Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13](Cl)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7])[CH:14]=[CH2:13]
Reactant: C=CCCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimide potassium salt was alkylated with allyl chloride in DMF to produce N-allylphthalimide. Under the Heck reaction conditions (Patel et al. 1977), N-allylphthalimide reacted with aryl bromide to give N-cinnamyl phthalimide. Upon treatment with hydrazine, cinnamyl amine was obtained from N-cinnamyl phthalimide (FIG. 28).
Reaction SMILES: C(OCC(COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)OC(=O)CCCCCCC/C=C\C/C=C\CCCCC)(=O)CCCCCCCCCCCCCCC.[C:62]([O:79][CH2:80][C@H:81]([CH2:102][O:103][C:104](=[O:106])[CH3:105])[O:82][C:83](=[O:101])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90]/[CH:91]=[CH:92]\[CH2:93]/[CH:94]=[CH:95]\[CH2:96][CH2:97][CH2:98][CH2:99][CH3:100])(=[O:78])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77]>>[C:62]([O:79][CH2:80][C@@H:81]([CH2:102][O:103][C:104](=[O:106])[CH3:105])[O:82][C:83](=[O:101])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90]/[CH:91]=[CH:92]\[CH2:93]/[CH:94]=[CH:95]\[CH2:96][CH2:97][CH2:98][CH2:99][CH3:100])(=[O:78])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@@H](COC(C)=O)COC(=O)CCCCCCCCCCCCCCC
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC(COC(=O)CCCCCCCCCCCCCCC)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@H](COC(C)=O)COC(=O)CCCCCCCCCCCCCCC
Yield: 100 %

Procedure:
By using optically active (R)-1-palmitoyl glycerol and optically active (S)-1-palmitoyl glycerol as the starting materials, and by carrying out Example 1 and Example 3, respectively, heptane solutions of (R)-1-palmitoyl-2-linoleoyl-3-tritylglycerol and (S)-1-palmitoyl-2-linoleoyl-3-tritylglycerol were obtained. Except for using the optically active compounds instead of racemic 1-palmitoyl-2-linoleoyl-3-trityl-glycerol, (S)-1-palmitoyl-2-linoleoyl-3-acetyl-glycerol (45.8 g) and (R)-1-palmitoyl-2-linoleoyl-3-acetyl-glycerol (45.8 g) were obtained in the same manner as described in Preparation method-3 (theoretical amounts: 63.5 g, yield: 72.1%). (R)-enantiomer: {1H NMR (400 MHz, CDCl3): δ 0.85-0.92 (m, 6H), 1.20-1.33 (m, 38H), 1.62 (m, 4H), 2.03 (m, 4H), 2.07 (s, 3H), 2.36 (m, 4H), 2.77 (m, 2H), 4.14-4.31 (m, 4H), 5.23-5.36 (m, 5H)}, (S)-enantiomer: {1H NMR (400 MHz, CDCl3): δ 0.85-0.92 (m, 6H), 1.21-1.33 (m, 38H), 1.63 (m, 4H), 2.02 (m, 4H), 2.07 (s, 3H), 2.37 (m, 4H), 2.78 (m, 2H), 4.12-4.28 (m, 4H), 5.21-5.35 (m, 5H)}.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]#[C:9][NH2:10].[N+:11]([O-:14])([OH:13])=[O:12].C(OCC)C>C(O)C>[N+:11]([O-:14])([OH:13])=[O:12].[C:2]1([NH:1][C:9]([NH2:10])=[NH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CN
Solvent: CCOCC
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
To a solution of aniline (1.28 ml, 14 mmol) in ethanol (14 ml) was added cyanamide (1.25 ml, 16.1 mmol) and nitric acid (1 ml, 14 mmol), and the reaction was heated to reflux. After 16 hours, the reaction was cooled to room temperature and poured into diethyl ether. The resulting precipitate was filtered and dried to afford the title compound as a gray solid (2.50 g, 13 mmol, 90%). NMR (300 MHz, CD3OD): δ 7.47 (m, 2H), 7.36 (m, 1H), 7.30 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[S:10]([O-:13])([O-:12])=[O:11].[Na+:14].[Na+]>CC(C)=O.O>[I:1][C:2]1[CH:3]=[C:4]([CH2:5][S:10]([O-:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+:14]
Reactant: O=S([O-])[O-]
Reactant: BrCc1cccc(I)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])Cc1cccc(I)c1
Yield: 118.8 %

