Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH2:54][CH3:55].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[O:52][CH2:53][CH2:54][CH3:55])=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccccc1OB([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.8 ml) and then were added 2-propoxyphenyl borate (125 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed at 100° C. for 8 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(2-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 113) (46 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH2:9][CH2:8][C:7](=[C:10]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]3[CH:14]=[CH:13][S:12][C:11]2=3)[CH2:6][CH2:5]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:13]1[S:12][C:11]2[C:10](=[C:7]3[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:16][C:15]=2[CH:14]=1
Reactant: BrBr
Reactant: CN1CCC(=C2c3ccccc3OCc3ccsc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(=C2c3ccccc3OCc3cc(Br)sc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
Bromine (5 mL, 98 mmol) was added dropwise to a chloroform (300 mL) solution of 1-methyl-4-(10H-9-oxa-3-thiabenzo[f]azulen-4-ylidene)piperidine (19.3 g, 65.0 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours, and a saturated aqueous sodium hydrogencarbonate solution was then added thereto to allow the separation of an organic layer. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, the solvents were then distilled off under a reduced pressure, and the residue was purified by column chromatography (chloroform:methanol=9:1). The crystals were formed from a petroleum ether, to give 11.2 g (46%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][O:31][CH2:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[CH:42]=[CH:43][C:38]=2[O:37][C:36]1=[O:53].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:41]2[CH:42]=[CH:43][C:38]3[O:37][C:36](=[O:53])[N:35]([CH2:34][CH2:33][CH2:32][O:31][CH3:30])[C:39]=3[CH:40]=2)=[CH:7][CH:6]=1
Reactant: COCCCn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCCn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Yield: 36.1 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 363 mg) and 3-(3-methoxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (Example 11, step (ii), 234 mg) in acetonitrile (8 mL) were treated with aqueous sodium carbonate (2M, 0.70 mL) and nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. for 18 h. The mixture was purified by chromatography on silica eluting with 50-100% ethyl acetate/isohexane to yield the sub-titled compound (151 mg).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[N:43]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(5-trifluoromethyl(2-pyridyl))amino]ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-trifluoromethylpyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=O)[CH3:13])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CC(=O)NCCCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCNCCCc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
The product of Step d (1.10 g, 5.63 mmol, 1 eq.) was dissolved in THF at 25° C. under N2 then 1.0M LAH in THF (22.54 mL, 22.50 mmol, 4 eq.) was added dropwise via an addition funnel over 10 minutes. After the addition was complete, refluxed for 1 hour. Worked up by carefully adding water (0.86 mL)(Caution—lots of foaming and gas evolution were observed) dropwise via an addition funnel followed by 1N NaOH (3.42 mL). Stirred 20 minutes then filtered off the solids. The filtrate was stripped to give 0.90 g of a colorless oil as product. MS (ESI) detects (M+H)+=182.
Reaction SMILES: C([N:8]1[C:12]([CH2:13][CH2:14][C:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)([OH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:32]([NH:31][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:15]([OH:22])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:13][C:12]2[N:8]=[CH:9][NH:10][CH:11]=2)=[CH:28][CH:27]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)(CCc2cncn2Cc2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)NC(=O)c1ccc(C(O)(CCc2c[nH]cn2)c2ccccc2)cc1

Procedure:
1-benzyl-5-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxy-3-phenylpropyl]- 1H-imidazole (3,6 g, 7,7 mmol) is dissolved in aqueous ethanol (80 ml) and 10% Pd/C (0,36 g) is added. Ammonium formate (1,95 g, 31 mmol) is added to the boiling solution. The mixture is refluxed for four hours. After the refiuxing the solvents are evaporated. 2M sodium hydroxide is added to the residue and the product is extracted into ethyl acetate, dried and the solvent is evaporated. Yield 2,7 g, 93,5%.
