Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CC1CCNCC1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(C)CC3)n2n1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol) and 4-methylpiperidine (77 mg, 0.75 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (45-45% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (88.6 mg, 87%). Melting point (154.0-158.0° C.). 1H NMR (DMSO-d6) δ: 10.85 (s, 1H), 7.99 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.29 (s, 1H), 6.16 (s, 1H), 4.46 (d, J=12.1 Hz, 2H), 2.98-3.10 (m, 2H), 2.37 (s, 3H), 1.78 (d, J=12.9 Hz, 2H), 1.61-1.74 (m, 1H), 1.46 (s, 6H), 1.28-1.39 (m, 2H), 0.98 (d, 3H); ESI-MS: m/z 408.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH:13]([CH3:15])[CH3:14])[NH:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]Cl.[H-].[Na+].CN(C=O)C>C1COCC1>[N:5]1([C@@H:4]([CH:13]([CH3:15])[CH3:14])[C:3]([O:2][CH3:1])=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:12]
Reactant: COC(=O)[C@@H](NC(=O)CCCCCl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1CCCCC1=O
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
A solution of 105 mg (0.42 mmol) of the product of Step A in 10 mL of dry THF was treated with 17 mg (0.43 mmol) of 60% NaH in oil dispersion at 0° C. for 1 h. TLC analysis indicated starting material was present and 2 mL of DMF was added. After 1.5 h. at 0° C., the solvent was evaporated and the mixture was worked up in the standard to give 90 mg of product.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[N:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:7]([C:5]2[S:6][C:2]([Br:1])=[C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]=2)=[O:9])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1nc(-c2ccccc2)c(Br)s1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2nc(-c3ccccc3)c(Br)s2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.5, intermediate 48.3 replacing 5-bromo-4-phenyl-thiazole-2-carboxylic acid and (S)-4-(2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester replacing intermediate 8.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:31])[N:25]([CH2:29][OH:30])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[C:33]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35][CH2:34]1.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:17][CH2:18]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4\[NH:27][C:26](=[O:28])[N:25]([CH2:29][O:30][C:33](=[O:40])[CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:24]\4=[O:31])=[C:11]3[N:10]=2)[CH:7]=1
Reactant: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Reactant: O=C1CCCC(=O)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)CCCC(=O)OCN1C(=O)N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione (100 mg, 0.218 mmol) in pyridine (4.5 mL) was added glutaric anhydride (125 mg, 1.095 mmol), and DMAP (3 mg, 0.022 mmol). The reaction mixture was stirred at 75° C. overnight after which the reaction was not complete. Added glutaric anhydride (125 mg, 1.095 mmol) and DMAP (3 mg, 0.022 mmol) and stirred an additional 16 hours at 75° C. Cooled to 0° C. in ice bath and added 6M HCl until pH was less than 3 by pH paper. Filtered off the solid and washed with 0.1M HCl. Dried under vacuum to provide 40 mg (32%) of (Z)-5-((4-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methoxy)-5-oxopentanoic acid as a yellow solid. LCMS (ES): >95% pure, m/z 572 [M+1]+.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[C:15]=2[F:17])[C:10]([S:19][C:20]2[C:21]([F:31])=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]1[CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:14]1[C:15]([F:17])=[C:16]2[C:11]([C:10]([S:19][C:20]3[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]=3[F:31])=[C:9]([CH3:32])[N:8]2[CH2:7][C:6]([OH:33])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(CC(=O)OC(C)(C)C)c3c(F)c(Cl)ccc23)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Sc2c(C)n(CC(=O)O)c3c(F)c(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
To a stirred solution of compound 5 (200 mg, 0.40 mmol) in CH2Cl2 (10 mL) under inert atmosphere was added TFA (0.8 mL) at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with water (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was triturated with n-pentane (2×5 mL) to afford compound 6 (149 mg, 81%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.59-7.55 (m, 1H), 7.19-7.06 (m, 3H), 6.79-6.75 (m, 1H), 4.93 (s, 2H), 4.32 (q, 2H), 2.40 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); LC-MS: 98.7%; 440.3 (M++1); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 2.90 min. 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C[O:13][C:14](=O)[CH:15]=[CH:16][C:17]1[C:25]2[N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[N:22][C:21]=2[CH:20]=[C:19]([C:32]([F:35])([F:34])[F:33])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:14](=[O:13])[CH:15]=[CH:16][C:17]2[C:25]3[N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[N:22][C:21]=3[CH:20]=[C:19]([C:32]([F:34])([F:33])[F:35])[CH:18]=2)[CH2:8][CH2:7]1
Reactant: CN1CCNCC1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Yield: 52.9 %