Procedure:
A solution of 3-iodobenzyl bromide (3 g) and sodium sulphite (1.26 g) in acetone (15 ml) and water (30 ml) was heated at 70° for 3 h. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (3.8 g). LCMS RT=3.66 min.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]1>>[C:39]([CH:36]1[CH2:37][CH2:38][N:33]([C:15]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]2)=[O:17])[CH2:34][CH2:35]1)#[N:40]
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: N#CC1CCNCC1
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C#N)CC2)C1

Procedure:
4.00 g (8.84 mmol) of 3-methyl 1-(4-nitrophenyl) 5-[4-(trifluoromethyl)phenyl]piperidine-1,3-dicarboxylate (Example 58A) and 2.92 g (26.5 mmol) of piperidine-4-carbonitrile were reacted according to the General Method 8A. Yield: 3.15 g (77% of theory)
Reaction SMILES: [C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1>>[CH3:3][C@@H:2]([C@@H:24]([OH:25])[C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=Cc1cccnc1
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)c1cccnc1

Procedure:
Prepared from (4S)-N-propionyl-4-benzyl-2-oxazolidinone and pyridine-3-carboxaldehyde according to the procedure described in Example 1, paragraph A. 13C-NMR (100 MHz, CDCl3): δ 176.40, 152.83, 148.74, 147.85, 136.78, 134.80, 134.04, 129.34, 128.95, 127.45, 123.21, 109.75, 71.46, 66.23, 55.05, 44.28, 37.70, 10.64.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1C
Yield: 72.4 %

Procedure:
[Step 1] Reactions and treatments were carried out in the same manner as in Step 2 of Example 117, using 102.6 g of (2S,4S)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline instead of ethyl (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, and using 4-nitrophenol instead of benzoic acid. Thus, 118.2 mg (72.4%) of (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline was obtained as a pale yellow amorphous substance.
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]I.[SH:11][C:12]1[NH:16][N:15]=[N:14][CH:13]=1>C(O)C>[N:14]1[CH:13]=[C:12]([S:11][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][S:11][C:12]2[NH:16][N:15]=[N:14][CH:13]=2)[NH:16][N:15]=1
Reactant: ICCOCCOCCI
Reactant: Sc1cnn[nH]1
Solvent: CCO
Product: c1nn[nH]c1SCCOCCOCCSc1cnn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
10 ml of 1,2-bis(2-iodoethoxy)-ethane was dropped into the solution of 20 mmole 5-mercapto-1H-1,2,3-triazole (sodium salt) in 20 ml ethanol, and stirred for 24 hours at room temperature. After the solvent was evaporated in vacuum, the residual was separated with silica gel column. Elution with hexane/ethylacetate (1/3) first, and then with pure ethyl acetate gave 2.70 g product as viscous solid. Yield: 88%. 1H NMR (CDCl3): δ(ppm) 7.72 (2H, s), 3.74 (4H, t, JH-H=6.19), 3.65 (4H, s), 3.07 (4H, t, JH-H=6.19).
Reaction SMILES: [C:1]([C:4]1[C:8](=[O:9])[NH:7][C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][C:5]=12)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:7]1[C:8](=[O:9])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[C:6]12)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1c2cccccc-2[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2cccccc-2c(C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a warm suspension of 3-acetyl-1,2-dihydrocyclohepta[b]pyrrole-2-one [1.87 g, described by T. Nozoe et al., Bull. Chem. Soc. Japan, 38, 306 (1965)] in dimethyl formamide (DMF, 25 ml), potassium carbonate (1.66 g) and ethyl bromoacetate (2.84) were added successively. The mixture was stirred at 25° C. for 18 hr and then diluted with water. The precipitate was collected and dried to give 3-acetyl-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester, mp 162°-165° C.; nmr (CDCl3) δ1.33 (t, J=7 Hz, 3H), 2.75 (s, 3H), 4.25 (q, J=7 Hz, 2H), 4.9 (s, 2H), 7.4 (m, 4H), 9.4 (d, J=10 Hz, 1H).
Reaction SMILES: [Na].[F:2][C:3]([F:10])([F:9])[C:4]1O[N:7]=[CH:6][CH:5]=1.[Br-].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[NH2:25]>C(O)C>[C:6]([C:5]1[C:4]([C:3]([F:10])([F:9])[F:2])=[N:25][N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:15]=2[Cl:23])[C:26]=1[C:27]([F:30])([F:29])[F:28])#[N:7]
Reactant: FC(F)(F)c1ccno1
Reactant: NN(C(=O)C(F)(F)F)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Product: N#Cc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.3 %

