Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7][C:6]=2[C:5]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+:28]>O>[Na+:28].[Na+:28].[Na+:28].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:7][C:6]=2[C:5]([S:20]([O-:23])(=[O:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a warm solution of 106.4 g of (80.5%) 8-amino-1,3,5-naphthalenetrisulfonic acid in 100 ml of water and 45.0 ml of 5 N sodium hydroxide is slowly added 500 ml of absolute ethanol with vigorous stirring for 30 minutes. The mixture iw cooled to room temperature and filtered. The precipitate is washed with 80% aqueous ethanol, ethanol and ether and is dried in vacuo at 110° C. for 16 hours to give 103.7 g of 8-amino-1,3,5-naphthalenetrisulfonic acid trisodium salt.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:6]3[CH:11]=[CH:12][NH:13][C:14](=[O:15])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c3ccc(F)cc3c3c(=O)[nH]ccc32)cc1
Yield: 62.9 %

Procedure:
8-Fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (I-64a: 0.15 g, 0.00074 mol) was reacted with 1-(chloromethyl)-4-methoxybenzene (0.14 g, 0.00092 mol), NaH (0.058 g, 0.058 mol) and DMF (10 mL) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 0.15 g of the product (65.21% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]#[N:20])=[CH:11][C:10]=1[CH3:21])=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N:45]=[N+:46]=[N-:47])(C)C>O1CCCC1>[C:1]([O:4][CH2:5][C:6]1[N:8]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]#[N:20])=[CH:11][C:10]=2[CH3:21])[N:47]=[N:46][N:45]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Nc1cc(C(F)(F)F)c(C#N)cc1C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1cc(C(F)(F)F)c(C#N)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-{[4-cyano-2-methyl-5-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (Intermediate 61, 452 mg, 1.51 mmol) in tetrahydrofuran (10 mL) was added triphenylphosphine (790 mg, 3.01 mmol), di-isopropylazodicarboxylate (0.585 mL, 3.01 mmol) and trimethylsilylazide (0.400 mL, 3.01 mmol). The reaction was stirred at room temperature for 18 hours.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:19]([C:21]2[S:25][C:24]3[CH2:26][CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[C:30]([O:32]C(C)(C)C)=[O:31])[CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([S:16]([N:19]([C:21]2[S:25][C:24]3[CH2:26][CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[C:30]([OH:32])=[O:31])[CH3:20])(=[O:17])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CN(c1sc2c(c1C(=O)OC(C)(C)C)CCCC2)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1sc2c(c1C(=O)O)CCCC2)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
TFA (30 ml, 404 mmol) was added to a solution of tert-butyl 2-(3,4-dichloro-N-methylphenylsulfonamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (8.00 g, 16.8 mmol) in DCM (100 ml), and stirring was carried out for 1 h at room temperature. The reaction mixture was concentrated, and the TFA that remained was removed with toluene, DCM and diethyl ether. The residue was washed twice with diisopropyl ether.
