Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].OS(O)(=O)=O.[O:10]=[C:11]1[CH2:16][CH:15]2[CH:17]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)[CH:12]1[CH2:13][CH2:14]2.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[O:10]=[C:11]1[NH:1][CH2:16][CH:15]2[CH:17]([C:18]3[NH:19][C:20]4[N:21]([CH2:32][CH2:33][CH3:34])[C:22](=[O:31])[N:23]([CH2:28][CH2:29][CH3:30])[C:24](=[O:27])[C:25]=4[N:26]=3)[CH:12]1[CH2:13][CH2:14]2
Reactant: CCCn1c(=O)c2[nH]c(C3C4CCC3C(=O)C4)nc2n(CCC)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2nc(C3C4CCC3C(=O)NC4)[nH]c2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a solution of NaN3 (65 mg) in CHCl3 (2 ml) was added H2SO4 (0.5 ml). The resulting solution was cooled to 0° C. 8-(2-Oxo-bicyclo[2.2.1]hept-7-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (173 mg) in CHCl3 (3 ml) was added. The resulting solution was stirred at room temperature for 3 hrs. The reaction mixture was poured over ice and neutralized with NaHCO3, extracted with ethyl acetate (3×25 ml). The combined extract was dried over MgSO4, filtered, and concentrated. The crude product was purified by recrystallization from MeOH. Yield 155 mg. Mass (ES+ 360).
Reaction SMILES: F[C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C@H:29]([OH:31])[CH3:30]>>[CH2:22]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:3]2[C:2]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[C:29](=[O:31])[CH3:30])=[CH:7][C:6]3[NH:8][C:29]([CH:25]4[CH2:26][CH2:27][CH2:28][NH:24]4)=[N:9][C:5]=3[CH:4]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cc1
Reactant: C[C@@H](O)C1CCCN1
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(C4CCCN4)[nH]c3cc2N2CCC[C@@H]2C(C)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 369 or in accordance with the method or by combining it with an ordinary method but using 4-(4-ethanesulfonyl-phenoxy)-5-fluoro-2-nitro-phenylamine obtained in Example 259 (step 1) and 1-(R)-pyrrolidin-2-yl-ethanol.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC[C@H](O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NC[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 93.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-2-(S)-hydroxy-propionic acid (99 mg, 0.94 mmol) (Sigma-Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was concentrated and the residue was dissolved in water (70 mL). It was acidified by 1 N HCl to pH=3-4 and then extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 113 mg (0.29 mmol) in 93% yield. LC-MS ESI−: 391.98 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[CH:6]=1)=[O:4].Cl[C:14]1[NH:15][CH2:16][CH2:17][N:18]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([N:9]=[C:14]2[NH:18][CH2:17][CH2:16][NH:15]2)=[C:7]([CH3:12])[CH:6]=1)=[O:4]
Reactant: ClC1=NCCN1
Reactant: COC(=O)c1ccc(N)c(C)c1
Product: COC(=O)c1ccc(N=C2NCCN2)c(C)c1
Yield: 47 %

Procedure:
After reaction of the aniline from Step B with 2-chloro-2-imidazoline substantially as described in Example 2 there is isolated in 47% yield, 2-(4-methoxycarbonyl-2-methylphenylimino)imidazolidine, m.p. 193°-194.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C@H:13]([N:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:38][C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[C:22]3[CH:37]=[CH:36][C:25]([O:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH3:14])=[O:9])=[C:6]([CH3:44])[N:5]=[CH:4][N:3]=1.[Cl-].[NH4+:46]>>[C:31]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:25]2[CH:36]=[CH:37][C:22]([N:21]([CH2:38][C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[CH:18]3[CH2:19][CH2:20][N:15]([C@H:13]([CH3:14])[CH2:12][CH2:11][NH:10][C:8]([C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=4[CH3:44])=[O:9])[CH2:16][CH2:17]3)=[CH:23][CH:24]=2)=[CH:35][CH:34]=1)(=[O:33])[NH2:46]
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1
Reactant: [NH4+]
Agent: [Cl-]
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(Oc3ccc(C(N)=O)cc3)cc2)CC1
Yield: 153.6 %

