Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][C:15]([NH2:18])([CH3:17])[CH3:16]>CN1CCCC1=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][C:15]([CH3:17])([NH2:18])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(N)CN
Solvent: CN1CCCC1=O
Product: CC(C)(N)CNc1ccnc2cc(Cl)ccc12

Procedure:
52.8 g of 4,7-dichloroquinoline and 30.85 g of 1,2-diamino-2-methylpropane were stirred in 530 ml of N-methyl-2-pyrrolidone under argon at 150° C. for 5 hours. Thereafter, the solvent was evaporated in a vacuum and the residue was taken up in 1250 ml of water. After adjustment to pH 1 using conc. hydrochloric acid, the mixture was extracted once with 200 ml of ethyl acetate and twice with 100 ml of ethyl acetate each time, and subsequently treated with about 170 ml of 30% potassium hydroxide solution until the pH reached 12. Thereby, 88 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine separate out in crystalline form; m.p.: 169°-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[CH3:10].[C:11]([NH:13][C:14]([NH2:16])=[NH:15])#N.[OH-].[Na+]>Cl>[CH3:10][C:3]1[C:2]2[NH:1][C:11]([NH:13][C:14]([NH2:16])=[NH:15])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[CH3:9]
Reactant: Cc1ccc(N)c(N)c1C
Reactant: N#CNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nc(NC(=N)N)[nH]c2c1C
Yield: 38.3 %