Reaction SMILES: [C:1]([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:23])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].CI.CCOC(C)=O>C1COCC1>[C:6]([O:10][C:11](=[O:23])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:14]=1[CH3:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc(OC)c1
Reactant: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(NC(=O)OC(C)(C)C)c(C)c(OC)c1
Temperature: -65 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyllithium (200 mL, 340 mmol, 2.4 equiv, 1.7M in pentane) is added dropwise to a cold (−65° C.) solution of (3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester (36.1 g, 142 mmol) in THF (250 mL), under an argon atmosphere. The mixture is stirred for 15 min at −65° C. and then allowed to warm to −25° C. A solution of methyliodide (10.7 mL, 171 mmol, 1.2 equiv) in THF (140 mL) is then added. The reaction mixture is allowed to stir for 1 h at −25° C. and then poured onto a mixture of ice/H2O (300 mL) and EtOAc (300 mL). The layers are separated and the aqueous phase is extracted with EtOAc (2×150 mL). The combined organic phase is washed with H2O (3×150 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (Hex/acetone, 95:5-9:1, 4:1) to provide the title compound. ESI-MS: 268.1 [MH]+, TLC: Rf=0.25 (Hex/acetone, 9:1).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.S(Cl)(Cl)=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1COCC1.CCOC(C)=O>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[CH:24][CH:23]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
A solution of 1,1-cyclopropanedicarboxylic acid (3.07 g, 23.60 mmol) in THF (40 mL) was cooled to 0° C. and treated with Et3N (3.30 mL, 23.7 mmol) and thionyl chloride (1.72 mL, 23.6 mmol). The resultant reaction mixture was stirred 30 min at 0° C. 4-Fluoroaniline (2.30 mL, 23.9 mmol) was added and the reaction mixture was allowed to slowly warm to RT overnight. The slurry was diluted with EtOAc (200 mL) and was extracted into 1 N aq NaOH (3×60 mL). The aqueous portion was washed with ether (50 mL) and acidified to pH 1-2 with 6 N aq HCl. The resulting precipitate was collected by filtration and washed with water. The remaining solids were dissolved in a mixture of acetonitrile-MeOH and the solution was concentrated in vacuo until precipitation began. Complete dissolution was affected by warming to 70° C. The resultant solution was allowed to cool to RT overnight to provide large crystals. The crystals were isolated by filtration, washed with acetonitrile and dried in vacuo to provide 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (1.76 g). The mother liquors were concentrated to initiate a second crystallization, which provided an additional crop of 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (1.39 g, 60% yield overall). 1H NMR (400 MHz, DMSO-d6): δ 13.06 (s, 1H), 10.55 (s, 1H), 7.60 (m, 2H), 7.12 (m, 2H), 1.39 (s, 4H); MS (ESI) m/z: 224.1 (M+H+).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:70]([O:72][CH2:73][C:74](O)=[O:75])[CH3:71]>>[CH2:70]([O:72][CH2:73][C:74]([N:35]1[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][N:16]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:34]1)=[O:75])[CH3:71]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN1CCOCC1
Solvent: O
Product: CCOCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 20 %

Procedure:
The crude product obtained using dihydrochloride of Compound 18 (300 mg, 0.741 mmol), N-methylmorpholine (0.163 mL, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg, 1.04 mmol), 1-hydroxybenzotriazole monohydrate (130 mg, 0.963 mmol) and ethoxyacetic acid (0.0700 mL, 0.741 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=90/10), followed by recrystallization from mixed solvent of ethyl acetate/methanol to obtain Compound 128 (62.0 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].Cl.CN(C)CCCN=C=NCC>>[CH3:18][O:17][N:16]([CH3:15])[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:9]