Procedure:
Using general procedure E, COMPOUND 302 (103 mg, 0.17 mmol) and ammonium chloride (23 mg, 0.42 mmol) afforded COMPOUND 303 as a white solid (160 mg, 100%). 1H NMR (CDCl3) δ 0.87-1.21 (m, 2H), 1.01 (d, 3H, J=6.0 Hz), 1.49-1.60 (m, 1H), 1.71-1.85 (m, 3H), 2.11-2.22 (m, 1H), 2.53 (s, 6H), 2.55-2.62 (m, 1H), 2.71-2.92 (m, 3H), 3.25-3.38 (m, 1H), 3.48-3.61 (m, 1H), 3.82-3.94 (m, 1H), 3.83 (s, 2H), 5.77 (br s, 2H), 6.62 (d, 1H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 6.92 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=3.3 Hz), 7.26-7.32 (m, 1H), 7.73 (d, 2H, J=7.8 Hz), 8.81 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.80, 22.33, 29.50, 30.86, 31.03, 40.62, 43.96, 46.17, 52.59, 56.51, 60.90, 114.86, 116.77, 121.09, 121.80, 126.32, 126.87, 129.62, 131.31, 141.91, 146.46, 158.01, 162.73, 163.46, 166.72, 169.17. ES-MS m/z 613 (M+H). Anal. Calcd. for C34H40N6O3S.0.3CH2Cl2: C, 64.55; H, 6.41; N, 13.17. Found: C, 64.29; H, 6.38; N, 12.96.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:52][O:53][CH2:54][CH2:55]Cl>>[CH3:52][O:53][CH2:54][CH2:55][N:2]([CH3:1])[S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: COCCCl
Product: COCCN(C)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1

