Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[Cl:39])[C:5](=[O:30])[CH:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:7][CH2:8]O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[N-:54]=[N+:55]=[N-:56].[Na+]>C(Cl)Cl.O>[N:54]([CH2:8][CH2:7][CH:6]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:15][CH:16]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[Cl:39])=[O:30])=[N+:55]=[N-:56]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CCO)C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CCN=[N+]=[N-])C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-Cyclopropyl-N-(2,3-dichlorobenzyl)-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-4-hydroxybutanamide from the previous step (1 eq.) and Hunig's base (3.5 eq.) were combined in CH2Cl2 (0.024 M). At −78° C., methanesulfonyl chloride (1.5 eq) was added and the reaction mixture was stirred at −78° C. for 10 min and at 0° C. for 10 min. The resulting mixture was quenched with sat. aq. NaHCO3 and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated in vacuo. The resulting residue was taken up in DMF (0.06 M) and added sodium azide (5 eq). This mixture was then allowed to stir at RT for 24 h. The resulting mixture was poured into water and extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a viscous oil.
Reaction SMILES: N([C:4]1[CH:5]=[N:6][S:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]1)=C=S.[N:23](C1C=NSC=1N1CCC[C@H](NC(=O)OC(C)(C)C)C1)=[N+]=[N-].[P:45]([CH3:48])([CH3:47])[CH3:46]>C1COCC1>[CH3:46][P:45](=[N:23][C:5]1[CH:4]=[C:8]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]2)[S:7][N:6]=1)([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2sncc2N=C=S)C1
Reactant: CP(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2sncc2N=[N+]=[N-])C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cc(N=P(C)(C)C)ns2)C1
Reaction time: 0.17 h

Procedure:
tert-butyl ((3S)-1-(4-isothiocyanato-5-isothiazolyl)-3-piperidinyl)carbamate. A dry, 25 mL pear flask was charged with tert-butyl ((3S)-1-(4-azido-5-isothiazolyl)-3-piperidinyl)carbamate (213 mg, 0.66 mmol), a stirbar, and dry THF (4 mL). The flask was fitted with a septa/Ar inlet and immersed into a ice-water bath. The solution was stirred for 10 min and a 1.0 M solution of PMe3 in THF (0.69 mL, 0.69 mmol) was added dropwise. The solution was stirred cold for 15 min. The solution was taken up into a 5 mL syringe (total volume=4.4 mL) to afford (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)isothiazol-5-yl)piperidin-3-yl)carbamate. A dry, 25 mL pear flask was charged with dry THF (2 mL), carbon disulfide (0.79 mL, 13.11 mmol), and a stirbar. The flask was fitted with a septa/Ar inlet/PTFE addition needle and immersed into an ice-water bath. The solution was stirred for 15 min. The syringe containing (S)-tert-butyl (1-(3-((trimethylphosphoranylidene)amino)isothiazol-5-yl)piperidin-3-yl)carbamate, as described above, was fitted to the PTFE addition needle. The solution was added via syringe pump over a 1 h period. The solution was stirred for 1 h, and concentrated in vacuo. The residue was dried in a vacuum oven (60° C., <1 mm Hg) for 1 h to afford tert-butyl ((3S)-1-(4-isothiocyanato-5-isothiazolyl) -3-piperidinyl)carbamate. The material was used without characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.B.O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cccc(Cl)c1
Reaction time: 15 h
Yield: 75.3 %

Procedure:
3-(3-Chlorophenyl)propionic acid (5.00 g) was dissolved in tetrahydrofuran (100 ml), a tetrahydrofuran-borane.tetrahydrofuran solution (1 mol/l, 34.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 15 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (3.48 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][CH:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].O=C1CCC(=O)N1[O:40][C:41](=O)[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH3:44])[CH3:43].O>C1COCC1>[C:49]([O:48][C:46](=[O:47])[NH:45][C:42]([C:41](=[O:40])[NH:1][C@H:2]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][CH:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6]1)=[O:4])([CH3:44])[CH3:43])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccc(F)cc3)C2)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of 7-[(R)-2-Amino-3-(4-fluoro-benzyloxy)-propionyl]-2-methyl-4-phenyl-2,7-diaza-spiro[4.5]decan-1-one (130 mg, 0.3 mmol) (step 2) and 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (synthesis described in EP1486498A1 page 20) (89 mg, 0.3 mmol) in THF (4 ml)/water (1 ml) was treated with TEA (0.12 ml, 0.89 mmol). The resulting mixture was stirred at 50° C. for 6 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (25 ml) and 5% citric acid aqueous solution (10 ml). The organic phase was separated, washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 50-100% EtOAc in iso-hexane to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)[CH3:2].ClN1C(=[O:25])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:25])[CH2:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1cnc2ccn(-c3ccccc3)c2c1
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOc1cnc2c(c1)N(c1ccccc1)C(=O)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.7 %

Procedure:
The compound of step 3 (2.05 g, 8.60 mmol) was dissolved in DCM (30 ml) and N-chlorosuccinimide (1.26 g, 9.46 mmol) was added. The reaction mixture was stirred at room temperature for 3 days. The solvent was removed, and the obtained solid was dissolved in acetic acid (10 ml) and heated to 70° C. After addition of phosphoric acid (7.31 ml, 107 mmol, 85%), the reaction mixture was heated to 120° C. for 3 days. After cooling, the mixture was diluted with water and extracted with EA. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:6). 650 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCOc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
n-Octyloxybenzene (301 g, 1.46 mol), succinic anhydride (146.8 g, 1.468 mol) and carbon disulfide (1.3 l) were agitated at room temperature, followed by portion-wise feeding anhydrous aluminum chloride (392 g, 2.94 mol), further agitating the mixture at 50° C. for 4 hours after the reaction became quiet, cooling the mixture down to room temperature, adding it to ice (2 Kg), distilling off carbon disulfide, collecting solids, adding toluene (1 l), distilling off water on heating, filtering while hot, and distilling off toluene under reduced pressure to obtain oily β-(p-octyloxybenzoyl)-propionic acid (238 g, yield 53%).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[F:1][CH:2]([F:6])[C:3](=[O:4])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [Li]CCCC
Reactant: O=C(O)C(F)F
Solvent: CCOCC
Product: CCCCC(=O)C(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 3 liter, three-neck, round bottom flask, equipped with a magnetic stirrer, a dropping funnel filled with 39.9 g. of difluoroacetic acid and 200 ml. of ether, and a rubber septum is added 1350 ml. of ether. After cooling in a dry ice-acetone bath under nitrogen, one mole of n-butyl lithium (2.2 M, hexane) is added via a double tip needle. The difluoroacetic acid solution is slowly added to the cooled n-butyl lithium solution via the dropping funnel over 3 hours. The thick mixture is stirred at -78° C. for one hour and then quenched by pouring into a mixture of one liter of 4 N hydrochloric acid and one liter of ice, divided into three flasks, with stirring. The organic layers are combined and washed with water and brine. The 1500 ml. of solution is distilled at atmospheric pressure in a water bath. After the forerun is collected, the residue is fractionally distilled giving 18.8 g. (b.p. 100°-110° C.) of product that is 75% real.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: C=C1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylamino pyridine DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′—Carbonyldiimidazole (CDT) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0-570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, IRS); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]/[CH:14]=[CH:15]/[CH2:16]Cl)=[CH:9][CH:8]=1.ClC1C=CC(CC(Cl)C=C)=CC=1>Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:9][CH:8]=1