Procedure:
0.92 g (0.04 mol) of sodium is dissolved in 25 ml of ethanol, 5.48 g (0.04 mol) of 5-trifluoromethylisoxazole are added at 0° C. and the mixture is stirred at room temperature for 15 minutes. 16.16 g (0.04 mol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-trifluoroacetohydrazide bromide are added dropwise to this mixture, while cooling, and the mixtureis subsequently stirred at 25° C. for a further 10 hours. After the sodium bromide which has precipitated out is filtered off, the filtrate isconcentrated and the residue is separatad by column chromatography. 1.65 g (9.3% of theory) of 4-cyano-3,5-di(trifluoromethyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole of melting point 88° C.-92° C. are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=2)[CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>CO>[NH2:7][C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Reaction time: 1 h

Procedure:
To a solution of [(S)-6-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamic acid tert-butyl ester (0.70 g) in MeOH (5 ml) was added concentrated hydrochloric acid (5 ml). After one hour, the mixture was basified with concentrated sodium hydroxide solution and extracted three times with DCM. The combined organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 244.34 (C15H20N2O); MS (ESI): 245 (M+H+).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:37]I>>[CH2:33]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[N:11]([CH3:37])[CH:12]=1)=[O:7])[CH2:34][CH2:35][CH3:36]
Reactant: CI
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 68.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 271F, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (370 mg, 0.75 mmol) and methyl iodide (106 mg, 0.75 mmol) were converted to the title compound (260 mg, 68%). 1H NMR (CDCl3) δ 8.70 (d, J=1.2 Hz, 1H), 8.24 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.43 (s, 1H), 7.37-7.33 (m, 3H), 7.28-7.27 (m, 2H), 5.17 (s, 2H), 3.98 (s, 3H), 3.92 (br s, 2H), 3.45 (br s, 2H), 3.24 (s, 3H), 1.68-1.52 (m, 4H), 1.37-1.24 (m, 4H), 0.94-0.90 (m, 6H); MS(ESI+) m/z 507.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:5]#[N:6].[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:20]3[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=3)[CH:24]=2)[CH2:12][CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: N#Cc1ccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)c(F)c1
Yield: 38 %

Procedure:
This compound was synthesized from 3-fluoro-4-(piperazin-1-yl)benzonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (100 mg, yield 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.17-8.15 (dt, J=6.6 Hz, 1.7 Hz, 1H), 8.09 (s, 1H), 7.75-7.72 (m, 3H), 7.61-7.58 (dd, J=8.5 Hz, 1.5 Hz, 1H), 7.17-7.13 (t, J=8.7 Hz, 1H), 3.81 (m, 2H), 3.52 (m, 2H), 3.19 (m, 4H). MS (ESI) m/z: Calculated for C21H15F4N5O2: 445.12. found: 446.2 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[NH2:1][C:4]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 50 °C

Procedure:
A mixture of methyl 2-nitro-4-(trifluoromethyl)benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50° C. for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5% ethyl acetate/n-hexane to give 1.46 g (6.67 mmol 67%) of the title compound as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OCC(C)(C)CO2)=[CH:11][C:10]=1[Cl:23])(=[O:3])[CH3:2].[Br:33][C:34]1[CH:39]=[CH:38][C:37](I)=[C:36]([F:41])[CH:35]=1.C(=O)([O-])O.[Na+].O>COCCOC>[C:26]([O:25][CH2:24][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:37]2[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][C:36]=2[F:41])=[CH:11][C:10]=1[Cl:23])(=[O:28])[CH3:27]
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(=O)NC(CCc1ccc(B2OCC(C)(C)CO2)cc1Cl)(COC(C)=O)COC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)NC(CCc1ccc(-c2ccc(Br)cc2F)cc1Cl)(COC(C)=O)COC(C)=O
Reaction time: 24 h
Yield: 56.1 %

