Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:26]2[CH2:31][CH2:30][N:29]3[CH:32]=[CH:33][N:34]=[C:28]3[CH2:27]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>[CH2:1]([S:8]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[N:12]=[C:11]([N:26]2[CH2:31][CH2:30][N:29]3[CH:32]=[CH:33][N:34]=[C:28]3[CH2:27]2)[N:10]=1)=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(SCc2ccccc2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(N2CCC(O)CC2)nc(N2CCn3ccnc3C2)nc1S(=O)Cc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine (prepared in the above (5)) 93 mg in chloroform 2.5 ml is dropped a solution of m-chloroperbenzoic acid 44 mg in chloroform 4 ml over a period of 10 minutes on a ice bath, and the mixture is stirred for 1.5 hours. The mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylsulfinyl-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a slightly yellow foam, 83 mg.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:22][CH2:21][C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[C:8]3[C:7](=[CH:12][CH:11]=2)[NH:6][C:4](=[O:5])[CH2:3][CH2:2]3)[CH2:14][CH2:15]1)=[O:23]
Reactant: CCC(=O)NC1CCN(c2ccc(NC(=O)CCBr)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)NC1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 0 °C

Procedure:
2.7 Grams of N-(β-bromopropionyl)-p-[4-(N-methylacetylamino)-1-piperidyl]aniline and 28 g of pulverized aluminum chloride were suspended in 50 ml of carbon disulfide, then the mixture was refluxed by heating for 4 hours. The reaction mixture was poured into ice-water, then the precipitates formed were collected and washed with water, and with diethyl ether, then this substance was converted into a hydrobromide and recrystallized from methanol-diethyl ether to yield 0.8 g of 6-[4-(N-methylacetylamino)-1-piperidyl]-3,4-dihydrocarbostyril. Light yellow needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=2)[CH:3]=1
Reactant: Clc1ccc(I)cc1Cl
Reactant: COc1ccc2c(Cl)ccnc2c1
Product: COc1ccc2c(Cl)cc(-c3ccc(Cl)c(Cl)c3)nc2c1

Procedure:
The title compound, m. p. 122-131° C., MS: m/e=338 (M+), was prepared from 4-chloro-7-methoxyquinoline and 3,4-dichloroiodobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][N:13](COCC[Si](C)(C)C)[C:9]=2[C:8]([C:22]#[N:23])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[C:27]([F:44])[C:26]=2[O:45][CH3:46])[N:6]=1.C(=O)(O)[O-:53].[Na+]>O.S(=O)(=O)(O)O>[Cl:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[C:8]([C:22]([NH2:23])=[O:53])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)=[C:27]([F:44])[C:26]=2[O:45][CH3:46])[N:6]=1
Reactant: O=C([O-])O
Reactant: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)ccc(N2CCNCC2)c1F
Temperature: 90 °C

Procedure:
A mixture of the product of Example 43B (50 mg, 0.068 mmol) and 4 drops of water in sulfuric acid (1 mL) was heated at 90° C. for 40 minutes. The mixture was poured onto ice water, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to provide the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 8.37 (s, 1H), 7.63(dd, J=2.1 Hz, J=9.3 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.41 (m, 1H), 6.32 (t, J=9 Hz, 1H), 4.81 (s, 2H), 3.94 (s, 3H), 3.40 (m, 4H), 3.26 (m, 4H). MS: 544 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1/[CH:6]=[CH:7]/[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([O-:3])=[O:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1.C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1/[CH:6]=[CH:7]/[CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:23]1=[O:24])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1/C=C/CNCCNc1ccncc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1N(C/C=C/c2ccccc2[N+](=O)[O-])CCN1c1ccncc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 56.8 %

Procedure:
To a solution of 2.33 g of (E)-N-(2-nitrocinnamyl)-N'-(4-pyridyl)ethylenediamine dissovled in a mixture of 50 ml of tetrahydrofuran and 50 ml of chloroform was added 1.52 g of carbonyldiimidazole at 0° C. The mixture was stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol=3:1) and recrystallized from a mixture of isopropanol and methanol to give 1.44 g of (E)-1-(2-nitrocinnamyl)-3-(4-pyridyl)-2-imidazolidinone.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=2)[O:3]1.[Br:18]Br>C(O)(=O)C>[Br:18][C:5]1[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10]2
Reactant: BrBr
Reactant: CCOC(=O)c1ccc2c(c1)CCC(C)(C)O2
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)c2c(c1)CCC(C)(C)O2