Procedure:
To a stirred suspension of aluminium trichloride (1.46 mmol, 195 mg) in dichloromethane (3 ml) was added dropwise N-methylpiperazine (1.83 mmol, 203 l). The resultant mixture was stirred for 0.5 h and to this, a solution of 3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)acrylic acid methyl ester (0.73 mmol, 250 mg) was added dropwise. The resultant mixture stirred for 16 h at 60° C. Upon cooling, aqueous sodium carbonate (5%, 5 ml) was added and the mixture was shaken. The organic layer was isolated by filtration through a hydrophobic frit and evaporated under reduced pressure to give an off-white solid. Recrystallisation from diethyl ether afforded the title compound as a white powder (160 mg, 53%), m/z 415.2 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:28]=[CH:29][C:30]=1[OH:31].[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49][C:50](O)=O>O.ClC1C=CC=CC=1Cl>[CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49][C:50]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:26][C:25]=2[N:24]=1
Reactant: CCOC(=O)CCc1ccc(O)c(N)c1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)CCc1ccc2oc(Cc3ccc4ccccc4c3)nc2c1
Yield: 72.9 %

Procedure:
A mixture of phosphorus pentoxide (P2O5) (12.9 g), hexamethyldisiloxane (29.5 g) and 1,2-dichlorobenzene was heated for 10 minutes under reflux. To the mixture were added ethyl 3-(3-amino-4-hydroxyphenyl)propionate (4.75 g) and 2-naphthylacetic acid (4.23 g). The mixture was heated for 3 hours under reflux. The reaction mixture was poured into water and allowed to extraction with ethyl acetate. The ethyl acetatae layer was washed with water and dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:4, v/v), ethyl 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionate (5.95 g, 73%) was obtained. Recrystallization from ether-isopropyl ether gave colorless needles. Melting point: 81-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH2:20][CH3:21])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CCc1ccncc1Br
Reactant: O=C1NCCc2ccc(Cl)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1ccncc1N1CCc2ccc(Cl)cc2C1=O
Yield: 15.8 %

Procedure:
7-Chloro-3,4-dihydroisoquinolin-1(2H)-one (I-1d: 100 mg, 0.552 mmol) was reacted with 3-bromo-4-ethyl pyridine (133.5 mg, 0.718 mmol), 1,4-dioxane (5 mL), copper iodide (10.48 mg, 0.0555 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (7.8 mg, 0.055 mmol) and potassium phosphate (351 mg, 1.657 mmol for 48 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexane), followed by preparative HPLC afforded 25 mg of the product (15.72% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](S)=[S:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>C(OCC)C>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[S:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C(=S)S)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCc1ccc(C(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 102.1 %

Procedure:
To a 300 ml three neck flask provided with a stirrer, thermometer, cooling tube, and dropping funnel were added 11.1 g (56.7 mmol) of the 4-propyldithiobenzoic acid obtained by the procedures described above and 60 ml of diethyl ether, and 13.5 g (113.4 mmol) of thionyl chloride was added dropwise thereto while being stirred at room temperature in 5 minutes, and further heated to reflux for 8 hours. From the reaction mixture, diethyl ether was distilled off, and unreacted thionyl chloride was distilled off under a reduced pressure to obtain 11.5 g of dark purplish red oily 4-propylthiobenzoic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:29]=[N:28][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]4CCCC[O:21]4)[C:14](=[O:15])[C:9]=3[C:8]=2[CH:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)O)=[CH:4][CH:3]=1>C(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:29]=[N:28][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]=[O:21])[C:14](=[O:15])[C:9]=3[C:8]=2[CH2:30][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)=[CH:39][CH:40]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Temperature: 60 °C
Yield: 100.4 %

Procedure:
To a solution of 6-(4-chlorophenoxy)-5-((4-fluorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetra hydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 0.10 mmol) in HCOOH (3 mL) was added Zn dust (40.4 mg, 0.62 mmol). The reaction was heated at 60° C. for 2 h then cooled to RT and filtered. The filtrate was concentrated to give 3-((6-(4-chlorophenoxy)-5-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propylformate (50 mg, 100% yield) as a white solid. LCMS: MH+ 498 and TR=1.732 min. Used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=[O:3].CC(C)([O-])C.[K+]>C(O)(C)C.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.[Fe]>[Cl:11][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl[Ru]Cl
Agent: [Fe]
Agent: CC(C)(C)[O-]
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CC(O)c1ccc(Cl)c(Cl)c1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Benzeneruthenium(II) chloride dimer (1.0 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Fe, R=s-Bu, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in i-propanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 0.5 h at 85° C. After the mixture was cooled to room temperature, 3,4-dichloroacetophenone (0.4 mmol), i-propanol (3 mL) and a solution of potassium t-butoxide in i-propanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 72 h under H2 (3 atm) at −20° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(3,4-dichlorophenyl)ethanol was obtained and the ee value (ee=95%) was measured by GC analysis.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]1C[O:15][CH2:14][CH2:13]1.[CH2:17]([C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(=O)CC>C(OCC)(=O)C>[CH2:17]([C@@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:14](=[O:15])[CH2:13][CH3:12])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
1.57M n-butyllithium hexane solution (96 ml, 150 mmol) was slowly added dropwise to a THF (400 ml) solution of (R)-4-benzyl-2-oxazolidinone (25.36 g, 143 mmol) at −78° C. under stirring. Subsequently propionyl chloride (13.7 ml, 157 mmol) was added at once and the reaction solution was stirred at the same temperature for 30 minutes. After the reaction solution was warmed to room temperature for 30 minutes, it was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; heptane:ethyl acetate=5:1) to obtain the title compound (36.58 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.C([N:35]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:35])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (90 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg), 1-hydroxybenzotriazole ammonium salt (59 mg) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was crystallized from acetonitrile and the crystals were washed with acetonitrile-diethyl ether. The crystals were recrystallized from ethanol to give the title compound (58 mg, 64%) as off-white crystals. MS 461 (MH+). mp 225-227° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)[C@@H](N)Cc1ccccc1)=NNC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)cc2ccccc21
Reaction time: 4 h
Yield: 81.7 %