Procedure:
100 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) and 15 μL 2-chloroethyl methyl ether were reacted in the same manner as in Example 746, to give 90 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid (2-methoxyethyl)-methylamide. This product was subjected to the same reaction as in Example 618, dissolved in dichloromethane/methanol and recrystallized from ethanol/ether, to give 35 mg of the title compound as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][C:15]([F:16])([F:17])[F:18])[C:11]=1[O:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(OC)c(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Cl)cc(C(=O)O)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
Methyl 3-chloro-4-methoxy-5-trifluoromethoxybenzoate (1.70 g) was dissolved in tetrahydrofuran (12 mL) and water (6 mL), and lithium hydroxide monohydrate (1.00 g) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.51 g) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][C:6]=1[NH:7][S:8]([CH2:11]C)(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:31]2[CH2:36][CH2:35][O:34][C:32]2=[O:33])C=CC=CC=1>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:16]=[C:15]([CH:14]=[CH:13][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH:17]=[C:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]
Reactant: CCS(=O)(=O)Nc1ccc(C=O)cc1Oc1ccc(F)cc1F
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)Nc1ccc(C=C2CCOC2=O)cc1Oc1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
A mixture of 2'-(2,4-difluorophenoxy)-4'-formylethanesulfonanilide (2 g) and α-triphenylphosphoranylidene-γ-butyrolactone (2.2 g) in dimethyl sulfoxide (10 ml) was stirred at 80° C. for 6 hours. The mixture was dissolved in ethyl acetate, and the resulting mixture was washed with water, dried, and concentrated to dryness. The residue was purified by column chromatography on acetate (1:1) to give a powder of α-[3-(2,4-difluorophenoxy)-4-(methanesulfonamido)benzylidene]-γ-butyrolactone (1.7 g).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([N:67]1[CH2:78][CH2:77][CH2:76][C@H:68]1[C:69]([NH:71][CH2:72][C:73]([NH2:75])=[O:74])=[O:70])=[O:66])[CH2:58][CH2:59][CH2:60][NH:61][C:62](=[NH:64])[NH2:63])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52].CC(O)=O.CC(O)=O.C(N1CCOCC1)C>CN(C)C=O>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([N:67]1[CH2:78][CH2:77][CH2:76][C@H:68]1[C:69]([NH:71][CH2:72][C:73]([NH2:75])=[O:74])=[O:70])=[O:66])[CH2:58][CH2:59][CH2:60][NH:61][C:62](=[NH:63])[NH2:64])=[O:55])[CH2:50][CH:51]([CH3:52])[CH3:53])=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Boc-D-Trp-OH (5.5 g), dicyclohexylcarbodiimide (4.05 g) and 1-hydroxybenzotriazole (3.6 g) in dimethylformamide (70 ml) was stirred at ice-bath temperature for 90 min. A solution of H-Leu-Arg-Pro-Gly-NH2 diacetate (10 g, described by H. U. Immer et al., U.S. Pat. No. 3,835,108, cited above) in dimethylformamide (60 ml) was adjusted to pH 8 with N-ethylmorpholine and added to the above solution. The resulting mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated and the residue was dissolved in methanol. Diethyl ether was added and the precipitate was collected and chromatographed on silica gel using chloroform-methanol-35% aqueous acetic acid (5:3:1 v/v). The pure fractions were collected and evaporated. The residue was dissolved in methanol and diethyl ether was added. The precipitate was collected and dried to give 7.8 g of Boc-D-Trp-Leu-Arg-Pro-Gly-NH2 ; nmr (DMSO-D6)δ 0.80 (m, 6H) and 1.30 (s, 9H); uv max (methanol) 289 (ε=4433) and 281 nm (ε=5015); and amino acid analysis: Gly (1.00), Pro (0.98), Leu (0.97), Arg (0.95) and Trp (0.63); and [α]D25 -16.89° (c=1, 1% acetic acid).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([CH:26]([CH3:28])[CH3:27])[C:15]=2[C:29](OCC)=[O:30])=[CH:10][CH:9]=1>CCOCC>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([CH:26]([CH3:28])[CH3:27])[C:15]=2[CH2:29][OH:30])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
A slurry of LiAlH4 (775 mg, 20.4 mmol) in dry Et2O (70 ml) at 0° C. was treated with a solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxylic acid, ethyl ester (4.80 gm, 13.2 mmol) in Et2O (5 ml). After 2.5 hours, the reaction was quenched and diluted with H2O and the aqueous layer was extracted twice with Et2O and once with EtOAc. The combined organic layers were washed with H2O and brine, then dried (Na2 SO4), filtered and stripped. The resulting solid was dissolved in hot EtOAc and directly chromatographed (flash, Merck SiO2, 20% EtOAc in hexane) to give crude 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol. Recrystallization from hot hexane/EtOAc gave 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (3.30 gm) as a white solid. The mother liquor was stripped and recrystallized again to give an additional 230 mg of product (total 3.53 gm, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][C:2]1([Br:1])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]1[OH:16]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC1(Br)C=C(C(C)(C)C)C=C(C(C)(C)C)C1O
Temperature: 45 °C
Yield: 94.8 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1NN=[N:27][N:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Clc1ccccc1-c1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccccc2Cl)o1
Yield: 78.9 %

Procedure:
The title compound (1.65 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.35 g), 5-(2-chlorophenyl)tetrazole (1.0 g) and dicyclohexylcarbodiimide (0.16 g) according to the method of description 1.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[C:10](=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:9][CH2:8]2)(=O)C.[BH4-].[Na+]>CO>[CH3:19][N:17]([CH2:16][C:10]1[CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([NH2:4])[CH:14]=[CH:13][C:12]=2[CH:11]=1)[CH3:18]
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=CN(C)C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1=Cc2ccc(N)cc2CC1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
The obtained 6-acetamido-2-(N,N-dimethylaminomethylidene)-1-tetralone (4.50 g, 0.0173 mol) was dissolved in methanol (50 ml), and sodium borohydride (6.56 g, 0.173 mol) was added to the solution under ice-cooling, which was stirred for 2 hours. The reaction mixture was concentrated. Ethyl acetate and sodium hydrogencarbonate solution were added to the residue, and extraction was conducted. The ethyl acetate layer was concentrated, and 30 ml of tetrahydrofuran and 30 ml of 2N hydrochloric acid were added to the residue, which was refluxed with heating for 16 hours. The reaction mixture was concentrated, and ethyl acetate and 2N sodium hydroxide solution were added, and extraction was conducted. The ethyl acetate layer was concentrated, and the residue was refined using alumina column chromatography (development solvent; ethyl acetate:n-hexane=30:70), to give 6-[(N,N-dimethylamino)methyl]-7,8-dihydro-2-naphthaleneamine (1.60 g) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][C:9](OC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[BH4-].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(Br)cccc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl [3-bromo-2-(methyloxy)phenyl]acetate (8.20 g, 31.7 mmol) in 200 mL of dry THF under N2 at room temperature was added LiBH4 (32 mL, 63.32 mmol, 2M THF). After 1.5 hours, the reaction was warmed to reflux for 3 hours, and then cooled to room temperature. The solution was poured into EtOAc/1N HCl solution, and the layers were separated. The organic layer was washed with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 2[3-bromo-2-(methyloxy)phenyl]ethanol
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]O>>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 18 h