Reactant: ClC/C=C/Cc1ccc(Cl)cc1
Reactant: CCNCC
Agent: C=CC(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Product: CCN(CC)C/C=C/Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 30 ml diethylamine to 10.0 g (0.05 mole) of a 7:3 mixture of (E)-1-chloro-4-(4-chloro-2-butenyl)benzene and 1-chloro-4-(2-chloro-3-butenyl)benzene and stir at room temperature overnight. Dissolve reaction mixture in 100 ml 1N HCl and wash with 50 ml ethyl acetate. Extract ethyl acetate layer with 50 ml 1N HCl. Combine aqueous layers and add cold 4N NaOH until solution has pH=9. Extract aqueous phase with 5×60 ml Et2O. Dry ethereal extracts over Na2SO4 and then filter. Evaporate solvent to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[H-].[Na+].I[CH3:16]>CN(C=O)C>[Br:1][C:2]1[N:6]([CH3:16])[CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(Br)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0 g, 8.6 mmol) in anhyd DMF (30 mL) at 0° C. was added portionwise NaH (60% in mineral oil, 705 mg, 17.6 mmol) under nitrogen. After 1 h at ambient temperature, the reaction mixture was charged with iodomethane (1.5 mL, 24 mmol) and then stirred at ambient temperature overnight. The reaction mixture was quenched by cautious addition of water and then extracted with DCM. The combined extracts were washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluting with EtOAc-Hex (0:100 to 20:80), to provide the title compound (1.64 g, 78%) as a white solid. 1H-NMR (CDCl3): δ 7.33 (1H, s), 4.25 (2H, q), 3.58 (3H, s), 2.24 (3H, s), 1.33 (3H, t).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].CS[C:8]([NH2:10])=[NH2+:9].CSC(N)=[NH2+].Cl.Cl.[CH3:18][N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][NH2:26])[N:21]=[CH:20]1.[OH-].[Na+]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:18][N:19]1[CH:23]=[C:22]([CH2:24][CH2:25][NH:26][C:8]([NH2:10])=[NH:9])[N:21]=[CH:20]1
Reactant: O=S(=O)([O-])[O-]
Reactant: Cn1cnc(CCN)c1
Reactant: CSC(N)=[NH2+]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cnc(CCNC(=N)N)c1
Product: O=S(=O)(O)O

Procedure:
An aqueous of S-methylthiouronium sulphate (2.1 g) is added to a solution prepared from 1-methyl-4-(2-aminoethyl)imidazole dihydrochloride (3.0 g) and sodium hydroxide (1.21 g) in water. The resultant solution is heated under reflux for 17 hours. The product, isolated in a manner similar to that described in Example 1 is recrystallized from aqueous ethanol yielding pure 2-(1-methyl-4-imidazolyl)ethylguanidine sulphate, m.p. 280°-282° C.
Reaction SMILES: N1C=CC=C1C(OCC)=O.C(I)CCC.[CH2:16]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([OH:27])=[O:26])[CH2:17][CH2:18][CH3:19].[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1>>[CH2:16]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([OH:27])=[O:26])[CH2:17][CH2:18][CH3:19].[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[NH:28][C:25]([C:21]1[N:20]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:24]=[CH:23][CH:22]=1)=[O:27]
Reactant: Nc1nccs1
Agent: CCCCn1cccc1C(=O)O
Agent: CCOC(=O)c1ccc[nH]1
Solvent: CCCCI
Product: CCCCn1cccc1C(=O)Nc1nccs1

Procedure:
1-Butyl-pyrrole-2-carboxylic acid (130 mg) was prepared from ethyl pyrrole-2-carboxylate (139 mg, 1.0 mmol) and butyl iodide (0.12 mL, 1.0 mmol) following general procedures D and E. 1-Butyl-pyrrole-2-carboxylic acid thiazol-2-ylamide (100 mg) was prepared from 1-butyl-pyrrole-2-carboxylic acid (130 mg, 0.77 mmol) and 2-aminothiazole (80 mg, 0.80 mmol) following general procedure F.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=O)=[N:5]1)([CH3:3])[CH3:2].O.[NH2:18][NH2:19]>C(O)C>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:18][NH2:19])=[O:15])=[N:5]1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1nn(C(C)C)c2ccccc12
Solvent: CCO
Solvent: O
Product: CC(C)n1nc(C(=O)NN)c2ccccc21
Yield: 6715.2 %

Procedure:
To a stirred solution of methyl 1-isopropyl-1H-indazol-3-yl carboxylate (40.0 grams, 183.5 mmol, obtained in above step) in ethanol at room temperature hydrazine hydrate (130 mL, 2.56 mmol) was added. The reaction mixture was refluxed for 2 hours. The volatiles were removed under reduced pressure and the crude mass was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain the title compound (37.52 grams).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=2)=[C:26]2[C:41](=[O:42])[N:40]3[CH2:43][CH2:44][CH2:45][N:39]3[C:27]2=[N:28][C:29]=1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][C:29]2[N:28]=[C:27]3[N:39]4[CH2:45][CH2:44][CH2:43][N:40]4[C:41](=[O:42])[C:26]3=[C:25]([C:46]3[CH:54]=[CH:53][C:49]([C:50]([NH:18][CH2:12][C:13]4[O:17][CH:16]=[CH:15][CH:14]=4)=[O:51])=[CH:48][CH:47]=3)[C:24]=2[C:22]([O:21][CH2:19][CH3:20])=[O:23])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)c(=O)n1n2CCC1
Reactant: NCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
EDCI (31 mg, 0.16 mmol) was added to a solution of furfuryl amine (14 mg, 0.15 mmol), the product from Step E (71 mg, 0.15 mmol) and HOBT.H2O (20 mg, 0.15 mmol) in DMF (2.5 mL). The reaction was stirred 4 h at rt and then concentrated at reduced pressure. The remaining material was dissolved in CH2Cl2, washed with water, dried, filtered and concentrated. Chromatography on silica gel afforded the title compound as a yellow solid (30 mg, 0.05 mmol, 33%): 1H NMR (400 MHz, DMSO-d6) δ 9.06 (t, 1H, J=6), 7.89 (d, 2H, J=8), 7.56 (br s, 1H), 7.38 (d, 2H, J=8), 7.22 (br t, 2H J˜8), 7.07 (t, 2H, J=9), 6.37 (br s, 1H), 6.26 (d, 1H, J=3), 4.46 (d, 2H, J=6), 3.90 (m, 4H), 3.77 (t, 2H, J=7), 3.06 (m, 2H), 2.99 (m, 2H), 2.54 (quint., 2H, J=7), 0.78 (t, 3H, J=7) ppm; ESI-MS m/z 569 (M+H)+;
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[O:4].[CH3:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:20](=[O:30])[O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[CH:15][CH:14]=1>CCOC(C)=O>[Cl-:1].[CH2:38]([O:37][C:35]([C:34]1[CH:33]=[C:32]([NH:31][CH:19]([C:16]2[CH:17]=[N:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:20]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:2][C:3]([NH:5][C:6]4[CH:10]=[CH:9][O:8][N:7]=4)=[O:4])([CH2:25][CH2:26]3)[CH2:23]2)=[O:30])[CH:42]=[CH:41][CH:40]=1)=[O:36])[CH3:39]
Reactant: O=C(CCl)Nc1ccon1
Reactant: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccc(OC)nc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
2-Chloro-N-(isoxazol-3-yl)acetamide (18.3 mg, 0.11 mmol) was added to a solution of ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (C65) (50 mg, 0.11 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried. The product was purified by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-1-azoniabicyclo[2.2.2]octane chloride (26.2 mg, 38.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH2:11]([S:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O)[CH3:12].CCN=C=NCCCN(C)C.N1C=CC=CC=1>C1C=CC2N(O)N=NC=2C=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[S:13][CH2:11][CH3:12])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1ncc(Br)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of 5-bromo-N2-methylpyridin-2,3-diamine (0.70 g), 2-ethylsulfanylbenzoic acid (0.66 g), WSC (0.80 g), HOBt (23 mg), and pyridine (20 ml) was stirred under reflux at 120° C. for 30 minutes. After the reaction mixture was allowed to stand overnight, the mixture was stirred under reflux at 120° C. for 9.5 hours again. Into the reaction mixture cooled to room temperature, water was poured under ice-cooling, and extracted with ethyl acetate. The organic layer was washed with wafer and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. A mixture of the resulting residue and acetic anhydride (7 ml) was stirred under reflux at 140° C. for 1 hour. Aqueous sodium hydroxide solution was added to the reaction mixture cooled to room temperature to neutralize, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.60 g of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 42).