmol) in anhydrous THF (1.5 mL) was treated with 2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.250 g, 1.47 mmol) and triethylamine (0.3 g, 3.0 mmol) and subsequently allowed to stir at room temperature. After 4 hours the reaction was quenched with deionized H2O (10 mL). Following dilution with EtOAc (10 mL) the reaction mixture was washed twice with brine and once with saturated Na2HCO3(aq). The combined aqueous layers were then washed once with EtOAc. The combined organic layers were dried over anhydrous Na2SO4(s), filtered and then concentrated in vacuo. Purification over silica using a Methanol/CHCl3 gradient afforded the desired product in 87.9% yield (0.356 g, 1.3 mmol).