Procedure:
A 1 L round bottom flask equipped with a stir bar and reflux condenser was charged 5H2SO4 (4 mL), methanol (400 mL) and 3-fluoro-4-nitrobenzoic acid (10 g). The reaction mixture was heated at reflux temperatures with vigorous stirring for 18 h. The methanol was removed and the crude residue was triturated with hexane and concentrated to give a colorless solid (9.79 g) that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.COC1C=CC(C[CH2:30][NH2:31])=CC=1.C1CCN2C(=NCCC2)CC1.FC(F)(F)C(O)=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:31][CH3:30])[CH:12]=3)[CH:7]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CCn1c(=O)c(-c2cc(N)ccc2C)cc2cnc(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(N)ccc2C)cc2cnc(NC)cc21
Yield: 42.6 %

Procedure:
Using a procedure analogous to Example A26, 3-(5-amino-2-methylphenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (1.9 g, 6.4 mmol), 4-methoxybenzylmethylamine (1.5 g, 9.6 mmol), DBU (1.6 g, 9.6 mmol), and trifluoroacetic acid (10 mL, 134 mmol) were combined to give 3-(5-amino-2-methylphenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.84 g, 43% yield, 2 steps). 1H NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1 H), 7.56 (s, 1 H), 6.91-6.82 (m, 2 H), 6.47-6.39 (m, 2 H), 6.22 (s, 1 H), 4.80 (s, 2 H), 4.13 (q, J=6.9 Hz, 2 H), 2.84 (d, J=4.8 Hz, 3 H), 1.92 (s, 3 H), 1.19 (t, J=6.9 Hz, 3 H); MS (ESI) m/z: 308.9 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([CH:13]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH:14]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])#N.C(O)(=[O:32])C>C1C=CC=CC=1.C(OCC)C>[CH:11]([CH:13]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH:14]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:32]
Reactant: CC(=O)O
Reactant: N#CC1CCC2(OCCO2)C1CCCCCCCO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C

Procedure:
A solution of diisobutylaluminium hydride (53 g.) in dry benzene (145 ml.) was added, with rapid stirring, to a solution of 7-cyano-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (43.2 g.) in dry diethyl ether (432 ml.) at 10°-15° C. Stirring at ambient temperature was continued for 11/2 hours and the mixture was added to 2N aqueous acetic acid (1 liter) at a temperature lower than 15° C. The organic phase was separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate, dried over sodium sulphate, the solvents removed in vacuo and the residue distilled under reduced pressure to give 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (25.3 g.), b.p. 164°-200° C./0.04-0.05 mm.Hg, νmax. 1710 cm-1, 2700 cm-1 (liquid film).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>Cl.C(O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])[N:20]([CH2:19][C:18]([F:22])([F:21])[F:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Agent: Cl
Solvent: CCO
Product: Cc1cc(=O)c(OCc2ccccc2)cn1CC(F)(F)F
Temperature: 100 °C
Yield: 84.3 %

Procedure:
5-(Benzyloxy)-2-methyl-4H-pyran-4-one (4.32 g, 20.0 mmol) was mixed with trifluoroethylamine (6.92 g, 70.0 mmol) in 6N HCl (11.7 mL) and ethanol (5.8 mL). The reaction mixture was heated in a sealed flask at 100° C. for 20 hours. The mixture was then concentrated in vacuo and the residue was diluted with water. The solid was filtered, washed with water and ether to give 5-(benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (5.01 g) as white solid. Yield=84%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 7.99 (s, 1H), 7.14-7.65 (m, 5H), 6.80 (s, 1H), 4.91-5.25 (m, 4H), 2.53 (s, 3H).