Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].[K+].C([OH:38])(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:38])[CH:14]=[C:13]([NH:25][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cccc(C#N)c2)n1)c1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cccc(C(N)=O)c2)n1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
192 mg of (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile (Example 81) was added to 5 ml of t-butanol, and 384 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was stirred at 80° C. for 2 hours. 384 mg of potassium fluoride supported on activated alumina was added thereto, and the mixture was further stirred for 15 hours. The reaction solution was filtrated to remove precipitates, and then the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 158 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]4[S:32][N:31]=[CH:30][N:29]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)[N:17]([CH3:44])[CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: COc1cc(OC)cc(B(O)O)c1
Product: COc1cc(OC)cc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3,5-dimethoxyphenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(3,5-dimethoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78-3.88 (m, 9 H) 6.39 (t, J=2.23 Hz, 1 H) 6.77 (d, J=2.29 Hz, 2 H) 7.52 (dd, J=8.42, 1.55 Hz, 1 H) 7.75-7.89 (m, 4 H). m/z (ESI) 430.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH:20]=[C:13]34)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]3([CH2:17][CH2:16][CH2:15][N:14]4[CH:18]=[N:19][CH:20]=[C:13]34)[C:8](=[O:12])[N:9]2[C:24]([O:26][CH3:27])=[O:25])=[CH:5][CH:4]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(c1)NC(=O)C21CCCn2cncc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1C(=O)C2(CCCn3cncc32)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1 mmol of 6′-methoxy-6,7-dihydro-5H-spiro[imidazo[1,5-a]pyridine-8,3′-indol]-2′(1′H)-one in 5 ml of N,N-dimethyl formamide is treated with 1.2 mmol of sodium hydride (60% dispersion in oil). The reaction mixture is stirred for 20 minutes at room temperature, then 1.2 mmol of methyl chloroformate are added. The reaction mixture is stirred for 20 minutes at room temperature, then diluted with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:40])=[C:18]([CH:39]=2)[NH:19][C:20](=[O:38])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[S:30][CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[N:33]=3)[CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][C:49]#[N:50]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:34]([C:32]1[N:33]=[C:29]([CH2:28][O:27][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([NH:19][C:18]2[CH:39]=[C:14]([CH2:13][CH2:12][CH2:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:15]=[CH:16][C:17]=2[O:40][CH2:48][C:49]#[N:50])=[O:38])[S:30][CH:31]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: N#CCBr
Reactant: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3O)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(COc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC#N)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5'-[3-(4-Chlorobenzenesulfonyl)propyl]-2'-hydroxy-3-[(4-tert-butyl-2-thiazolyl)methoxy]benzanilide (1.60 g, 2.67 mmol) was dissolved in dimethylformamide (16 ml), potassium carbonate (0.55 g, 4.00 mmol), a catalytically effective amount of tetrabutylammonium bromide and bromoacetonitrile (0.22 ml, 3.20 mmol) were added in that order under ice-cooling, followed by overnight stirring at room temperature. Ice-water was added to the reaction solution and the mixture was extracted twice with benzene-ethyl acetate (1:1). The resulting organic layer was washed with 5% potassium carbonate aqueous solution and brine in that order, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. By crystallizing the resulting residue from acetonitrile, 3-[(4-tert-butyl-2-thiazolyl)methoxy]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-cyanomethoxybenzanilide was obtained as colorless crystals (1.34 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([Li])CCC.[B:24](OC)([O:27]C)[O:25]C.Cl>C(OCC)C.CCCCCC.O>[F:1][C:2]1[CH:3]=[C:4]([B:24]([OH:27])[OH:25])[CH:5]=[C:6]([F:17])[C:7]=1[O:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(C)Oc1c(F)cc(Br)cc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCC(C)Oc1c(F)cc(B(O)O)cc1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
14.5 g of 1-bromo-3,5-difluoro-4-(1-methylheptyloxy)benzene from step 1 were dissolved in 150 ml of diethyl ether and cooled to −70° C. At this temperature, with cooling, firstly 31.0 ml of a 15% solution of butyllithium in n-hexane were slowly added dropwise, the mixture was stirred at the same temperature for 1 h, and then 5.6 ml of trimethyl borate were slowly added dropwise, and the mixture was stirred for a further h. The temperature of the reaction solution was slowly allowed to rise to −10° C. The mixture was then hydrolysed with distilled water, and the pH was adjusted to 2 using hydrochloric acid. The organic phase was separated off, and the aqueous phase was extracted with MTB ether. The product was subjected to conventional purification and dried over Na2SO4, giving 13.9 g of 3,5-difluoro-4-(1-methylheptyloxy)phenylboronic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:22][C:13]1=[N:14][CH:15]=[C:16]([C:18]([O:20]C)=[O:19])[CH:17]=[C:12]1[CH2:11]2.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:22][C:13]1=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]1[CH2:11]2
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Temperature: 23 °C

