Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:19]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:27]([N:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:10])=[O:9])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1Br)N(Cc1ccccc1)Cc1ccccc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 88.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (1.0 g, 3.91 mmol) and triethylamine (455 mg, 0.63 mL, 4.5 mmol) were dissolved in THF (15 mL), and the mixture was cooled to 10° C. Dibenzylamine (849 mg, 0.83 mL, 4.3 mmol) was then added dropwise. The cooling bath was removed, and the reaction mixture was stirred for 10 h at rt and then an additional 6 h at 60° C. After cooling to rt, the solvent was removed under reduced pressure, and ethyl acetate was added. The organic layer was successively washed with 1N HCl, water, semi-saturated aq Na2CO3 solution, water, and brine. After drying with Na2SO4 and filtration, the solvent was removed under reduced pressure to afford the title compound as off-white crystals (1.44 g, 88%). 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 4H), 7.08 (m, 4H), 7.27 (m, 6H), 7.41 (m, 2H), 7.78 (d, 1H), 8.19 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.C(O)=[O:15].O>[Ni].C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:15]
Reactant: O=CO
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [Ni]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cc(C(F)(F)F)ccc1F
Reaction time: 8 h

Procedure:
A mixture of 18.7 g (0.0988 mol) of 2-fluoro-5-(trifluoromethyl)benzonitrile (prepared according to G. C. Finger et al., Chem. Comm., 1965, 430), 398 ml of 90% formic acid, 296 ml of water and 17.5 g of Raney nickel is heated for 5 hours at reflux and is then left standing overnight. The mixture is poured into 2.5 liters of water and extraction is carried out with methylene chloride (once 1 l and two times 500 ml). Filtration, washing with water, drying over Na2SO4, filtration and distillation are carried out. Yd.: 10.1 g (53%) B.p.14 =70°-72° C. IR: νc-o =1680 cm-1
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:18]2[C:13]([N:10]3[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccnc2OCc2ccncc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2nccnc2OCc2ccncc2)C1
Reaction time: 1 h
Yield: 170.1 %

Procedure:
To compound {1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1 g, 2.6 mmole) was added 50% TFA/DCM. The mixture was stirred for 1 hour, and concentrated in vacuo to give 1-[3-(Pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine (1.2 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Cl:13][C:14]1[S:18][C:17]([NH:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([C:32]#[N:33])[CH:24]=2)(=[O:22])=[O:21])=[N:16][CH:15]=1>>[Cl:13][C:14]1[S:18][C:17]([NH:19][S:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)=[O:28])=[C:25]([C:32]#[N:33])[CH:24]=2)(=[O:22])=[O:21])=[N:16][CH:15]=1
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 4-(trifluoromethyl)benzylamine and 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}-2-cyanobenzoic acid of Preparation 22, following Method O described for Example 344. The reaction mixture was stirred at room temperature for 18 hours.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([NH2:3])[CH:5]=2)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[CH3:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cccc(O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a 80 ml of anhydrous N,N-dimethylformamide suspension containing 2.18 g of sodium hydride (55 wt %) was added 5.45 g of 3-aminophenol, and the mixture was stirred at room temperature for 20 minutes. Subsequently, 14.3 g of N-(5-chloro-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester (Japanese Patent Application (Kokai) No. Hei 11-193276) was added in small amounts, and the mixture was stirred at 100° C. for 6 hours. The reaction mixture was concentrated, followed by addition of water and neutralization using 3N hydrochloric acid and sodium bicarbonate powder. The insoluble product which deposited was filtered, washed with water, and then dried under reduced pressure to give the title compound (16.6 g, 92% yield).
