Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH2:15]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])[CH2:16][C:17]#[CH:18].CC1C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C(NC(C)C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I>[CH3:11][O:10][N:8]([CH3:9])[C:6]([C:5]1[CH:12]=[CH:13][C:2]2[O:1][C:17]([CH2:16][CH2:15][N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH3:24])=[CH:18][C:3]=2[CH:4]=1)=[O:7]
Reactant: CON(C)C(=O)c1ccc(O)c(I)c1
Reactant: C#CCCN1CCC[C@H]1C
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
The product from Example 71D (11.6 g, 37.77 mmol) in acetonitrile (50 mL) was treated sequentially with a 0.12M solution of the product from Example 68B (378 mL, 45.33 mmol), Pd(OAc)2 (0.254 g, 1.13 mmol), tris(4-methylphenyl)phosphine (0.518 g, 1.699 mmol), and diisopropyl amine (39.7 mL, 283.3 mmol). After stirring at 25° C. for 10 minutes, the mixture was treated with copper iodide (2.158 g, 11.33 mmol) and heated at 50° C. in an inert atmosphere for 18 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel using 95% DCM, 9.9% MeOH, 0.1% NH4OH to provide the title compound (1.22 g, 10.2% yield). 1HNMR (300MHz, CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.47 (m, 1H), 1.78 (m, 2H), 1.91-2.34 (m, 2H), 2.50 (m, 2H) 3.06 (m, 2H), 3.26 (m, 2H), 3.38 (s, 3H), 3.59 (s, 3H), 6.63 (s, 1H), 7.51 (q, 2H), 7.84 (1H); MS (ESI) m/z 317.2 (M+H)+.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.C([O:45][C:46]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])C>>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:36])[F:35])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:11]([N:51]5[CH2:52][CH2:53][CH:48]([C:46]([OH:47])=[O:45])[CH2:49][CH2:50]5)=[O:12])[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Nc1ccc(C2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Product: O=C(Nc1ccc(C2CCN(C(=O)N3CCC(C(=O)O)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to above, 1-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-piperidine-4-carboxylic acid was prepared from 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid 4-nitro-phenyl ester and piperidine-4-carboxylic acid ethyl ester. LCMS calcd for C29H29F3N4O5 (m/e) 570, obsd 571 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:12]([O:11][CH:8]([CH3:9])[CH2:7][C:1]1[CH:6]=[CH:5][C:4]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)Cc1ccc(-c2ccccc2)cc1
Reaction time: 4 h
Yield: 98.5 %

Procedure:
In a four-necked flask equipped with a thermometer and stirrer, were placed 17.0 g (0.08 mole) of the compound (XII-1) obtained in Preparation Example 1, 50 ml of toluene and 20 ml of pyridine, thereafter 10.2 g (0.1 mole) of acetic anhydride and 0.1 g of 4-dimethylaminopyridine was added thereto, and the resulting mixture was stirred at 40°-50° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 50 ml of 4N hydrochloric acid to conduct extraction and layer separation. The organic layer obtained was washed successively with 1% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water. The organic layer was then concentrated under reduced pressure to obtain 20.0 g of 4-(2-acetoxypropyl)biphenyl (XIII-1). Yield: 98.5%, nD20 1.3405
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[S:10][C:9]([C:11]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](=[O:32])[N:17]([CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:18]3=[O:23])=[O:12])=[CH:8][CH:7]=1.N1C=CC=CC=1>ClCCl.O>[C:1]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][N:17]2[C:16](=[O:32])[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:9]3[S:10][C:6]([Cl:5])=[CH:7][CH:8]=3)=[O:12])[C:18]2=[O:23])[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: O=C(Nc1cccc2c1C(=O)N(CCC1CCNCC1)C2=O)c1ccc(Cl)s1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCC(CCN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)CC1
Reaction time: 1 h

Procedure:
At room temperature, 17 μl (0.24 mmol) of acetyl chloride are added dropwise to a solution of 50 mg (0.12 mmol) of 5-chloro-N-{1,3-dioxo-2-[2-(4-piperidinyl)ethyl]-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide and 0.1 ml of pyridine in 1 ml of absolute dichloromethane. After 1 h at room temperature, a few drops of water are added and the mixture is diluted with dichloromethane. The mixture is washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude product is purified by chromatography on silica gel (dichloromethane/methanol 98:2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>N1CCCCC1.O.[Cu]I.C1(P([Pd](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:10][CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccccc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccc2N)cc1
Temperature: 60 °C
Reaction time: 26 h