Procedure:
3,4-Diamino-o-xylene (6.80 g 0.05 mol) and cyanoguanidine (4.20g 0.05 mol) were refluxed together for 2 hours in 5N hydrochloric acid (20 ml). The hot reaction mixture was basified with excess 40% sodium hydroxide and the resulting precipitate filtered, washed with water and dried. Recrystallisation from aqueous ethanol gave 4,5-dimethyl-2-guanidinobenzimidazole (3.89 g, 38%) as pale brown microcrystals m.p. 122°-124°C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1F)([O-:5])=[O:4].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[O:19][C:20]1[CH:16]=[CH:17][C:18]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4])([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
This compound was made by the procedure of Example 2 from Compound A (46.5 g, 0.010 mole), NaH (4 g as 60% oil suspension, 0.10 mole) and 2,4-dinitrofluorobenzene (27.9 g, 0.15 mole) in THF (150 ml). The final product was purified by distillation to give a liquid product, yield 45.0 g (71.3%). Bp. 150°-160° C./0.5 mm. H1NMR (CDCl3): δ8.80 (d, J=2.5 Hz, 1H), 8.70 (dd, J=2.5, 10 Hz, 1H), 7.24 (d, J=10 Hz, 1H), 4.68 (t, J=12 Hz, 2H); F19NMR (CDCl3): -71.3 (d, J=10.1 Hz, 2F), -77.4 (m, 1F), -80.2 (q, J=7.6 Hz, 3F), -82.5 to -86.0 (m, 4F), -122.9 (t, J=11.6 Hz, 2F), -145.9 (q, J=19.4 Hz, 1F).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[C:1](=[O:12])([S:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)CCS
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and isoamylmercaptan as starting materials to give the aimed compound.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O.CCOCC>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(C)=O)cc1
Temperature: 21 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
The scandium salt of dibutylaminosulfonylmalononitrile, obtained in Example 40, was used as catalyst in a Friedel-Crafts reaction of acylation, by operating in the following manner. In 40 ml of anhydrous nitromethane, there is added 570 mg (700 μmoles) of Sc(DBSM)3, and 1.08 g (10 mmoles) of anisol and 2.04 g of acetic anhydride. After stirring during 10 min at 21° C., the reaction mixture was diluted with 50 ml of ether and the reaction was inhibited by using 100 ml of a saturated solution of sodium bicarbonate NaHCO3. After filtration on Celite, the solution was extracted with three fractions of 50 ml of ether, and the collected ether phase was washed with a saturated solution of potassium chloride. After drying the ether phase with magnesium sulfate and evaporation, 1.46 g of p-methoxyacetophenone (97% yield) was recovered, with a purity characterized by a proton RMN higher than 99%.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:3].C(N(CC)CC)C.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1>[CH3:3][CH:2]([NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][Br:16])=[CH:23][CH:22]=1)(=[O:25])=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CCCCCC(C)N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 2-aminoheptane (1.67 ml, 0.011 mol) and triethylamine (1.55 ml, 0.011 mol) in dry THF (100 ml) was added powdered 4-bromomethylbenzenesulphonyl chloride (3.0 g, 0.011 mol) in one portion. The mixture was stirred for 3 h at room temperature. The reaction mixture was treated with saturated ammonium chloride (60 ml) , extracted with ethyl acetate (3×80 ml), the organics combined and washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulphate, filtered and evaporated. The resulting oil was purified by chromatography (silica: 1:2 hexane:ethyl acetate) to give N-1-methylhexyl 4-bromomethylbenzenesulphonamide (1.45 g, 39%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][CH:3]=1.C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N+:4]([O-:14])[CH:3]=1
Reactant: NC(N)=O
Reactant: COC(=O)c1nc(Cl)cnc1C
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(Cl)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (8.6 g, 46.1 mmol) and hydrogen peroxide urea adduct (8.1 g, 86 mmol) in dichloromethane (100 mL) was added 2,2,2-trifluoroacetic anhydride (10.9 ml, 78 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with water. The aqueous layer was extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6 mmol, 95% yield) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (1H, s), 4.02 (3H, s), 2.65 (3H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].[C:5]([O:9][C:10]([NH:12][N:13]1[CH2:18][C:17](/[C:19](/Cl)=[N:20]/[OH:21])=[N:16][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]1=[O:30])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:5]([O:9][C:10]([NH:12][N:13]1[CH2:18][C:17]([C:19]2[CH2:1][C:2]([CH3:4])([CH3:3])[O:21][N:20]=2)=[N:16][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]1=[O:30])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: C=C(C)C
Reactant: CC(C)(C)OC(=O)NN1CC(/C(Cl)=N/O)=NN(C(=O)OC(C)(C)C)C1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1CC(C2=NOC(C)(C)C2)=NN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into an argon-flushed round-bottom flask equipped with rubber septa and argon balloon at −78° C. was condensed gaseous 2-methylprop-1-ene (2.97 g, 53.0 mmol) via cannula. After addition of a solution of tert-butyl 4-(tert-butoxycarbonylamino)-6-[(Z)—C-chloro-N-hydroxy-carbonimidoyl]-3-oxo-5H-1,2,4-triazine-2-carboxylate (2.30 g, 5.30 mmol) in CHCl3 (10.0 mL), triethylamine (0.747 mL, 5.30 mmol) was slowly added via syringe. After completion of the addition, the reaction mixture was allowed to slowly warm up to room temperature overnight. After 20 h stirring, the reaction mixture was quenched with sat. NH4Cl, and the aqueous layer extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The obtained sticky oil was used as obtained. LCMS (Method K) RT 0.96 min. [M−H]− 410.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[Sn](CCCC)(CCCC)CCCC)[CH:7]=1.Br[C:25]1[N:26]=[C:27]2[C:33]([CH:34]=[O:35])=[CH:32][N:31]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]2=[N:29][CH:30]=1.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][C:10]=2[C:25]2[N:26]=[C:27]3[C:33]([CH:34]=[O:35])=[CH:32][N:31]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]3=[N:29][CH:30]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3ncn4cc(F)ccc34)cnc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 105.4 %

Procedure:
In a round-bottomed flask, 6-fluoro-1-tributylstannyl-imidazo[1,5-a]pyridine (577 mg, 0.81 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (210 mg, 0.59 mmol) were dissolved in DMF (5 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.029 mmol) and copper (I) iodide (22 mg, 0.12 mmol) were added. The reaction mixture was stirred at 80° C. in an oil bath for 4 h then cooled to room temperature. Water was added and the resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 256 mg (95%) of 2-(6-fluoro-imidazo[1,5-a]pyridin-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[N:32](C3CCCCO3)[N:31]=2)=[N:4][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:11]([CH3:28])[CH:10]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH3:28])[C:12]([CH:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:13][N:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)ncc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cn3)ncc2Cl)n[nH]1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(6-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidine-1-carboxylate in DCM (1 mL), was added TFA (1 mL). The mixture was stirred for 1 h and concentrated to afford 5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamine as brownish oil. The product was used directly for subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].Cl>COCCOC.CCOC(C)=O.[F-].[Cs+]>[F:20][C:19]([F:22])([F:21])[CH:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=1)[OH:12]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(OCCCC(F)(F)F)cc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: OC(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 123.4 %