Procedure:
Reaction Scheme 6B discloses a synthetic route to specific preferred benzopyran (chromene) compounds of the invention where with reference to Formula 1 the Z group is also CONH (amide derivatives). In accordance with this scheme, dihydrocoumarine (Compound 213) is subjected to a Grignard reaction with methyl magnesium chloride followed by heating a tertiary alcohol intermediate with acid, to provide 2,2-dimethylchroman (Compound 214). Compound 214 is converted into 6-acetyl-2,2-dimethylchroman (Compound 215) in a Friedel--Crafts reaction, and the latter is oxidized with NaOCl in the presence of sodium hydroxide and thereafter esterified to give ethyl 2,2-dimethylchroman-6-carboxylate (Compound 216). Compound 216 is treated with bromine in glacial acetic acid to give ethyl 8-bromo-2,2-dimethylchroman-6-carboxylate (Compound 217). Compound 217 is oxidized with chromium trioxide to form a ketone function in the 4-position of the chroman ring and yield ethyl 8-bromo-2,2-dimethyl-4-chromanone-6-carboxylate (Compound 218). Reaction of Compound 218 with the Grignard reagent made from 4-bromotoluene, and subsequent heating with p-TSOH to complete dehydration of the intermediate tertiary alcohol, provides ethyl 8-bromo-2,2-dimethyl-4-tolyl-4(2H)-chroman-6-carboxylate (Compound 219). Saponification of Compound 219 with base gives the corresponding free carboxylic acid, 8-bromo-2,2-dimethyl-4-tolyl-4(2H)-chroman-6-carboxylic acid (Compound 220). Compound 220 is condensed with ethyl 2-fluoro-4-aminobenzoate and ethyl 2,6-difluoro-4-aminobenzoate, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and of 4-dimethylaminopyridine (DMAP) to provide ethyl 2-fluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoate (Compound 221) and ethyl 2,6-difluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoate (Compound 222), respectively. Saponification of Compounds 221 and 222 yields the corresponding free carboxylic acids, 2-fluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoic acid (Compound 204) and 2,6-difluoro-4-[[8-bromo-2,2-dimethyl-4-tolyl-6-chromanyl)carbonyl]amino]-benzoic acid (Compound 205), respectively. ##STR14##
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: Cc1cnccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cnccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-methylisonicotinic acid (100 mg, 0.729 mmol) suspended in DCM (2.5 mL) was added thionyl chloride (260 mg, 2.188 mmol). The reaction mixture was stirred at room temperature for about 3 hours. The solvent was removed under reduced pressure and the residue was dried under high vacuum for 1 hour to give 3-methyl-isonicotinoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](Cl)(=O)[CH:12]([CH3:14])[CH3:13]>O1CCOCC1.CN(C)C=O>[CH3:10][C:4]1[CH:5]=[C:6]([OH:9])[N:7]2[N:8]=[C:11]([CH:12]([CH3:14])[CH3:13])[N:1]=[C:2]2[N:3]=1
Reactant: Cc1cc(=O)n(N)c(N)n1
Reactant: CC(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1cc(O)n2nc(C(C)C)nc2n1

Procedure:
A solution of Intermediate 1 (0.35 g, 2.497 mmol) and iso-butyryl chloride (FLUKA, 0.262 mL, 2.497 mmol) in a mixture of 1,4-dioxane (4 mL) and N,N-dimethylformamide (1 mL) was heated under reflux overnight. The reaction was then concentrated under vacuum and the residue was purified by flash chromatography (Si, eluting with DCM:MeOH mixtures, gradient from 100:0% to 90:10%) to yield the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][O:12][CH3:13].O>CN(C)C=O>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: COCCCBr
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCn1cccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 363.9 %

