Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22])[CH3:5].C1(=O)[NH:28][C:27](=O)C2=CC=CC=C12.[K].CNN>CN(C)C=O.CCOC(C)=O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:28][CH3:27])[S:7]1(=[O:22])=[O:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: CNN
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNCCC(C)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 36.6 %

Procedure:
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.25 mmol) was dissolved in dimethylformamide (2 mL) in a microwave cuvette and potassium phthalimide (0.06 g, 0.3 mmol) was added. The mixture was irradiated at 100° C. for 3 minutes. Upon cooling the mixture was diluted with EtOAc and washed with water and brine then dried with Na2SO4. Upon concentration, the residue was dissolved in MeOH (5 mL), methyl hydrazine (0.06 g, 1.25 mmol) was added and the mixture heated to reflux for 5 hours. Upon cooling the reaction was concentrated and water (10 ml) added followed by acetic acid (to pH 4). After 1 hour the mixture was filtered and basified to pH 14 with NaOH then extracted with dichloromethane. The organic extracts were washed with water, dried with Na2SO4 and purified via Isco chromatography (Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in dichloromethane) to afford 32 mg of 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][CH2:58][C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][CH2:58][C:59]([NH:61][CH2:62][C:63]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:64])=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 74 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 74%. [α]D =+14.2° (c=1.00, tetrahydrofuran).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:43])C.[OH-].[Na+].Cl>C(O)C>[CH3:42][S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]#[C:31][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([CH3:43])[CH:9]=3)[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=2)=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (168 mg; 0.26 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 120 mg (75%). HPLC-MS: m/z: 614.1 (M+H)+; Rt: 2.45 min.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([N+:19]([O-])=O)=[C:12]([O:22]CC2C=CC=CC=2)[CH:11]=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.[Pd].C(OC1C([N+]([O-])=O)=CC([N+]([O-])=O)=C(OCC2C=CC=CC=2)C=1)C1C=CC=CC=1.[Pd]>[ClH:1].[ClH:1].[NH2:16][C:15]1[CH:14]=[C:13]([NH2:19])[C:12]([OH:22])=[CH:11][C:10]=1[OH:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Product: Nc1cc(N)c(O)cc1O

Procedure:
In detail, the process according to the invention is carried out, for example, as follows: a suspension of Pd (5%)/activated carbon catalyst in 1 to 30% by weight hydrochloric acid is initially introduced into a hydrogenation autoclave of a material which is resistant to aqueous hydrochloric acid. Under preferred hydrogenation conditions (60 to 80° C.; 10 to 20 bar H2), a 10 to 80% by weight solution or suspension of 1,3-dibenzyloxy-4,6-dinitrobenzene in toluene is pumped in within the course of 30 to 90 minutes, the concentration of 1,3-dibenzyloxy-4,6-dinitrobenzene, relative to the total quantity of toluene and aqueous hydrochloric acid, being 5 to 20% by weight and the 1,3-dibenzyloxy-4,6-dinitrobenzene/palladium weight ratio being, for example, 85:1. After the absorption of hydrogen has ceased, the stirring of the reaction mixture is continued, for example for 60 minutes, at 60 to 80° C. and 10 to 20 bar H2, the stirrer is stopped and about 66% of the two-phase reaction mixture of toluene and aqueous 4,6-diamino-resorcinol dihydrochloride solution containing hydrochloric acid is forced out of the hydrogenation autoclave by means of nitrogen through a riser consisting of a corrosion-resistant material and provided with a frit into a receiver. After the organic solvent (toluene) has been separated off by simple phase separation, the stable 4,6-diaminoresorcinol dihydrochloride can be isolated from the resulting aqueous solution containing hydrochloric acid, if appropriate after stripping of toluene and clarification from activated carbon, in the usual manner, for example by concentrating the aqueous solution and/or by precipitation with concentrated hydrochloric acid and/or by introducing gaseous HCl and/or, if appropriate, by salting out, for example with NaCl, or in any desired manner known to those skilled in the art, if appropriate after previous addition of a stabilizer, for example SnCl2. In the same way, several hydrogenations can be carried out successively with the Pd (5%)/activated carbon catalyst employed without a decrease in the catalyst activity, which leads to a very low catalyst consumption.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCc2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CN1CCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of 1-methyl-5-nitro-2,3-dihydro-1H-indole (0.2 g, 1.13 mmol) in ethyl acetate (12 ml) was added stannous chloride dihydrate (1.26 g, 5.6 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction was then neutralized with aqueous sodium hydroxide solution. The organic layer was separated, washed with water, dried, and then concentrated to oil. The crude compound was purified by column chromatography over silica gel using ethyl acetate/pet ether (1:1) as eluent to give 1-methyl-2,3-dihydro-1H-indol-5-ylamine (0.12 g, 72%) as solid.
Reaction SMILES: C([O:8][C@@H:9]([C:11]1[O:12][C:13]2[C:18]([C:19](=[O:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:17][C:16]([F:28])=[CH:15][CH:14]=2)[CH3:10])C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:28][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C@H:9]([OH:8])[CH3:10])=[C:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:19]2=[O:27]
Reactant: C[C@@H](OCc1ccccc1)c1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@H](O)c1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.9 %