Reactant: CNOC
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Yield: 92 %

Procedure:
In a manner analogous to that described in Example 1 d), the condensation of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N,O-dimethylhydroxylamine hydrochloride by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride yielded the title compound (92% yield) as a colorless oil. MS (ISP): m/z=239.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]=[C:6]([O-:8])[CH3:7])[CH3:2].[Na+].Br[CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C.O>CN(C)C=O>[C:6]([CH:5]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[O:9])(=[O:8])[CH3:7]
Reactant: CCOC(=O)C=C(C)[O-]
Reactant: CC(C)(C)C(=O)CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium 4-ethoxy-4-oxobut-2-en-2-olate (1.50 g) in N,N-dimethylformamide (50 mL) was added 1-bromo-3,3-dimethylbutan-2-one (2.0 mL), and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.51 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[S:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:29])[C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[S:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCCc1ccc(F)cc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)sc3c2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-{trans-4-[3-(4-fluorophenyl)-propylamino]cyclohexyl}-3H-benzthiazol-2-one (0.24 g, 0.67 mmol) in MeOH (10 mL) containing H2O (0.5 mL) was added p-formaldehyde (0.1 g, 3.3 mmol). The reaction mixture was stirred for 3 hours. Sodium triacetoxyborohydride (0.2 g, 0.9 mmol) was added, and the mixture was stirred overnight. Solid NaOH was added until the solution became clear. The reaction mixture was concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography (eluent 9.5:1:1 CH2Cl2:MeOH:NH4OH) gave 6-(trans-4-{[3-(4-fluorophenyl)-propyl]methylamino}cyclohexyl)-3H-benzthiazol-2-one (55 mg, 15%), as a pale yellow solid: mp 256-261° C.; IR (KBr): 2942, 1683, 1509 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 7.41 (s, 1H), 7.31-7.03 (m, 6H), 3.29 (m, 2H), 3.01 (m, 2H), 2.70 (s, 3H), 2.64 (m, 2H), 2.11 (m, 1H), 2.08 (m, 1H), 1.99 (m, 2H), 1.87 (m, 2H), 1.98-1.61 (m, 4H); API-MS (m/z): 399 [M+H]+; calcd for C23H27FN2OS, 399.1906; found, 399.1909; HPLC: method A, 5.85 minutes (>99%); method B, 11.48 minutes (>99%); Anal. Calcd for C23H27FN2OS.HCl.0.75NaCl: C, 57.69; H, 5.89; N, 5.85. Found: C, 57.72; H, 5.96;N, 5.51.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)CCC.CN(C=O)C.[OH-].[Na+]>[Cu]I.C(Cl)(Cl)Cl>[N+:11]([C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccncc2)c2occc2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
7-Iodo-5-nitrobenzofuran (2.00 g, 0.00692 mol), 4-tributylstannylpyridine (2.80 g, 0.00761 mol), copper(I)iodide (132 mg, 0.692 mmol) and dichlorobis(triphenylphosphine) palladium(II) (49 mg, 0.0692 mmol) were added to a 50 mL test tube followed by DMF (20 mL). The mixture was heated at 100° C. overnight in a StemBlock. After cooling to room temperature, aqueous sodium hydroxide (2 M; 4 mL) was added and the solution was stirred for 15 min. Chloroform (20 mL) was added and the mixture was filtered through Celite. The aqueous layer was then extracted with chloroform (3×) and the combined organic phases were evaporated. The residue was then triturated with ether and the precipitate was dried in vacuo overnight to yield a light brown solid. Yield: 686 mg (41%); HLPC (System A) purity=99%, m/z=241 (M+H)+, 1H NMR (270 MHz, DMSO-d6) δ ppm 7.33 (d, J=2.23 Hz, 1H) 7.98 (m, 2H) 8.38 (d, J=2.23 Hz, 1H) 8.50 (d, J=2.47 Hz, 1H) 8.75 (d, J=2.23 Hz, 1H) 8.79 (m, 2H).