Reaction SMILES: [CH:1]([C:4]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]#[C:22][Si](C)(C)C)=[CH:15][C:5]=1[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:3])[CH3:2].[F-].[Cs+].C1COCC1>O>[C:21]([C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([CH:15]=1)[O:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:22]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#C[Si](C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(Oc2cnc(N)nc2N)c(C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
5-(2-Isopropyl-4-methoxy-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine (0.75 g, 2 mmol) and Cesium Fluoride (0.46 g, 3 mmol) were added to 10 mL of dry THF under nitrogen, and the reaction mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 50 g of flash silica (3%-6% MeOH/CH2Cl2) to give 0.54 g of 5-(5-ethynyl-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, MS (M+H)=299.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:11].O[CH2:13][CH:14]([CH2:16]O)O.S(=O)(=O)(O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[Br:11][C:3]1[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[C:10]2[C:2]=1[N:1]=[CH:16][CH:14]=[CH:13]2
Reactant: OCC(O)CO
Reactant: Nc1ccc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: O=C(O)c1cc(Br)c2ncccc2c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4-Amino-3-bromo-benzoic acid (1 eq) and glycerol (2.4 eq) was added to sulfuric acid (6.4M, reaction conc. 0.6M) at 0° C. After 15 min, the bath was removed and 3-nitro-phenylsulfonic acid sodium salt (1.3 eq) was added portionwise. The reaction mixture was heated gradually until exothermic reaction started (between 110-140° C.), the internal temperature was maintained below 170° C. for 1 h. The reaction mixture was cooled to 50° C. and poured slowly into NH4OH-ice (2:1). The title product isolated by filtration, dissolved in warm 5% NH4OH/MeOH and diluted with CH2Cl2. This solution was filtered through silica gel eluting with (NH4OH, MeOH, CH2Cl2, 3:30:70). The residue was stirred in EtOH and the title product isolated by filtration.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1.[I-].[K+].[OH-].[Na+]>CC(O)(CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: O=[N+]([O-])c1ccc(OCCCn2ccnn2)cc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
1-(3-Chloro-propoxy)-4-nitro-benzene (7 g, 32.5 mmol) is dissolved in 2-methyl-2-butanol (35 ml) followed by the addition of 1H-1,2,3-triazole (3.43 g, 48.7 mmol), potassium iodide (0.54 g, 3.25 mmol) and sodium hydroxide (1.95 g, 48.7 mmol). The mixture is stirred for 20 h at 120° C., evaporated to dryness and suspended in toluene. Washing with water, drying over sodium sulfate and concentration in vacuo yields a crude product, which is washed with ether yielding 1-[3-(4-nitro-phenoxy)-propyl]-1H-[1,2,3]triazole as a colorless solid. Yield 6 g (75%)
Reaction SMILES: C([O:8][C:9](=[O:29])[CH2:10][N:11]1[C:16]([CH3:17])=[C:15]([Cl:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]1=[O:28])C1C=CC=CC=1.C1COCC1.CO.O[Li].O>O>[Cl:18][C:15]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:12](=[O:28])[N:11]([CH2:10][C:9]([OH:29])=[O:8])[C:16]=1[CH3:17]
Reactant: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)nc(NCCc2ccccc2)c(=O)n1CC(=O)O
Reaction time: 2 h

Procedure:
Water (1 ml) was added to a stirred solution of (5-chloro-6-methyl-2-oxo-3-phenethylamino-2H-pyrazin-1-yl)acetic acid benzyl ester (436 mg) in 1:1 THF/MeOH (6 ml) and LiOH.H2O was added to the resulting mixture. After 2 h, the reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with 10% KHSO4 solution to give a cloudy mixture that was extracted with methylene chloride. The organic layer was dried (Na2SO4) and evaporated in vacuo to give 1-4 as a crystalline solid. 1H NMR (DMSO-d6) δ2.19 (s, 3 H, Me), 2.84 (t, J=7.0 Hz, 2 H, PhCH2), 3.45 (q, J=7.0 Hz, 2 H, CH2NH), 4.70 (s, 2 H, CH2CO2), 7.18-7.31 (m, 5 H, Ph), 7.46 (br s, 1H, NH).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=O)C1C=CC=CC=1.[N:29]1[C:38]2[C:33](=[N:34][C:35]([CH:39]=O)=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.N1CCCCC1>CC(O)C>[N:34]1[C:33]2[C:38](=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:37]=[CH:36][C:35]=1[CH:39]=[C:15]1[NH:11][C:12]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:27])[F:28])=[N:13][C:14]1=[O:16]
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2C(F)(F)F)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2ccccc2C(F)(F)F)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 4-oxo-2-(2-trifluoromethyl-benzylamino)-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.4 mg, 0.18 mmol), 1,5-naphthyridine-6-carboxaldehyde (28.7 mg, 0.18 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH and ether. The solid was then re-crystallized from AcOEt-MeOH to give 5-[1,5]naphthyridin-2-ylmethylene-2-(2-trifluoromethybenzylamino)-1,5-dihydro-imidazol-4-one as a light yellow crystalline material (11.6 mg, 16.2%). HR-ES (+) m/e calcd. for C20H14F3N5O: (M+H)+ 398.1223. Found: 398.1222.
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14]([N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N+:2]=1[O-:1])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [O-][n+]1ccccc1NCCCO
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(OCc1ccccc1)N(CCCO)c1cccc[n+]1[O-]

Procedure:
3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino] propanol was prepared by reaction of 3-[N-(1-oxido-2-pyridinyl)amino] propanol (obtained as described in MILLER, W. H. et al. Bioorg. Med. Chem. Lett. 1999, 9 1807-1812) with benzyl chloroformate according to the standard procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CO>[NH2:1][C:2]1[C:3]([C:4]([OH:6])=[O:5])=[C:7]([F:11])[C:8]([Br:12])=[CH:9][CH:10]=1
Reactant: Nc1cccc(F)c1C(=O)O
Reactant: BrBr
Solvent: CO
Product: Nc1ccc(Br)c(F)c1C(=O)O
Temperature: -78 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 2-amino-6-fluorobenzoic acid (12.0 g, 77.35 mmol) in methanol (150 mL) was added bromine (15.7 mL) at −78° C., and the mixture was stirred 2 hours at −78° C. The reaction mixture was quenched with ice-water (100 mL) and aqueous solution of sodium sulfothioate, and extracted with ethyl acetate (150 mL×3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title crude product (9.0 g, 50%). MS (ES+) C7H5BrFNO2 requires: 232, found: 233, 235 [M+H]+.