Procedure:
To (R)-2-(1-(benzyloxy)ethyl)-6-fluoro-3-phenyl-4H-chromen-4-one (0.63 g, 1.68 mmol) in dichloromethane (6 ml) cooled to 0° C., aluminium chloride (0.330 g, 2.52 mmol) was added portion wise and stirred at RT for 6 h. The reaction mixture was quenched with 2N HCl solution, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as yellow solid (0.348 g, 73%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.83 (m, 1H), 7.76 (m, 2H), 7.46 (m, 3H), 7.30 (m, 2H), 5.60 (d, J=4.9 Hz, 1H), 4.53 (m, 1H), 1.38 (d, J=6.5 Hz, 3H). Mass: 285.2 (M++1). Purity: 86.82%. [α]25D −1.18 (c=1, CHCl3). Enantiomeric excess: 97.8%, enriched in the late eluting isomer (retention time: 11.39 min.) as determined by HPLC on a chiralpak AD-H column.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[C:7]([OH:21])=[CH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:4].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:5][C:6](=[O:22])[C:7]([OH:21])=[CH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:12]=1)=[O:10])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)=CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a suspension of 0.88 g (22 mmol) of sodium hydride (60% dispersion in mineral oil) in THF (50 ml) was added under ice-cooling, 2.94 g (10 mmol) of 4-(5-chloroindol-3-yl)-2-hydroxy-4-oxo-2-butenoic acid ethyl ester prepared in Example 1 (1). After stirring for 15 min at room temperature, to the mixture was added dropwise a solution of 2.12 g (12 mmol) of benzenesulfonyl chloride in THF (20 ml). After stirring for 2 hours at room temperature, to the mixture was added DMF (8 ml). After stirring for additional 30 min, the reaction mixture was poured into ice-water containing 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was concentrated and the residue was crystallized from ether to give crude crystal, which was washed with ether to give 3.75 of the titled compound. Yield: 87%. Subsequent recrystallization from ethyl acetate afforded the pure ester, melted at. 156-157° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH:25][C:26]([NH2:28])=[S:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8](=[N:24][NH:25][C:26]([NH2:28])=[S:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: NNC(N)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=NNC(N)=S)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
6.2 g of 3,5-di-t-butyl-4-hydroxybenzophenone and 2.2 g of thiosemicarbazide were dissolved in 20 ml of toluene, and 0.4 g of p-toluenesulfonic acid was added. The solution was refluxed for 16 hours while removing water. After the reaction, dilute hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column, and recrystallized from dichloromethane/n-hexane to give 3,5-di-t-butyl-4-hydroxybenzophenone thiosemicarbazone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4](Cl)[N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:3]=1
Reactant: CCOC(=O)c1cnn(-c2cc(Cl)nc(N)n2)c1C
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cc(NCc3ccc(OC)cc3)nc(N)n2)c1C
Temperature: 25 °C