Procedure:
To 2.5 g 2-amino-4′-bromo-biphenyl (WO0264562) in piperidine (25 ml) under nitrogen were added in sequence CuI (0.1 g), bis(triphenylphosphino)palladium dichloride (0.35 g) and trimethylsilylacetylene (2.8 ml). The mixture was stirred for 22 hours at room temperature and for a further 26 hours at 60° C. After cooling the reaction mixture was diluted with water and extracted with ethylacetate. Then the organic phase was washed with water and dried over sodium sulfate. After evaporation of the solvents in vacuum the mixture was chromatographed on silica gel (hexane:ethylacetate 9:1) to yield 2- amino-4′-(trimethylsilyl)ethinyl-biphenyl (2 g) (Compound No.12.02).
Reaction SMILES: [CH2:1](CC(=O)C)C(C)=O.C(=O)C1C=CC=CC=1.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18]>>[CH3:18][C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH2:1]
Reactant: CC(=O)c1ccccc1
Reactant: CC(=O)CCC(C)=O
Solvent: O=Cc1ccccc1
Product: C=C(C)c1ccccc1

Procedure:
Polar substances contained in the recovered main fraction were quantified by gas chromatography (GC-14A, Shimadzu Corp.). The amount of polar substances was taken to be the total amount of acetonylacetone, 3-methyl-2-cyclopetenone, benzaldehyde and acetophenone. The polar substance removal rate was determined based on the following formula 1. Removal rate (%)=Amount of reduction in polar substances (ppm)/Content of polar substances before purification (ppm)×100
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:11]([O-])=[CH:10][C:9]=2[N:19]=1)(=[O:3])[CH3:2].[NH4+:25].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:20][C:21]([F:24])([CH3:23])[CH3:22])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:25])[C:9]=2[N:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)(C)F
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)F
Reaction time: 1 h

Procedure:
[1-(2-Fluoro-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate (1.67 g, 5.03 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (1.05 g, 5.53 mmol) was carefully added. Rapid stirring was continued for 1 hour. The reaction mixture was then treated with 20 mL of H2O. The layers were separated and the organic portion was washed successively with 5% Na2CO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered, and; concentrated under reduced pressure. Chromatography (SiO2, 2.5% methanol/CHCl3) gave 1.13 g of [4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as a light-yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11]C(=O)OC(C)(C)C)[CH:2]=1.Cl>CO>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc2cccnc2c1
Agent: Cl
Solvent: CO
Product: Nc1cnc2cccnc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 1,5-naphthyridin-3-ylcarbamate (D-12) (4.040 g, 16.5 mmol, 1.0 eq) in methanol (24 mL), concentrated hydrochloric acid (36.5%, 10 mL, 120 mmol, 7.27 eq) was added. The resulting mixture was stirred at 50° C. for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated under reduced pressure to afford the desired product 1,5-naphthyridin-3-amine (D-13), which was used for next reaction without further purification. 1HNMR (300 MHz, DMSO-d6) 8.85 (m, 1H), 8.77-8.75 (m, 2H), 7.63-7.69 (m, 1H), 7.4 (d, J=1.8 Hz, 1H); ESI-MS m/z: 146.10 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cn1

Procedure:
By carrying out the operation analogously to example 213, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 2-methoxy-5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: C(OC([N:8]([CH3:51])[C@@H:9]([CH3:50])[C:10]([NH:12][C@H:13]1[C:19]2([CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[O:18][C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]([CH2:29][C:30]2[C:39](OC)=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])=[CH:35]3)[C:14]1=[O:49])=[O:11])=O)(C)(C)C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]>C(Cl)Cl>[F:55][C:54]([F:57])([F:56])[C:52]([OH:58])=[O:53].[CH2:52]([O:53][C:35]1[C:36]2[C:31](=[C:30]([CH2:29][N:15]3[C:14](=[O:49])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:51])[CH3:50])[C:19]4([CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[O:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]3=4)[CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[C:42]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])=[O:43])[CH3:54]
Reactant: COc1ccc2cc(C(=O)NS(C)(=O)=O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1c(C(=O)NS(C)(=O)=O)ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)NC)C4(CCOCC4)Oc4ccccc43)cccc12
Yield: 67 %