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8]CCCC)[CH2:3][CH2:4]O.C(Cl)(=O)CCCCC.[CH2:21]([O:23][C:24](=[O:29])[CH:25]=[C:26]([CH3:28])[CH3:27])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH2:27][CH2:4][CH2:3][CH2:2][CH2:6][CH2:7][CH3:8])[CH3:22]
Reactant: CCCCCCCC(C)CCO
Reactant: CCOC(=O)C=C(C)C
Agent: CCCCCC(=O)Cl
Product: CCCCCCCC(C)CC(=O)OCC

Procedure:
The starting compound 3-methyl-undecanol (b.p.0.5 :105° C.) is prepared, in the same way as that described in Example 1 for the preparation of 3-methyldecanol, from hexanoic acid chloride and dimethylacrylic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([N:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=4)=[C:30]([CH3:42])[CH:29]=3)[O:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:30]1[CH:29]=[C:28]([NH:27][C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:12]4[O:13][CH:14]5[CH2:15][NH:8][CH2:9][CH:10]5[N:11]=4)[CH:18]=3)[N:23]=[CH:22][N:21]=2)[CH:33]=[CH:32][C:31]=1[O:34][C:35]1[CH:36]=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CN(C(=O)OC(C)(C)C)CC6O5)cc34)cc2C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CNCC6O5)cc34)cc2C)cn1

Procedure:
N4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine is prepared from 2-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazole-5-carboxylic acid tert-butyl ester by standard BOC deprotection methods using TFA in methylene chloride. MS APCI (+) m/z 468 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.42 (s, 1H), 8.21 (bs, 1H), 8.13 (d, 1H), 7.68 (m, 2H), 7.60 (m, 2H), 7.28 (m, 2H), 6.98 (d, 1H), 5.18 (m, 1H), 4.74 (m, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.86 (m, 2H), 2.50 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH3:19]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OC(C)C)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
1-(4-Hydroxyphenyl)ethanone (15.0 g, 110 mmol) was dissolved in acetone (125 mL), added sequentially with potassium carbonate (30.4 g, 220 mmol) and 1-methylethyl iodide (16.5 mL, 165 mmol), and the mixture was stirred at 70° C. for 8 hours. The reaction solution was filtered, washed with acetone and concentrated in vacuo. The obtained residue was added water and ethyl acetate, extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 1-[4-(1-methylethoxy)phenyl]ethanone (18.2 g (yield 93%)) was obtained as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@:4](C)([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@](C)(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a mixture of methyl (S)-3-[4-nitrophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (72 g, 222 mmol), zinc dust (˜325 mesh, 145.2 g, 2.2 mole, 10 equiv.) and ammonium chloride (178.1 g, 3.3 mole, 15 equiv.) was added methanol (1 L) and water (500 mL) at room temperature. After addition of water, an exothermic reaction ensued and the internal temperature rose to 45 to 50° C. The suspension was stirred for 30 min to 1 h at room temperature, at which time TLC analysis of the mixture indicated the absence of starting material, and the reaction mixture was filtered through a pad of celite and the filtered cake was washed with methanol (1 L) and water (500 mL). Concentration to remove most of the methanol and some water afforded white solids which were collected by filtration and washed with water. After air drying, 65.5 g (100% yield) of (S)-3-[4-aminophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester was isolated as a white solid (mp 86-89° C.). ES(+)-HRMS m/e calcd. for C15H22N2O4 (M+H)+ 294.1621, obsd. 294.1614.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:6]=1[NH:19][C:20](=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:6]2[NH:19][C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:1][S:2](=[O:4])(=[O:3])[C:5]=2[CH:10]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=NS(=O)(=O)c2cc(OCc3ccccc3)ccc2N1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