Procedure:
A mixture of methyl (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (30.0 g, 102 mmol) and aqueous 6 N sodium hydroxide solution (50.8 mL, 305 mmol) in MeOH (920 mL) was heated at reflux for 1 h. The mixture was allowed to cool to 23° C. before it was acidified to pH ˜6 with aqueous 1 N hydrochloric acid solution, resulting in a black precipitate which was removed by filtration. The filtrate was concentrated under reduced pressure to a volume of ˜100 mL and then partitioned between water (500 mL) and 2-methyltetrahydrofuran (2-MeTHF, 250 mL). The aqueous layer was extracted with 2-MeTHF (5×250 mL), and the combined organic layers were dried over sodium sulfate and concentrated to provide the title compound. MS: m/z=282.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]=[C:5]([C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O)[C:6]([O:8][CH3:9])=[O:7].[CH3:31][O:32][C:33](=[O:38])/[CH:34]=[C:35](\[NH2:37])/[CH3:36]>CC(O)C>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]1[C:34]([C:33]([O:32][CH3:31])=[O:38])=[C:35]([CH3:36])[NH:37][C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])=[C:5]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
92.1 g of methyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate was dissolved in 108 ml of 2-propanol at 80° C. 31.3 g of methyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 24 hours. The mixture was evaporated to dryness. The residue was dissolved in 162 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The solid was filtered off and washed with 83 ml of glacial acetic acid. The solid was suspended in 68 ml of methanol and agitated for 30 minutes. The solid was filtered off, washed with 23 ml of methanol and dried. The product was recrystallized from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:6][CH:7]=1.[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])#[CH:46].CCN(CC)CC>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:44][C:37]1[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=1[CH2:35][O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][N:8]1[C:5]1[N:6]=[CH:7][C:2]([C:46]#[C:45][Si:47]([CH3:50])([CH3:49])[CH3:48])=[CH:3][N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(Br)cn2)cc1F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)nc1
Yield: 9.1 %

Procedure:
A solution of 0.68 g (1 mmol) (2S,4R)-5-Bromo-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, 15 mg (0.022 mmol) of bis(triphenylphosphine)palladium(II)dichloride and 9.5 mg copper(I)iodide in 0.4 ml DMF was treated at 80° C. for 1 h with a solution of 0.35 ml (2.5 mmol) ethinyltrimethylsilane and 1.87 ml Et3N in 1.5 ml DMF. The same solution was added again during 1 h and after 4 h extracted with pentane (3×)/H2O (2×). The organic phase was dried (Na2SO4), evaporated and purified by flash-chromatography on silica gel (toluene) to give 0.063 g (9%) (2S,4R)-2-[2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-5-trimethylsilanylethynyl-pyrimidine, MS: 694 (MH+). TFA/triisopropylsilane deprotection (see General method for S-deprotection, Method D) gave (3R,5S)-5-(2,4,5-Trifluoro-benzyloxymethyl)-1-(5-trimethylsilanylethynyl-pyrimidin-2-yl)-pyrrolidine-3-thiol, MS: 452 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH3:16])[C:6](=[O:17])[C:5]=1[NH2:18])(=[O:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH3:16])[C:6](=[O:17])[C:5]=1[NH:18][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1c(-c2ccccc2)nn(C)c(=O)c1N
Product: CC(=O)c1c(-c2ccccc2)nn(C)c(=O)c1Nc1cccc(F)c1

Procedure:
The title compound was synthesized from 5-acetyl-4-amino-2-methyl-6-phenylpyridazin-3(2H)-one (Dal Piaz, V., Ciciani, G, Giovannoni, M. P., Heterocycles, 1991, 32, 1173-9) and the corresponding 3-fluorophenylboronic acid following the procedure of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][OH:16])([O-:3])=[O:2].[H-].[Na+].[CH2:19](Br)[C:20]#[CH:21]>CN(C=O)C.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:21][C:20]#[CH:19])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(NCCO)c([N+](=O)[O-])c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h
Yield: 64.9 %