Procedure:
A mixture consisting of 3.0 g of ethyl 1-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-4-pyrazolecarboxylate, 3.5 ml of 4-methoxybenzylamine, and 150 ml of tetrahydrofuran was heated under reflux for 99 hours. The reaction mixture was cooled to room temperature and concentrated. Water was added to the residue, and the mixture was extracted three times with chloroform. The combined organic layers were washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography using a 49:1 mixture of chloroform and methanol as a developing solvent. The fraction containing the desired product was concentrated to afford 4.08 g of the title compound (amorphous).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18][C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20].CN1CCOCC1.CN(C=O)C>CCOC(C)=O>[NH:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18][C:19]([NH:21][CH2:22][C:23]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:24])=[O:20]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)O
Temperature: 25 °C

Procedure:
On one hand, H-Val-Leu-OH (1 eq.) was added to a solution of MSA (2.72 eq.) in AcOEt. The slurry was stirred at 25° C. until a solution was obtained. The solution was then cooled to −15° C. On the other hand, Boc-Gly-Gly-OH (1.05 eq., commercially available) was added together with NMM (1.0 eq.), AcOEt and DMF. The slurry was stirred until complete dissolution and then cooled to −25° C. IBCF (1.0 eq.) was added to the Boc-Gly-Gly-OH solution to activate the carboxylic function. The silylated Val-Leu was then added and left to stir at least 30 min. The reaction mixture was conditioned to 25° C. before being quenched by the addition of water. The mixture was then diluted with AcOEt and washed with a solution of KHSO4 under stirring. The aqueous phase was discarded and the organic layer was washed again with a solution of NaCl. The organic phase was finally concentrated and the tetrapeptide crystallized under gentle stirring for at least 8 h at 5° C. The solid was recovered by filtration, once washed with cold AcOEt at 5° C. After drying under vacuum, 85% of Boc-Gly-Gly-Val-Leu-OH (SEQ ID NO 19) was recovered.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16]Cl)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6].[I-:61].[Na+]>CC(C)=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12]([CH2:16][I:61])[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6]
Reactant: [I-]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in (A) was dissolved in 50 ml of acetone, and 670 mg (4.47 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extracted solution was washed with a 5% sodium thiosulfate aqueous solution, with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby the above identified compound was obtained as a powdery substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.OO.BrC1[CH:13]=[N+:14]([O-])C=C(Br)C=1.C(N(CC)CC)C.C[Si](C#N)(C)C>ClCCl.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O.C[Re](=O)(=O)=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: [O-][n+]1cc(Br)cc(Br)c1
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ncc(Br)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,5-Dibromopyridine (30.5 g, 0.12 mol) was dissolved in dichloromethane (80 mL) and methyltrioxorhenium (150 mg, 0.603 mmol) was added. Hydrogen peroxide (aqueous, 30%, 27 mL) was added slowly over 5 minutes, and the mixture was stirred at ambient temperature for 3 hours. An additional 40 mL of 30% hydrogen peroxide was added, and the reaction was stirred for 16 hours. Manganese dioxide (100 mg) was added, and the suspension was stirred for 40 minutes. The mixture was extracted with dichloromethane, dried (sodium sulfate), filtered and concentrated under reduced pressure. Ethyl acetate was added, and the suspension was refluxed for 30 minutes until solids dissolved, and then the mixture was allowed to cool to ambient temperature and left for 48 hours. 3,5-Dibromopyridine-1-oxide (28.05 g, 79%) was collected by vacuum filtration. MS (LC-MS) m/z 254 (M+H)+. 3,5-Dibromopyridine-1-oxide (25.09 g, 0.099 mol) was then dissolved in acetonitrile (200 mL) and triethylamine (28 mL, 0.198 mol) and trimethylsilylcyanide (40 mL, 0.297 mol) were added. The reaction was stirred for 16 hours, diluted with dichloromethane, aqueous sodium carbonate, water, and then filtered through diatomaceous earth eluting with dichloromethane. The mixture was extracted with dichloromethane and the organics were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30-70% ethyl acetate in hexanes) provided the title compound. MS (LC-MS) m/z 263 (M+H)+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1)=O.[N+]([O-])(O)=O.[F:22][C:23]([F:38])([O:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([NH2:37])=[NH:36])[CH:31]=[CH:32][CH:33]=1)[CH:24]([F:26])[F:25]>>[F:22][C:23]([F:38])([O:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:37]=[C:5]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[N:9][CH:8]=3)[CH:4]=[CH:3][N:36]=2)[CH:31]=[CH:32][CH:33]=1)[CH:24]([F:25])[F:26]
Reactant: CN(C)C=CC(=O)c1cncc2ccccc12
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Solvent: O=[N+]([O-])O
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3cncc4ccccc34)n2)c1