Procedure:
5-(((S)-3-((S)-2-(tert-Butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-N-(methylsulfonyl)-2-naphthamide dissolved in DCM (1 mL) and 0.25 mL TFA was added. After 90 min the mixture was concentrated, the residue was dissolved in MeCN/H2O, and lyophilized to afford the title compound (45.4 mg, 67%) as a white solid. MS m/z 625.4 (MH+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C@H:31]1[O:33][CH2:32]1)[Cl:30].[O-]S([O-])(=O)=O.[Mg+2]>CO>[CH2:21]([N:20]([CH2:32][C@H:31]([OH:33])[CH2:29][Cl:30])[CH2:19][CH2:18][CH2:17][CH2:16][C@H:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNCc1ccccc1)C(=O)OC(C)(C)C
Reactant: ClC[C@@H]1CO1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN(Cc1ccccc1)C[C@H](O)CCl)C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
A mixture of Nε-benzyl-Nα-BOC-L-lysine t-butyl ester (24) (16.0 g, 40.76 mmol), CH3OH (40 ml), (S)-(+)-epichlorohydrin (4.17 g, 45.0 mmol) and anhydrous MgSO4 (5.33 g. 44.28 mmol) was stirred under N2 for three days. The solids were filtered off and washed with CH3OH. The filtrate was concentrated at room temperature to give a yellow oil. The resulting oil was purified by flash chromatography on silica gel (66% hexane/ethyl acetate) to give 13.23 g of (25) (77%) as a colorless oil. 1H NMR (C6D6) δ 7.18 (m, 5H), 5.00 (br d, 1H), 4.40 (m, 1H), 3.62 (m, 1H), 3.40-3.10 (m, 4H), 2.20-2.00 (m, 4H), 1.63 (m, 1H), 1.40 (s, 9H), 1.20 (m, 2H). 13C NMR (C6D6) δ 171.7, 155.2, 138.8, 128.8, 127.9, 127.0, 80.8, 78.8, 67.7, 58.8, 57.2, 53.9, 53.7, 47.3, 32.5, 28.0, 27.5, 26.3, 22.8. HRMS m/z calcd. for C25H42ClN2O5 485.2782, found 485.2775. [α]25D+5.3° (c=1.00, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:10]2)[CH:5]=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:13](=[O:14])[N:9]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH:3]=3)[N:10]=2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Product: O=c1n(Cc2cncc(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 86, 72 mg (0.15 mmol) of the compound from Example 28A and 59 mg (0.23 mmol) of 2-chlorophenylboronic acid were reacted with one another. This gave 49 mg (64% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][N:12]([CH2:37][C:38]1[N:39]([S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[CH:40]=[CH:41][N:42]=1)[C:13](=[O:36])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([NH:28][N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1)(=[O:5])=[O:4].Cl[C:51]([O:53][CH3:54])=[O:52]>>[CH3:47][N:46]([CH3:48])[S:43]([N:39]1[CH:40]=[CH:41][N:42]=[C:38]1[CH2:37][N:12]([CH2:11][C:7]1[N:6]([S:3]([N:2]([CH3:1])[CH3:49])(=[O:5])=[O:4])[CH:10]=[CH:9][N:8]=1)[C:13]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C@H:22]2[CH2:27][CH2:26][C@H:25]([NH:28][N:29]([CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH3:35])[CH2:24][CH2:23]2)[C:51](=[O:52])[O:53][CH3:54])=[CH:16][CH:15]=1)=[O:36])(=[O:45])=[O:44]
Reactant: CCCN(CCC)N[C@H]1CC[C@H](NCc2ccc(C(=O)N(Cc3nccn3S(=O)(=O)N(C)C)Cc3nccn3S(=O)(=O)N(C)C)cc2)CC1
Reactant: COC(=O)Cl
Product: CCCN(CCC)N[C@H]1CC[C@H](N(Cc2ccc(C(=O)N(Cc3nccn3S(=O)(=O)N(C)C)Cc3nccn3S(=O)(=O)N(C)C)cc2)C(=O)OC)CC1

Procedure:
The same operation as in Example 13 was performed, except for using the compound (200 mg) obtained in Example 16 and methyl chloroformate (54 mg), and then the obtained crude product was purified by silica gel chromatography (ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→85:15) to obtain the title compound (210 mg) having the following physical properties.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:17]=[CH:16]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(F)ccc32)cc1
Yield: 100 %