Reaction SMILES: C(OC(N1CC[CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.OC([C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[C:50]#[N:51])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH:39]([N:34]1[C:33]([C:27]2[N:26]=[C:25]3[C:24]4[CH:42]=[CH:43][C:21]([O:20][CH:17]([C:47]5[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=5)[C:50]#[N:51])[CH3:14])=[CH:22][C:23]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:37][C:36]([CH3:38])=[N:35]1)([CH3:41])[CH3:40]
Reactant: CC(O)c1cccc(C#N)c1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)c4cccc(C#N)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (300 mg, 0.92 mmol), 3-(1-hydroxyethyl)benzonitrile (390 mg, 2.65 mmol) and triphenylphosphine (600 mg, 2.28 mmol) in dioxane (10 mL) was added dropwise DIAD (449 ul, 2.28 mmol) and the reaction mixture was stirred at RT for 18 h under an argon atmosphere. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was stirred in aq. NaOH (2M) for 15 min and then was filtered off. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 50-100% 0.1% HCO2H in acetonitrile/water) affording 191 (29 mg, 7%). LCMS: RT 4.81 min [M+H]+ 455.2. 1H NMR (DMSO, 400 MHz): δ 8.26 (1H, d, J=8.97 Hz), 7.93-7.89 (1H, m), 7.82-7.74 (3H, m), 7.60 (1H, t, J=7.78 Hz), 6.80 (1H, dd, J=9.00, 2.57 Hz), 6.57 (1H, d, J=2.54 Hz), 5.87-5.75 (1H, m), 5.66 (1H, q, J=6.38 Hz), 4.49-4.40 (4H, m), 2.25 (3H, s), 1.59 (3H, d, J=6.35 Hz), 1.45 (6H, d, J=6.60 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([F:11])[CH:3]=1.[I:12]I.[OH-].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.C(OCC)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:12])=[N:7][NH:8]2)=[C:4]([F:11])[CH:3]=1
Reactant: II
Reactant: Fc1cc(Cl)cc2[nH]ncc12
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1cc(Cl)cc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
6-Chloro-4-fluoro-1H-indazole (7.6 g, 44.6 mmol) was dissolved in DMF (110 ml). Iodine (22.6 g, 89.1 mmol) was added followed by potassium hydroxide (9.5 g, 169 mmol). The reaction was stirred at room temperature for 1.5 h. Water, 1 M sodium thiosulfate solution and diethyl ether were added. The layers were separated and the aqueous layer was extracted once more with ether. The organic layers were washed with water and sodium chloride solution, and then dried over sodium sulfate. Evaporation of the solvent gave 11.16 g (85%) of 6-chloro-4-fluoro-3-iodo-1H-indazole as a light brown solid (M−H)−=295.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])c(N)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 2-amino-6-chloro-3-nitropyridine (2.77 g, 16.0 mmol) in DMF (55 mL) was added 4-acetylaminophenol (2.67 g, 17.5 mmol) followed by K2CO3 (3.3 g, 5.0 mmol) and stirred at room temperature for 2 hrs. The solvent was removed by evaporation. To the residue, water was added to form a precipitate. The solid was collected by filtration, washed with water and ethyl acetate then dried under reduced pressure to give the title compound (4.32 g, 94%): MS m/e 289 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O>C(#N)C>[CH:5]1[C:6]([C:10]#[N:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[CH:5][C:4]=3[C:3]=12
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2[nH]c3c4[nH]c5ccc(C#N)cc5c4c4c5cc(C#N)ccc5[nH]c4c3c2c1
Temperature: 60 °C
Reaction time: 10 h
Yield: 87.2 %

Procedure:
10 ml of acetonitrile was poured into a 200 ml three-neck flask, and 1.42 g of indole-5-carbonitrile was dissolved therein. On the other hand, an oxidant solution was prepared by dissolving 16.2 g of ferric chloride anhydrate and 5.4 g of water in 40 ml of acetonitrile and agitating the resultant mixture for 10 minutes. Then the prepared oxidant solution was dripped into the indole-5-carbonitrile solution for 30 minutes, which was then agitated for 10 hours at the temperature of 60° C. Color of the reaction solution changed from yellow to green with slight heat generation, and the pH was less than 1. After the end of the reaction, the reaction solution was suction-filtered with a perforated funnel, and the filtrate was washed with acetonitrile and then methanol, and then dried to obtain 1.22 g of 6, 11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole-2,9,14-tricarbonitrile (indole-5-carbonitrile trimer) with a green color (yield: 86%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.50 S/cm. The result of elemental analysis was: <C9.00H4.03N1.97Cl0.10>3. Further the result of X-ray diffraction crystal analysis indicated that the interlaminar spacing was 0.44 nm.