Procedure:
In accordance with the general procedure described in Example 1, reaction of 226.2 mg (1.0 mmol) of 3-dimethylamino-(4-isoquinolyl)-2-propen-1-one and 185 g (0.60 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-(4-isoquinolyl)-2-pyrimidine-amine; FAB-MS:415 (M+ +1), m.p. 158°-160° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6](=[O:12])[N:5]3[C@H:13]([CH2:15][N:16]4[CH2:21][CH2:20][C:19]([NH:23]C(=O)C(F)(F)F)([CH3:22])[CH2:18][CH2:17]4)[CH2:14][N:3]1[C:4]=23.C(=O)([O-])[O-].[K+].[K+]>>[NH2:23][C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([CH2:15][C@H:13]2[N:5]3[C:4]4[N:3]([C:2](=[O:1])[CH:11]=[CH:10][C:9]=4[CH:8]=[CH:7][C:6]3=[O:12])[CH2:14]2)[CH2:21][CH2:20]1
Reactant: CC1(NC(=O)C(F)(F)F)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(N)CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
N-(1-{[(1R)-4,9-Dioxo-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl]methyl}-4-methyl-4-piperidinyl)-2,2,2-trifluoroacetamide (171 mg, 0.417 mmol) was treated with a 7% solution of potassium carbonate (450 mg in 2 ml water/5 ml methanol) and stirred at rt for 2 h, and then at 70° C. for 18 h then evaporated and dissolved in 5% MeOH/DCM (100 ml), filtered and purified by SCX (5 g, eluting with MeOH and then 0.5M NH3/MeOH and then 2M NH3/MeOH). Fractions containing product were then evaporated to give product as a pink solid (60 mg, 46%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH2:7].[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([NH:17][C@H:18]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:24][CH:23]=3)=[N:14][C:13]=2[CH:42]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([NH:17][C@H:18]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:19][NH:20][C:21](=[O:34])[C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30](=[O:31])[NH:7][C:2]4[NH:3][CH2:4][CH2:5][CH2:6][N:1]=4)=[CH:26][CH:27]=3)=[N:14][C:13]=2[CH:42]=1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3cc(Br)ccc3o2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)Nc1nc2cc(Br)ccc2o1
Reaction time: 4 h
Yield: 45.2 %

Procedure:
1,4,5,6-tetrahydro-2-pyrimidinamine (94 mg) is added to the ester 10-6 (140 mg) in 3 ml of THF, and agitation is carried out at ambient temperature for 4 hours. After evaporating under reduced pressure, the dry extract obtained is purified by chromatography eluting with a CH2Cl2/AcOEt 80/20 then CH2Cl2/MeOH 85/15 mixture. 71 mg of expected product 10-7 is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(N(CC)C(C)C)(C)C.Br[CH2:31][CH2:32][O:33][CH3:34]>C(#N)C>[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][N:15]([CH2:31][CH2:32][O:33][CH3:34])[CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1
Reactant: COCCBr
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cncn23)CC1
Yield: 57.1 %

Procedure:
1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridine-6-yl)ethanone hydrochloride (16 mg, 0.052 mmol), N,N-diisopropylethylamine (27 μL, 0.16 mmol) and 1-bromo-2-methoxyethane (4.9 μL, 0.052 mmol) were stirred in acetonitrile (1.0 mL) for 22 hours at 65° C. Purification by preparative LCMS (pH 10) gave the desired compound (10 mg, 60%). LCMS calculated for C16H22ClN4O2 (M+H)+: m/z=337.1. found: 336.9.