Procedure:
The title compound was prepared from toluene-4-sulfonyl chloride and 5-fluoro-1H-indole, according to Method A, described above. Yield 100%; mp 106-108° C.; 1H NMR (CDCl3) δ 8.13-8.19 (dd, J=4, 8 Hz, 1H), 7.96 (d, J=8 Hz, 2H), 7.82 (d, J=4 Hz, 1H), 7.40-7.48 (m, 3H), 7.25-77.38 (m,1H), 6.83 (d, J=4 Hz, 1H), 2.55 (s, 3H); 13C NMR (CDCl3) δ 161.9, 158.1, 145.6, 135.4, 132.2, 132.1, 131.6, 130.3, 128.5, 127.2, 115.0, 114.9, 113.2, 112.8, 109.4, 109.3, 107.5, 107.1, 21.9.
Reaction SMILES: [Li+].[F:2][C:3]([F:21])([F:20])[C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O-:19])=O)[CH2:11][CH2:10]2)=[N:6][N:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:63]([F:66])([F:65])[F:64])([O-:49])=[O:48].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C)C=O.O1CCCC1>[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:58][CH2:59][N:60]([C:17](=[O:19])[CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][N:9]([C:7]4[S:8][C:4]([C:3]([F:2])([F:21])[F:20])=[N:5][N:6]=4)[CH2:14][CH2:13]3)[CH2:61][CH2:62]2)=[CH:52][C:51]=1[C:63]([F:66])([F:64])[F:65])([O-:49])=[O:48]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: O=C([O-])CCN1CCN(c2nnc(C(F)(F)F)s2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2nnc(C(F)(F)F)s2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 54 %

Procedure:
3-[4-(5-Trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazin-1-yl]-propionic acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 123) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (0.75 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are added and the reaction is then stirred. After 4 hours at room temperature, aluminium oxide (90 active basic) is added and stirring is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (16 mg; 0.027 mmol). The structure was confirmed using Protocol I-D. Calculated mass=582; observed mass=582; HPLC retention time=1.41 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1F
Reaction time: 3 h

Procedure:
A mixture of methyl 2-fluoro-5-nitrobenzoate (14.52 g, 72.92 mmol) and Pd/C (10%, Degussa type, 726 mg) in methanol was agitated under 60 psi of H2 using a Parr apparatus for 3 h. The reaction mixture was filtered and the filtrate was concentrated to give methyl 5-amino-2-fluorobenzoate.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C([O-])(=O)C.[Na+:13]>C(O)(=O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[Na+:13]
Reactant: O=C(O)/C=C/C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])/C=C/C(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sodium sulfamate and solid acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: Cc1nn(C)c(C)c1N
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1ccc(Br)cc1F
Yield: 59.3 %

Procedure:
Prepared from 4-bromo-2-fluorobenzenesulfonyl chloride (0.75 g, 2.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) in pyridine (4.5 ml) according to the method of intermediate 1, to give the title compound as an orange solid (0.59 g, 1.6 mmol, 60%). δH (D-6 DMSO, 300K) 9.60 (1H, s), 7.90 (1H, d J 9.4 Hz), 7.56 (1H, d J 8.2 Hz), 7.51 (1H, d J 7.7 Hz), 3.56 (3H, s), 1.89 (3H, s), 1.69 (3H, s). m/z (ES+, 70V) 364.0 (MH+).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[N:7]([CH3:19])[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17]C)=[N:15][CH:16]=2)[N:10]=1.C(Cl)Cl.Cl.C(=O)(O)[O-].[Na+]>CC#N>[CH3:19][N:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:10]=[C:6]1[CH:2]=[O:1]
Reactant: CCc1ccc(-c2cn(C)c(C3OCCO3)n2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(-c2cn(C)c(C=O)n2)cn1
Temperature: 45 °C
Yield: 78.3 %

Procedure:
A mixture of 5-(2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-4-yl)-2-ethylpyridine (140 mg, 0.571 mmol), DCM (5 mL), and 4 N HCl (5 mL) was heated to 45° C. for 16 h. Then the mixture was cooled to room temperature, the pH was adjusted to 6 with saturated sodium bicarbonate solution at 0° C., and the mixture was concentrated to give a crude product. 30 mL of CH3CN was added and the mixture was filtered. The filtrate was then concentrated to afford a white solid (90 mg). MS (ESI): m/z 202.1 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.C(=O)(O)O.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1>C(O)CC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:29]=[C:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:31])[F:18])[CH:21]=3)[N:28]=2)[CH:8]=1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=CC(=O)c1cccnc1
Agent: O=C(O)O
Solvent: CCCO
Product: FC(F)(F)c1cccc(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
A 7.04 g amount of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one (U.S. Pat. No. 4,281,000) and 18.72 g of [3-(trifluoromethyl)phenyl]guanidine carbonate in 500 ml of n-propanol was heated at reflux temperature for 16 hours. The solvent was evaporated to near dryness, then water was added and the precipitate which formed was collected by filtration, then recrystallized from hexane to give 5.55 g of the desired product, mp 170°-171° C.