Procedure:
2-(2,4-dinitrophenylamino)ethanol (s-1a) (410 mg, 1.80 mmol, 1.0 equiv.) was dissolved in 3 mL of DMF and slowly added to a slurry of NaH (86.4 mg, 3.6 mmol, 2 equiv.) in 5 mL of DMF in a flame dried flask pre-cooled to 0° C. To the resulting slurry, 80% propargyl bromide (0.240 mL, 2.16 mmol, 1.2 equiv.) in toluene, cooled to 0° C., was added slowly. The ice bath was removed and the reaction was allowed to stir at room temperature for an additional 15 hours. The reaction was then re-cooled to 0° C., quenched with saturated NH4Cl, and extracted with diethyl ether (3×150 mL). The organic layers were combined, dried, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% CH3OH in CHCl3, then 2.5% CH3OH in CHCl3) to yield 2,4-dinitro-N-(2-(prop-2-ynyloxy)ethyl)aniline (s-2a) as a dark yellow solid (310 mg, 64.8%). IR (thin film) 3356 (m), 3285 (m), 3105 (w), 2871 (w), 2117 (w), 1616 (s), 1584 (s), 1521 (s), 1499 (m), 1423 (m), 1274 (s), 1089 (s), 920 (m); 1H NMR (400 MHz, CDCl3) δ 9.16 (d, J=2.6 Hz, 1H), 8.76 (bs, 1H), 8.28 (dd, J=9.5, 2.7 Hz, 1H), 6.96 (d, J=9.5 Hz, 1H), 4.25 (d, J=2.4 Hz, 2H), 3.91-3.84 (m, 2H), 3.65 (d, J=5.3 Hz, 1H), 2.50 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 149.5, 136.3, 130.7, 130.4, 124.4, 114.1, 78.9, 75.5, 67.3, 58.7, 43.3. HRMS (ES+) calc'd for C11H11N3O5 (M+H) m/z 266.0732 Found 266.0771.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][O:13]C(C)(C)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][CH:9]([CH2:10][OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(OCc2ccccc2)CO1
Solvent: CO
Product: OCC(CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a methanol (50 ml) solution of the 5-(benzyloxy)-2,2-dimethyl-1,3-dioxane (6.5 g, 29.2 mmol) obtained in the step (9b), DOWEX(R) 50W-X8 (5 g) was added and stirred at room temperature. After 2 hours, the reaction mixture was filtered and concentrated to obtain the title compound (5.0 g, 93.8%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[O:25][CH3:26])[CH2:16][NH:17][O:18][CH:19]=[C:20]=[O:21])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31](=[O:41])[NH:32][N:33]=[C:34]([O:37][CH:38]([CH3:40])[CH3:39])[C:35]=1Cl.CN(C)C>CO>[Cl:29][C:30]1[C:31](=[O:41])[NH:32][N:33]=[C:34]([O:37][CH:38]([CH3:39])[CH3:40])[C:35]=1[N:17]([O:18][CH:19]=[C:20]=[O:21])[CH2:16][C:15]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)[CH:14]=1
Reactant: COc1ccc(CNOC=C=O)cc1N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)Oc1n[nH]c(=O)c(Cl)c1Cl
Agent: CN(C)C
Solvent: CO
Product: COc1ccc(CN(OC=C=O)c2c(OC(C)C)n[nH]c(=O)c2Cl)cc1N1CCN(Cc2ccc(N)cc2)CC1
Reaction time: 48 h
Yield: 81.5 %

Procedure:
A mixture comprising 1.6 g of 3-[4-(4-aminobenzyl)piperazin-1-yl]-carbonylmethoxy-4-methoxybenzylamine, 770 mg of 4,5-dichloro-6-isopropoxy-3(2H)-pyridazinone, 460 mg of trimethylamine and 20 ml of methanol, was refluxed under heating with stirring for 2 days. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→chloroform:methanol=15:1) and then crystallized from diethyl ether to obtain 1.6 g of the above-identified compound as white crystals.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]([CH2:28][C:29]1[CH:30]=[C:31]([NH:35]C(=O)OC(C)(C)C)[CH:32]=[CH:33][CH:34]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=2)[CH:14]=1)(=[O:10])[CH3:9].FC(F)(F)C(O)=O>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([N:11]1[CH2:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[NH:35][C:22]2=[N:21][C:20](=[C:25]([Cl:26])[CH:24]=[N:23]2)[NH:19][C:15]2=[CH:14][C:13](=[CH:18][CH:17]=[CH:16]2)[CH2:12]1)(=[O:10])[CH3:9]
Reactant: CC(=O)N(Cc1cccc(NC(=O)OC(C)(C)C)c1)Cc1cccc(Nc2nc(Cl)ncc2Cl)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc(c2)C1
Temperature: 70 °C
Yield: 31.6 %