Procedure:
To a solution of 1H-pyrrole (5.0 g) in N,N-dimethylformamide (40 mL) was added drop by drop sodium hydride (3.58 g) under ice-cooling, and then the mixture was stirred at room temperature for 20 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (2.74 g) in N,N-dimethylformamide (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=100/1→20/1) to give 1-(3-methoxypropyl)-1H-pyrrole [REx(105-1)] (9.07 g) as a colorless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1.[Si:16]([O:23][CH2:24]/[CH:25]=[N:26]/[S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CCOC(C)=O>[Si:16]([O:23][CH2:24][C@@H:25]([NH:26][S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[C:7]1[C:8]([O:14][CH3:15])=[N:9][CH:10]=[C:11]([F:13])[CH:12]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: COc1ncc(F)cc1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc(F)cc1[C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of n-butyl lithium (10.8 mL, 17.3 mmol, 1.6 M in hexanes) in toluene (100 mL) at −78° C. was added a solution of 3-bromo-5-fluoro-2-methoxypyridine (3.27 g, 15.9 mmol) in toluene (5 mL) dropwise, maintaining the internal temperature below −70° C. The mixture was stirred at −78° C. for 1 hour, then treated with a solution of (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (4.0 g, 14.4 mmol) in toluene (10 mL) dropwise, maintaining the internal temperature below −65° C. After stirring at −78° C. for 3 hours the mixture was treated with brine (100 mL) and EtOAc (100 mL) and stirred at ambient temperature for 20 minutes. Saturated NaHCO3 solution (50 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography, eluting with 10% EtOAc/hexanes to 20% EtOAc/hexanes, to afford (S)-N-((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.40 g, 24% yield) mixed with a less polar impurity as a colorless oil. MS (apci) m/z=405.0 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=23)O1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=23)[CH:25]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1(C)OB(c2cnn3cccnc23)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Clc1cc(-c2cnn3cccnc23)ncn1
Temperature: 100 °C
Yield: 10.6 %

Procedure:
To a stirred solution of compound 13g (14.3 mmol) in DMF (90 mL), was added 4,6-dichloropyrimidine (14.3 mmol), K3PO4, (42.7 mmol) and PCy3 (1.4 mmol) at rt. The mixture was purged with Ar for 45 min, Pd2(dba)3 (0.70 mmol) added and again the mixture purged with Ar for 30 min and heated to 100° C. for 1 h. The reaction was cooled to rt, EtOAc (800 mL) added, and the mixture filtered through Celite®. The combined filtrate was washed with water (3×200 mL), 2N aq. HCl solution (400 mL), sat. aq. NaHCO3 and brine solution (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated to give a crude compound as a brown residue. The crude compound 7f was purified by column chromatography (100-200 mesh silica gel, 0-70% EtOAc/Petroleum ether). The product was obtained as a solid (350 mg, 10.6%). TLC system: EtOAc: Pet ether (7:3). Rf value: 0.56. mp: 260-270° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[C:5]([N:12]=O)=[C:4]([NH2:14])[N:3]=1.[ClH:15]>[Pd].C(O)C>[ClH:15].[ClH:15].[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[C:5]([NH2:12])=[C:4]([NH2:14])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(OCCO)n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1nc(N)c(N)c(OCCO)n1
Reaction time: 19 h
Yield: 84.2 %

Procedure:
1.5 g (0.04 mol %) of palladium on carbon (5%) was added to a solution of 6.57 g (0.033 mol) of 2-[(2,6-diamino-5-nitrosopyrimidin-4-yl)oxy]ethan-1-ol from step 4.2 in 400 ml of ethanol, and shaking was performed at room temperature for 19 h under hydrogen-1 atmosphere. Then the reaction mixture was poured into 150 ml of diluted hydrochloric acid (0.30 mol), the catalyst was filtered off, and the filtrate was concentrated almost to dryness. The precipitated crystals were sucked off and post-washed with tert-butyl methyl ether. 2-[(2,5,6-triaminopyrimidin-4-yl)oxy]ethanol, dihydrochloride (7.17 g, 84%) was obtained as light-yellow crystals.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=12.[CH3:31][NH2:32]>CO>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([CH2:29][CH3:30])=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:32][CH3:31])=[CH:14][CH:13]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2nsnc2c1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2nsnc2c1
Temperature: 85 °C