Reaction SMILES: [CH2:1]([CH:5]1[C:12]2[CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[NH:9][C:8]=2[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>>[CH2:1]([CH:5]1[C:12]2[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[NH:9][C:8]=2[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc2c([nH]1)CCC2CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC1CCc2[nH]c(C(=O)O)cc21
Yield: 62.4 %

Procedure:
The title compound was synthesized from methyl 4-isobutyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (37 mg, 0.17 mmol) and lithium hydroxide monohydrate (28 mg, 0.67 mmol) according to General Procedure 7. The crude product was dried onto Silica gel and was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-isobutyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (11) as a light yellow solid (22 mg, 63%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.94 (d, J=6.62 Hz, 3H), 0.98 (d, J=6.59 Hz, 3H), 1.23-1.32 (m, 1H), 1.40-1.48 (m, 1H), 1.73-1.84 (m, 1H), 1.89-2.01 (m, 1H), 2.53-2.76 (m, 3H), 2.95-3.05 (m, 1H), 6.59 (s, 1H); LCMS-MS (ESI−) 206.2 (M−H); HPLC (UV=100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:24]2[CH2:23][CH2:22][N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=3)[CH2:26][CH2:25]2)=[O:12])[CH:3]=[CH:2]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1cccc2cc[nH]c12
Solvent: CN(C)C=O
Product: O=C(c1cccc2cc[nH]c12)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75 %

Procedure:
To a cooled solution of indole 7-carboxylic acid (3.22 g; 0.02 moles) in 30ml dimethylformamide was added N,N'-carbonyldiimidazole (3.24 g; 0.02 moles). After 45 minutes, a solution of 4-(3-(trifluoromethyl)phenyl)piperazine (5.76 g; 0.025 moles) in 10 ml DMFwas added. This was stirred for 18 hours at ambient temperature. The solvent was then concentrated off and the resulting oil was partitioned between ethyl acetate and water. The aqueous was extracted twice with ethyl acetate and the organics were washed with water and dried (saturatedNaCl, MgSO4). The desired amine was purified via flash chromatography (10% ethyl acetate/dichloromethane), to give 5.6 g (77%) of a solid, m.p. 147°-151° C. The solid was recrystallized from methanol to give 3.14 g (43%) of 1-(1H-indol-7-ylcarbonyl)-4-[3(trifuoromethyl)phenyl]piperazine, m.p. 149°-151° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][OH:12])[N:5]=1)(=[O:3])[CH3:2].[CH3:13]I.[H-].[Na+]>COCCOC.[Ag]=O>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][CH3:13])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1cc(C)n(CCO)n1
Agent: O=[Ag]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCn1nc(C(C)=O)cc1C
Reaction time: 2 h
Yield: 22 %

Procedure:
3-Acetyl-1-(2-hydroxyethyl)-5-methylpyrazole (0.63 g, 3.77 mM) in ethylene glycol dimethyl ether (10 ml) was treated with silver oxide (0.87 g, 3.77 mM) and methyl iodide (0.28 ml, 4.5mM). Sodium hydride (0.17g 60% dispersion in oil, 4.14 mM) was added and the mixture stirred for 2 h, then filtered through celite and evaporated. Purification on silica gel eluting with ethyl acetate gave the title compound (0.157 g, 22%): νmax 1681 cm-1 ; δH (CDCl3) 2.32 (3H, s), 2.50 (3H, s), 3.30 (3H, s). 3.78 (2H, t, J5.4 Hz), 4.25 (2H, t, J5.4 Hz), and 6.51 (1H, s); EI m/e 182 (65% ).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C>O1CCCC1.CCCCCCC>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: *CC*
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(O)cc1

Procedure:
Separately, a polyethylene film having a thickness of 0.1 mm was inserted into a glass ampoule, and subsequently, a tetrahydrofuran-n-heptane mixed solution (1:2 by volume) containing 20 wt% of p-acetoxystyrene monomer was added thereto, followed by heat-sealing the glass ampoule in vacuum. After irradiation of γ-rays of 105 rad/hr at a temperature of 25° C for 10 hours, the resulting film was taken out of the glass ampoule and sufficiently washed with acetone to remove the p-acetoxystyrene homopolymer. The thus treated film was then refluxed in a concentrated hydrochloric acid-methanol mixed solution (1:4 by volume) under heating for a period of 30 minutes, followed by hydrolysis to obtain a film in which a p-hydroxystyrene side chain was grafted at a grafting ratio of 52 wt% (based on the polyethylene). This film was further immersed in concentrated sulfuric acid at a temperature of 25° C for 72 hours and then sulfonated to obtain a cationic exchange membrane. The thus obtained cationic exchange membrane was used as a diaphragm. To the cationic exchange membrane to be used as a diaphragm was subjected a pre-treatment in which the membrane was immersed in a 0.5N sodium hydroxide aqueous solution at a temperature of 80° C for a period of 2 hours prior to the electrolysis. This cationic exchange membrane had a cation transport number of 0.97, an electric resistance, in 0.5N sodium chloride, of 1.7 Ω-cm2, and an acidic ion-exchange capacity of 2.2 meq/g. A current of 1.0 A (10 A/dm2) was passed for 5 hours. It was found that the concentration of sodium hydroxide in the catholyte was 16.8& by weight, that the concentration of sodium chloride was 0.02% by weight, and that the current efficiency was 83%.