Procedure:
A solution of tert-butyl {3-[(acetyl {3-[(2,5-dichloropyrimidin-4-yl)amino]benzyl}amino)methyl]phenyl}carbamate trifluoroacetate (10 mg, 16 μmol) in acetonitrile (1.5 mL) was treated with trifluoroacetic acid (75 μL, 0.97 mmol) and heated at 70° C. for 16 h. The reaction mixture was cooled and purified by preparative LCMS to give the desired product (2.5 mg, 32%) as a solid. LCMS for C20H19ClN5O (M+H)+: m/z=380.0. 1H NMR (300 MHz, CD3OD): δ 8.14 (d, J=1.8 Hz, 1H), 7.78 (s, 1H), 7.63-7.61 (m, 1H), 7.40-7.21 (m, 2H), 7.19-7.05 (m, 3H), 6.98-6.96 (m, 1H), 4.71-4.62 (m, 4H).
Reaction SMILES: C([O:5][C:6]([C@@H:8]([NH:10][C:11]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)=[O:14])[CH3:9])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([C@@H:8]([NH:10][C:11]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[O:21][CH2:22][O:23][C:19]=2[CH:18]=1)=[O:14])[CH3:9])([OH:7])=[O:5]
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc2c(c1)OCO2)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of (S)-2-[1-(tert-butoxycarbonyl)ethylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (104 mg) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.6 mL), and the mixture was stirred for 2 hour at ambient temperature. The resulting mixture was evaporated in vacuo and the residue was triturated with diethyl ether to give (S)-2-(1-carboxyethylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (76 mg) as a solid substance.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28](C3CCCCO3)[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:35])(=[O:9])=[O:8].C([SiH](CC)CC)C.CO>ClCCl.FC(F)(F)C(O)=O>[F:35][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[NH:28][N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2ccn[nH]2)cc1F
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclohexyl}oxy)benzenesulfonamide (366 mg, 0.547 mmol) prepared in Example 22b and triethylsilane (0.40 mL) in dichloromethane (4.0 mL), trifluoroacetic acid (4.0 mL) was added at room temperature, and the reaction solution was stirred for 1 hour. To the reaction solution, methanol (4.0 mL) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=95:5) to yield the title compound (182 mg, 61%) as a colorless solid.
Reaction SMILES: N([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[N+:17]=[N-])=[N+]=[N-].C(O)C.C(=O)=O>OCC(CO)O>[CH:15]1[C:10]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:17]=[N:16][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=Nc1ccccc1-c1ccccc1N=[N+]=[N-]
Agent: O=C=O
Solvent: CCO
Solvent: OCC(O)CO
Product: c1ccc2c(c1)nnc1ccccc12
Yield: 50.8 %

Procedure:
160 mg of 2,2'-diazidobiphenyl was dissolved in a small amount of diethyl ehter and then the solution thus obtained was dissolved in 500 ml of glycerol and the resultant solution was poured into a quarty cylindrical cell. The cell was dipped into a mixed coolant of ethyl alcohol and solid carbon dioxide to convert the solution to low-temperature rigid solution. The cell was irradiated with light in the same manner set forth in Example 1. After the irradiation, the cell was taken out of the coolant. After fluidized, the reaction product was extracted with 2l of diethyl ether. Diethyl ether was removed off by distillation. 62 mg of pure benzo[C]cinnoline was obtained by recrystallization of the residue using a mixed solvent of hexane and diethyl ether. Yield was about 52%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[Cl:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])=[CH:25][C:24]=1[Cl:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(Cl)c2)c(O)c([N+](=O)[O-])c1
Yield: 59.6 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (750 mg, 3.84 mmol) and 4-benzyloxy-3-chlorobenzaldehyde (1 g, 3.84 mmol) were reacted according to the same procedure as Preparation 15 to give 970 mg (Yield 59%) of the title compound.