The product of Example 352A (292 mg, 0.744 mmol) and sodium carbonate (394 mg, 3.722 mmol) in anhydrous ethanol (12 mL) was heated to reflux under a nitrogen atmosphere for 6.5 hours. The reaction was cooled to room temperature, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 3% methanol/dichloromethane to give the title compound as a white solid (237 mg, 85%). MS (ESI−) m/z 373 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=6.99 Hz, 3 H) 3.67 (s, 2 H) 4.16 (q, J=6.99 Hz, 2 H) 5.20 (s, 2 H) 7.39 (m, 8 H) 12.21 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([CH:13]3[C:17](=[O:18])/[C:16](=[CH:19]/[C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)/[CH2:15][C:14]3=[O:27])[N:12]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:28])=[C:11]([CH:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=4)[CH2:15][C:14]3=[O:27])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C/C(=C\c2ccc(F)cn2)C1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CC(Cc2ccc(F)cn2)C1=O
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-[1-(5-fluoro-pyridin-2-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (70 mg, 0.17 mmol) in glacial acetic acid (2 ml) was added zinc powder (10 mg), and the reaction heated to 80° C. for 17 hours. The crude reaction mixture was then dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-4-(5-fluoro-pyridin-2-ylmethyl)-cyclopentane-1,3-dione (55 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[S:28])=[CH:25][CH:24]=1>>[C:3]([C:2]([NH:1][C:27](=[S:28])[C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:31][CH:30]=1)([CH3:20])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:17])([F:18])[F:19])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2ccc(OC(F)(F)F)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2ccc(OC(F)(F)F)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-trifluoromethoxy-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 30) and 4-trifluoromethylthiobenzoyl chloride (0.12 mL), the title compound was isolated as a white solid (142 mg, 83%). MS (ES): M/Z [M+H]=490. 1H NMR: (400 MHz, CHLOROFORM-d): 1.75 (s, 3H), 5.48 (d, J=13.4 Hz, 1H), 5.52 (d, J=13.3 Hz, 1H), 7.47 (d, J=10.6 Hz, 1H), 7.85-7.91 (m, 4H), 8.05 (br s, 1H), 8.12 (d, 1H, J=9.3 Hz) and 8.98 (br s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −57.43 (s, 3F) and −41.96 (s, 3F).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](=[O:7])[CH3:6].[CH2:11](O)[CH2:12][CH2:13][OH:14].C(OC)(OC)OC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:8]1([CH3:9])[O:14][CH2:13][CH2:12][CH2:11][O:10]1)\[C:5](=[O:7])[CH3:6]
Reactant: OCCCO
Reactant: CON=C(C(C)=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CO/N=C(\C(C)=O)C1(C)OCCCO1
Yield: 94.6 %

Procedure:
Starting from 103 g (0.72 mol) of pentane-2,3,4-trione 3-(O-methyloxime), 275 g (3.62 mol) of 1,3-propanediol, 80 g (0.76 mol) of trimethyl orthoformate and 1.6 g of p-toluenesulfonic acid (9 mmol) and using the procedure of Example 2, 137 g (94% yield) of a reddish oil were obtained which, according to HPLC, had a purity of 70% (phys. data see Tab. 1).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[O:19][C:20]1[S:24][C:23]([CH2:25][NH:26][C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])=[CH:22][CH:21]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(SC)C=CC=CC=1>[OH:15][C:16]1[CH:17]=[C:18]([CH:39]=[CH:40][CH:41]=1)[O:19][C:20]1[S:24][C:23]([CH2:25][NH:26][C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(NCc1ccc(Oc2cccc(OCc3ccccc3)c2)s1)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(NCc1ccc(Oc2cccc(O)c2)s1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Trifluoroacetic acid (1.0 mL) and thioanisole (100 μl) were added to the resulting quinoline-6-carboxylic acid (5-(3-benzyloxy-phenoxy)-thiophene-2-ylmethyl)-amide (73 mg, 0.156 mmol), and the solution was stirred for 30 minutes at room temperature. The reaction solution was neutralized with an aqueous solution of saturated sodium bicarbonate, then, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (ethyl acetate: methanol), and the title compound (47 mg, 80%) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[CH2:1]([C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:13]=1[O:14][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])[CH:2]=[CH2:3]
Reactant: BrCCCCCBr
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Product: C=CCc1cc(C(=O)OC)ccc1OCCCCCBr
Yield: 69.2 %

Procedure:
Using the procedure of Example 1, 5.62 g (29.2 mmole) of methyl 3-allyl-4-hydroxybenzoate and 13.8 g (60 mmole) of 1,5-dibromopentane gave 6.9 g (69%) of the title compound as an oil. Calc: C, 56.32; H, 6.20; Found; C, 55.91; H, 6.20.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([N:11]1[N:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[C:3]([OH:22])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A solution of 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid methyl ester (1.76 g, 5.85 mmol) in methanol (3.9 mL, 1.5M) was treated with a 4N aqueous sodium hydroxide solution (1.61 mL, 6.44 mmol) and stirred at 25° C. for 4 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (100 mL) and was acidified with a 2N aqueous hydrochloric acid solution and then extracted with a solution of 90/10 methylene chloride/methanol (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid (1.58 g, 94%) as a white solid; ES+-HRMS m/e calcd for C16H18N2O3 [M+H+] 287.1390, found 287.1390.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:5]([C:11]([OH:13])=O)[C:4]1=[O:14])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([NH:22][C:11]([C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCn1c(C)c(C)cc(C(=O)O)c1=O
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C)c(C)cc(C(=O)NCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
1-Ethyl-3-carboxy-5,6-dimethyl-2-pyridone (3-003-04) (195 mg) was dissolved in DMF (3 mL), and to the reaction mixture were added benzylamine (0.17 mL), diisopropylethylamine (0.35 mL), and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 624 mg), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed twice with hydrochloric acid and aqueous sodium bicarbonate solution, respectively, and water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue (0.40 g) was subjected to silica gel (30 g) column chromatography (chloroform) to give 1-ethyl-2-oxo-5,6-dimethyl-1,2-dihydropyridine-3-carboxylic acid benzylamide (3-003) (259 mg, 91.1%) as a crystal, followed by recrystallization from methylene/n-hexane to give colorless needle crystal (207 mg, 72.9%, m.p. 117° C.)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][N:20]([C:22]2[C:36]([F:37])=[CH:35][C:25]([C:26]([NH:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:31])[F:32])=[O:27])=[C:24]([F:38])[CH:23]=2)[CH2:19]1)#[N:16]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(=CC#N)C2)cc1F)C(F)(F)F
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol), 4-[3-(cyanomethylene)azetidin-1-yl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (1.78 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL, 2.1 mmol) in acetonitrile (20.2 mL) was heated at 50° C. overnight. After cooling, the solvent was removed under reduced pressure. The residue was used in the next step without further purification. LCMS cacld. for C24H28BF5N5O3 (M+1)+: m/z=540.2. Found: 540.1.
Reaction SMILES: CN1CCOCC1.Cl.Cl.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]1.[CH3:24][O:25][C:26]([NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:39]([O-])=[O:40])=[CH:36][C:35]=2[CH:42]=1)=[NH:30])=[O:27].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:24][O:25][C:26]([NH:28][C:29]([C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:39]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:16]3)=[O:40])=[CH:36][C:35]=2[CH:42]=1)=[NH:30])=[O:27]
Reactant: COC(=O)NC(=N)c1ccc2oc(C(=O)[O-])cc2c1
Reactant: CCOC(=O)CCN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCC(NC(=O)c2cc3cc(C(=N)NC(=O)OC)ccc3o2)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
N,N-Dimethylformamide (14 ml) and N-methylmorpholine (0.57 ml, 5.20 mmol) were added to ethyl 3-(4-aminopiperidino)propionate dihydrochloride (567 mg, 2.08 mmol) and the mixture was stirred at 60° C. for 20 minutes under a nitrogen atmosphere. This solution was added to a mixture of 5-(methoxycarbonylamidino)-2-benzofurancarboxylate acid (364 mg, 1.39 mmol), 1-hydroxy-1H-benzotriazole (207 mg, 1.54 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (294 mg, 1.54 mmol) added to N,N-dimethylformamide (15 ml). The mixture was stirred at room temperature for 18 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure. The residue was purified by column chromatography (chloroform/methanol=10/1) to give 338 mg of compound (187) as a yellow solid (55%).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=Cc1ccncc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2Cc2ccncc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with 4-pyridine carboxaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-pyridin-4-ylmethyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 445.3 [M+H]+.