Procedure:
To the solution of Intermediate 2A (26.7 g, 114 mmol) and trimethyl(trifluoromethyl)silane (16.9 g, 119 mmol) in anhydrous DME (112 mL) was added CsF (500 mg, 3.29 mmol). The reaction was stirred at rt for 16 h. To the mixture was added 4 N aq HCl (114 mL) and the reaction was stirred at rt for 2.5 h. The reaction was diluted with EtOAc (300 mL) and washed with water, sat'd aq NaHCO3, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated to provide Intermediate 2B (42.5 g, 122%) as an oil. The crude product was used without further purification. LCMS Anal. Calc'd for C12H12F6O2 302.21, found [M−H] 301.2.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[CH:19]1(C2C=CC(F)=C(B(O)O)C=2)[CH2:21][CH2:20]1>>[CH:19]1([C:7]2[CH:6]=[CH:5][C:4]([F:10])=[C:3]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)[CH:2]=2)[CH2:21][CH2:20]1
Reactant: OB(O)c1cc(C2CC2)ccc1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2cc(C3CC3)ccc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (5-cyclopropyl-2-fluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C([Li])CCC.Cl[C:51]([O:53][CH2:54][CH3:55])=[O:52]>C1COCC1>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([N:36]([CH3:37])[C:51](=[O:52])[O:53][CH2:54][CH3:55])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N(C)C(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.163 mmol) in THF (2 mL) at −78° C. under N2 added n-butyllithium (0.203 ml, 0.325 mmol). After 10 mins, ethyl chloroformate (61.8 mg, 0.569 mmol) was added to the reaction mixture. And the reaction mixture was warmed to room temperature and stirred overnight under N2. The reaction mixture was quenched with 5 ml water extracted with 3×10 mL ethyl acetate. The organic layers were combined, washed with 2×5 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Silica gel chromatography eluted with ethyl acetate/hexane (20-100%) resulted in 38 mg (34%) of Ethyl (5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran -3-carbonyl)(methyl)carbamate (Compound 208) as a white solid. LC-MS (ES, m/z) C35H28F2N4O7S: 686. Found: 687 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[CH:5]=[O:6].[Mn]([O-])(=O)(=O)=[O:17].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5]([OH:17])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC

Procedure:
2,3-Dimethoxy-6-nitrobenzaldehyde from Procedure 6 (331 g) was added to acetone (2.5 l) in a 12 l flask. A saturated solution (approximately 60-65 g/l) of potassium permanganate was added until TLC showed no starting material. Approximately 7 l was required. The reaction mixture was filtered to remove the MnO2 and was washed with 2.5N KOH and acetone (2 l each). The combined filtrates were evaporated to dryness and acidified with concentrated HCl. The precipitated solid was collected on a filter, washed with water (250 ml) and dried overnight. The solid was dissolved in 2 l acetone, treated with MgSO4 and charcoal, evaporated to 500 ml and cooled to 5°. The crystals were filtered, washed with acetone and hexane and dried to afford dimethoxy acid (234 g, 65.7%) mp 187°-189° C.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])=[CH:3]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27](O)=[O:28])=[C:18]([C:31]([O:33]C)=[O:32])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([C:4]3[CH:5]=[CH:6][O:2][CH:3]=3)[CH:8]=2)=[O:28])=[C:18]([CH:17]=1)[C:31]([OH:33])=[O:32]
Reactant: NCc1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: Cl
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-3-yl)benzylamine.hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-3-yl)benzyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 77%). Note that 3-(furan-3-yl)benzylamine.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:29])([CH3:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH3:28][C:19]([NH:29][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:18])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CCc1ccncc1
Product: CC(C)(CCc1ccncc1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 1,1-dimethyl-3-pyridin-4-yl-propylamine (55 mg, 0.32 mmol) as starting materials and isolated (60.0 mg, 74%) as white solid; LC-MS (UV peak area, ESI) 94.93%, 380.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10](OCC)=[O:11])=[CH:6][CH:5]=[C:4]([Cl:15])[N:3]=1.[H-].[Na+].Cl>O1CCOCC1>[Cl:15][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][CH2:9][C:10](=[O:11])[NH:1][C:2]=2[N:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CNc2ccc(Cl)nc2N1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
To a solution of ethyl 2-(2-amino-6-chloropyridin-3-ylamino)acetate (E-25) (4.58 g, 20 mmol, 1.0 eq) in dry 1,4-dioxane (50 mL) was added sodium hydride (60% in mineral oil, 240 mg, 6 mmol, 0.3 eq), the resulting mixture was stirred at reflux for 2 h then cooled to RT and neutralized with con. HCl to adjust the pH value to 8˜9, concentrated in vacuo to remove most of solvent and then filtered, the filter cake was washed with water and ethyl acetate/petroleum ether (1:1) and dried to afford the desired product 6-chloro-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (E-26) (2.5 g, 68% yield) as a pale solid. 1H NMR (300 MHz, DMSO-d6) δ: 10.86 (bs, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H), 6.35 (bs, 1H), 3.78 (d, J=1.5 Hz, 2H); ESI-MS m/z: 183.95[M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH:8]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1.F[B-](F)(F)F.[CH3:21][O+](C)C>C(Cl)Cl>[CH3:21][O:15][C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]([CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(C=Cc2cccs2)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CCc2cccs2)CCCC1

Procedure:
The product of Example 173 is reacted with trimethyloxonium tetrafluoroborate in CH2Cl2 by the method of Example 3 to produce the title material.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]1[C:35]([CH3:36])=[C:34]([CH3:37])[C:33]([CH3:38])=[C:32]([CH3:39])[C:31]=1[CH3:40])(=[O:29])=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][S:27]([C:30]3[C:31]([CH3:40])=[C:32]([CH3:39])[C:33]([CH3:38])=[C:34]([CH3:37])[C:35]=3[CH3:36])(=[O:28])=[O:29])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: Cc1c(C)c(C)c(S(=O)(=O)NCCN=[N+]=[N-])c(C)c1C
Product: Cc1c(C)c(C)c(S(=O)(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)c(C)c1C

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.120 g, 0.434 mmol) was reacted with N-(2-azidoethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide (0.141 g, 0.434 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(2,3,4,5,6-pentamethylphenylsulfonamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), δ 7.01 (s, 1H), δ 6.44 (s, 1H), δ 6.17 (s, 2H), δ 4.35 (s, 2H), δ 3.34 (s, 2H), δ2.47 (s, 2H), δ 2.48 (s, 6H), δ 2.20 (m, 11H), δ 1.43 (m, 15H) ppm; 13C NMR (75 MHz, CDCl3) δ 149.6, 148.1, 139.7, 136.2, 134.9, 134.3, 122.4, 84.9, 53.7, 50.2, 42.5, 31.1, 29.3, 28.9, 28.4, 28.2, 25.6, 19.1, 17.9, 17.2 ppm; HRMS (ESI) calcd for C28H43N7O4S (M+) 573.3097. found 573.3086, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2,3,4,5,6-pentamethylbenzenesulfonamide hydrochloride (0.143 g, 76% yield). 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), δ 6.42 (s, 1H), δ 4.48 (s, 2H), δ 3.34 (s, 2H), δ 2.65 (s, 2H), δ 2.40 (s, 8H), δ 2.12 (s, 9H), δ 1.58 (s, 4H), δ 1.19 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 159.9, 147.3, 139.6, 136.1, 134.8, 134.0, 127.8, 127.6, 108.6, 108.4, 54.1, 51.5, 41.8, 36.5, 28.2, 28.1, 27.7, 24.1, 23.7, 18.2, 16.8, 16.1 ppm; HRMS (ESI) calcd for C23H35N7O2S (M+) 473.2573. found 473.2565.