Procedure:
To a stirred solution of 4-(2-(benzo[c][1,2,5]thiadiazol-5-yl)-1-(4-(2-chloro-ethoxy)phenyl)but-1-enyl)phenol (83 mg) in 10 mL MeOH was added 3 mL CH3NH2 (30% aq.) and heated at 85° C. for 15 h. The organic solvent was removed in vacuo, and the remaining mixture was extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH(NH3 gas)=50/1) to give the desired product (11 mg, Z/E=1/1) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.15 & 7.06 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.78 & 6.72 (d, J=8.6 Hz, 2H), 6.48 & 6.42 (d, J=8.6 Hz, 2H), 4.12 & 3.92 (t, J=4.8 Hz, 2H), 3.03 & 2.91 (t, J=4.8 Hz, 2H), 2.60 (q, J=7.2 Hz, 2H), 2.55 & 2.47 (s, 3H), 0.97 (t, J=7.2 Hz, 3H); m/z=432[M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[N:20]=[C:19]([CH:22](OC)[O:23]C)[C:18]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[N:20]=[C:19]([CH:22]=[O:23])[C:18]([CH2:27][C:28]([OH:30])=[O:29])=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1nc2c(cc1CC(=O)OC(C)(C)C)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(NC(=O)N2CCCc3cc(CC(=O)O)c(C=O)nc32)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of tert-butyl 2-(8-((5-cyanopyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acetate (intermediate 48, 33 mg, 0.071 mmol) in THF (1 ml) and H2O (1 ml) was added conc. HCl (0.5 ml). The suspension was stirred at room temperature for 2 days, then conc. HCl (0.5 ml) was added and the reaction mixture was stirred at room temperature for 2 days. Then conc. HCl (0.5 ml) was added and the reaction mixture was stirred for 1 h. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (5×). The aqueous phase was acidified with conc. HCl and extracted with DCM (3×). All aq. and organic phases were combined and evaporated. The residue was subjected to reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100). The product containing fractions were lyophilized to give the title compound as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10][C:11]([C:13]1([Br:16])[CH2:15][CH2:14]1)=[O:12])[C:4]1C=CC=CC=1.BrC1(C(Cl)=O)CC1.CC(N)CO>>[OH:1][CH2:2][CH:3]([NH:10][C:11]([C:13]1([Br:16])[CH2:14][CH2:15]1)=[O:12])[CH3:4]
Reactant: O=C(N[C@@H](CO)c1ccccc1)C1(Br)CC1
Agent: CC(N)CO
Agent: O=C(Cl)C1(Br)CC1
Product: CC(CO)NC(=O)C1(Br)CC1

Procedure:
Analogously to the production of amide 110, 2.18 g of acid chloride 107 is reacted with 780 mg of DL-2-amino-1-propanol, whereby 1.7 g of 1-bromocyclopropanecarboxylic acid-2-hydroxy-1-methylethylamide 112 is obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CC(C)=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Nc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
A flask with a stirrer was charged with 10.9 g of 2-aminophenol, 10.1 g of triethylamine and 100 ml of acetone, and a solution of 19.1 g of p-toluenesulfonyl chloride in 50 ml of acetone was dropwise added with cooling with ice over 30 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethyl acetate/n-hexane mixed solvents, to give 13.0 g of an end product. Melting point 140.0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:28][CH2:27]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(c4ccccc4F)CC3)C2)c1
Yield: 45.4 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]propanal (30.3 mg, 0.122 mmol), 1-(2-fluorophenyl)piperazine (20.0 mg, 0.111 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (70.5 mg, 0.333 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 20.8 mg (50.3%) of the target compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[N:15]=[CH:14][N:13]([CH3:16])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[N:15]=[CH:14][N:13]([CH3:16])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CCCCN
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1ncn2C
Yield: 78 %

Procedure:
2.5 g. of 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester is refluxed for 10 minutes with 10 ml. of butylamine. The excess butylamine is removed and the residue dissolved in ether. The mixture is filtered and cooled. The 7-butylamino-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester precipitates and is recrystallized from petroleum ether, yield 78%, m.p. 62°-63°.