Reaction SMILES: [F:1][CH:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[N+:20]([C:12]1[CH:13]=[C:8]([O:7][CH:2]([F:1])[C:3]([F:5])([F:4])[F:6])[CH:9]=[CH:10][C:11]=1[N:14]1[CH2:18][CH2:17][O:16][C:15]1=[O:19])([O-:22])=[O:21]
Reactant: O=C1OCCN1c1ccc(OC(F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OCCN1c1ccc(OC(F)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
2.79 g (10 mmoles) of the oxazolidinon of Step 2 are dissolved in 7 ml concentrated sulfuric acid and nitrated at 0° C. with a mixture of 0.43 ml (10 mmoles) fuming nitric acid and 3.6 ml concentrated sulfuric acid.
Reaction SMILES: [C:1]([NH:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH2:14])=[C:9]([Cl:15])[N:8]=1)=[O:6])(=[NH:3])[NH2:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[NH2:13][C:12]1[C:7]([C:5]([N:4]=[C:1]([NH:2][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:3][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:6])=[N:8][C:9]([Cl:15])=[C:10]([NH2:14])[N:11]=1
Reactant: CCOC(=O)Cl
Reactant: N=C(N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: c1ccncc1
Product: CCOC(=O)NC(=NC(=O)c1nc(Cl)c(N)nc1N)NC(=O)OCC
Reaction time: 2 h

Procedure:
To a stirred suspension of N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide (27.6 g., 0.12 mole) in pyridine (300 ml.) is added ethyl chloroformate (12.0 ml., 0.15 mole) during a 5 minute period. The reaction is stirred at 25° for 2 hours during which time the starting material dissolves and the hydrochloride of the starting material precipitates. The latter is filtered from the reaction and discarded. The filtrate is treated with water (700 ml.) to give 16 g. (71%) of 3,5-diamino-6-chloro-N-[bis(ethoxycarbonylamino)methylene]-2-pyrazinecarboxamide which melts at 213° C. after recrystallization from ethanol.
Reaction SMILES: [CH:1]1([N:4]([CH2:19][CH3:20])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][C:7]=2[CH3:18])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([CH2:19][CH3:20])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:18])[CH2:3][CH2:2]1
Reactant: CCN(Cc1ccc(C#C[Si](C)(C)C)cc1C)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; cyclopropyl-ethyl-(2-methyl-4-trimethylsilanylethynyl-benzyl)-amine (Intermediate 160, 650.0 mg, 2.30 mmols) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (495 mg, 99%) was used directly in the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])[CH:2]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])[CH:2]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)ccc34)nc12)c1cccnc1
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)ccc34)nc12)c1cccnc1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
2-[6-Chloro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide (50 mg, 0.076 mmol) was combined with dichloromethane (1 mL) and trifluoroacetic acid (0.17 ml, 2.27 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.15 ml, 2.27 mmol) was added. The reaction mixture was stirred for 20 min then concentrated in vacuo and the residue was triturated with water (2 mL). The precipitate was filtered, washed with water and dried to afford 29 mg (68%) of 2-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a yellow solid. MS: (M+H)+=531; 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.71 (br. s., 1H), 8.43-8.58 (m, 3H), 8.29-8.38 (m, 1H), 8.05 (s, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.36 (br. s., 1H), 7.15 (d, J=8.3 Hz, 1H), 5.35 (t, J=6.9 Hz, 1H), 4.65 (br. s., 2H), 3.50 (br. s., 4H), 3.33 (br. s., 4H), 2.84 (br. s., 2H), 1.68 (d, J=6.3 Hz, 3H).