Procedure:
1-Methylindole-2-carboxylic acid (72 mg, 0.41 mmol) and 3(S)-(phenylalaninyl]amino4-oxobutanoic acid, t-butyl ester semicarbazone (154 mg, 0.41 mmol) were dissolved in methylene chloride (2 mL) and both DMAP (53 mg, 0.43 mmol) and EDAC (109 mg, 0.57 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution, successively, dried over sodium sulfate, and concentrate to give a white solid. Trituration of the solid with ether afforded the title product as a white powder (179 mg, 82%) TLC: (methanol/methylene chloride: 5/95, silica gel): Rf=0.44.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH2:25])[CH2:20][CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=1)[CH2:20][CH2:19]2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: NC1CCc2cc(F)ccc21
Product: O=[N+]([O-])c1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
2-Chloro-6-nitro-quinoline (2.7 g, 13 mmol) and rac-5-fluoro-indan-1-ylamine (CAS 148960-33-2, 3.9 g, 26 mmol) were heated at 130° C. for 24 h. The reaction mixture was purified by flash chromatography on silica gel (dichloromethane). rac-(5-Fluoro-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine was obtained as a yellow solid (2.99 g, 71%), MS: m/e=324.4 (M+H+).
Reaction SMILES: C(OC([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(OCC)=O)=[C:9]([N+:19]([O-:21])=[O:20])[N:8]=1)=O)C.[OH-].[K+]>>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:19]([O-:21])=[O:20])[N:8]=1
Reactant: CCOC(=O)Nc1ccc(NC(=O)OCC)c([N+](=O)[O-])n1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(N)c([N+](=O)[O-])n1

Procedure:
4.0 g of the biscarbamate of Example 9 are boiled in 200 ml of an ethanolic 3 percent potassium hydroxide solution for 18 hours with reflux. This is followed by filtering and the filtrate is acidified with concentrated sulphuric acid, whereupon it is concentrated in vacuo. The residue is taken up in methanol. The desired product then crystallizes as hydrochloride (melting point 241° C.).
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.[NH4+].[Cl-]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[NH:13][C:1]([CH3:3])=[CH:2]2
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(F)c2[nH]1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1600 ml of a 0.5M solution of isopropenylmagnesium bromide in THF are cooled to −25° C. under an argon atmosphere, a solution of 37.65 g of 2-fluoronitrobenzene in 250 ml of THF is then added dropwise and the mixture is left stirring at −20° C. for 1 hour. The reaction mixture is poured into a saturated NH4Cl solution, the aqueous phase is extracted with ether and the combined organic phases are concentrated under vacuum. The residue is taken up in water and extracted with DCM, the organic phase is washed with water and with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a cyclohexane/EtOAc mixture (95/5; v/v). 12.35 g of the expected compound are obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1>C(Cl)Cl>[Cl:1][C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:10][Cl:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ClCc1cn2ccccc2n1
Solvent: ClCCl
Product: ClCc1nc2ccccn2c1Cl
Reaction time: 2 h
Yield: 90.4 %

Procedure:
N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml) at RT under an atmosphere of nitrogen. Stirring was continued for 2 h (reaction was monitored by TLC) upon which the reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (400 mg, 76%,) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (d, 1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.1 (t, 1H), 4.85 (s, 2H). MS: [M+H]+: m/z=201.8. HPLC: (98.3%, Condition-A).
Reaction SMILES: [N-:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[Na+].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>CN(C(N1CC1)=O)C>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:10]=1[C:11]#[N:12]
Reactant: c1cn[n-]c1
Reactant: COc1cccc(F)c1C#N
Agent: CN(C)C(=O)N1CC1
Agent: [Na+]
Product: COc1cccc(-n2cccn2)c1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of 0.273 mol of sodium pyrazolide (prepared from equimolar amounts of pyrazole and sodium hydride) in 140 ml of N,N-dimethylethyleneurea is added dropwise at 50° C., under nitrogen, to a solution of 41.2 g (0.273 mol) of 2-methoxy-6-fluorobenzonitrile (preparation: J. Heterocycl. Chem. 25 (1988), 1173) in 50 ml N,N-dimethylethyleneurea and the mixture is stirred at 60° C. for 2h. After the mixture has been cooled and stirred into 4 l of ice water and the precipitated crystals have been filtered off under suction and dried, 37.1 g of the product of melting point 93°-94° C. are obtained.