Procedure:
A mixed solution of N-{1,1-bis(acetoxymethyl)-3-[2-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl}acetamide (2.05 g) of Reference Example 22, 1-bromo-3-fluoro-4-iodobenzene (1.39 g), sodium hydrogen carbonate (2.02 g) and tetrakistriphenylphosphine palladium (51 mg) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100° C. for 9 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Pyridine (20 mL) and acetic anhydride (2 mL) were added to the residue, and the mixture was stood at room temperature for one day. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.30 g) as white crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][C:16]([NH:28][C:29](=[O:33])[NH:30][CH2:31][CH3:32])=[CH:17][C:18]=3[C:19]3[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=3)=[CH:10][N:11]=2)[C:6](=[O:34])[C:5]([C:35]([O:37]CC)=[O:36])=[CH:4]1)[CH3:2]>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][C:16]([NH:28][C:29](=[O:33])[NH:30][CH2:31][CH3:32])=[CH:17][C:18]=3[C:19]3[S:20][CH:21]=[C:22]([C:24]([F:26])([F:27])[F:25])[N:23]=3)=[CH:10][N:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3CC)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3CC)cn1
Temperature: 90 °C
Yield: 77.4 %

Procedure:
To a stirred suspension of ethyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Example 3, 150 mg, 0.267 mmol) in ethanol (10 mL) 10% potassium hydroxide (0.56 mL) was added. The reaction mixture was heated to 90° C. for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature then concentrated under reduced pressure to a residue. The residue was diluted with water and acidified with 2N HCl up to pH 2-3 to obtain solid which was filtered, washed with water and dried to afford 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid 110 mg (77%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)=[O:7].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)[C@H:9]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:10]2)=[CH:16][CH:17]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1c[nH]c2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)C2)cc1
Yield: 99.5 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(4-nitrobenzyl)piperazine (360 mg), iron powder (360 mg), ammonium chloride (36 mg) and water (1.5 ml) in ethanol (6 ml) was heated under reflux for 40 minutes. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.34 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][OH:34])[O:13][CH:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[N:37]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][C:41]=1[Cl:48])=[N+:38]=[N-:39]>CN(C=O)C>[N:37]([C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:34][CH2:33][C@H:14]2[O:13][CH:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:15]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:42][C:41]=1[Cl:48])=[N+:38]=[N-:39]
Reactant: COC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1O[C@H](COCc2ccc(N=[N+]=[N-])c(Cl)c2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Methyl 2,3,4-tri-O-benzyl-D-glucopyranoside (1.16 g, 2.5 mmol) was dissolved in DMF (10 ml) and thereto was added sodium hydride (60% in oil, 120 mg, 3.00 mmol) at 0° C., followed by stirring for 15 min. Then 4-azido-3-chlorobenzyl bromide (740 mg, 3.00 mmol) was added portionwise. The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 3 hr. Ice-water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to give the title compound as a yellow oil (1.48 g, yield 94%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[CH:7][C:8]([CH3:28])=[C:9]([CH:27]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)([F:18])[CH2:14][CH2:13]1)=[O:11])=O.Cl.[C:34](=[NH:37])([NH2:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:29]1([C:6]2[C:5]([C:3]3[NH:37][C:34]([CH3:35])=[N:36][CH:2]=3)=[CH:27][C:9]([C:10]([N:12]3[CH2:13][CH2:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=4)([F:18])[CH2:16][CH2:17]3)=[O:11])=[C:8]([CH3:28])[CH:7]=2)[CH2:30][CH2:31][CH2:32]1
Reactant: CC(=N)N
Reactant: Cc1cc(C2CCC2)c(C(=O)CBr)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ncc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile (compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in CH3CN (10 mL). Acetimidamide hydrochloride (7.6 mg, 0.08 mmol, 1.00 equiv) and potassium carbonate (33.4 mg, 0.24 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 80° C. in an oil bath, then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (29.0% CH3CN up to 43.0% in 8 min, up to 100.0% in 2 min, down to 29.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 13 mg (35%) of the title compound as a white solid. m/z (ES+) 457 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.78 (d, 2H), 7.65 (d, 2H), 7.50-7.46 (m, 2H), 7.35 and 7.23 (2 s, amide rotamers, 1H), 4.91-4.83 (m, 1H), 3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30 (m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH3, 3H), 2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).