Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:3]=1[CH:4]=[O:5]
Reactant: C1COCCN1
Reactant: O=Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1c(Cl)cccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-6-fluorobenzaldehyde (8.00 g, 50.5 mmol, 1.00 equiv), morpholine (6.60 g, 75.8 mmol, 1.50 equiv), potassium carbonate (17.4 g, 126 mmol, 2.50 equiv), and dimethyl sulfoxide (50 mL). The resulting solution was stirred for 3 hour at 100° C. in an oil bath and then diluted with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL) and the organic layers were combined, washed with H2O (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to yield 5.00 g (44%) of 2-chloro-6-(morpholin-4-yl)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 226 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][C:8](C4C=CC=CC=4)=[CH:9][CH:10]=3)[C:5]([CH3:29])([CH3:28])[C:4]=2[CH:3]=1.[CH2:30](O)[CH3:31].C(=O)([O-])[O-].[K+].[K+].[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>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.CO>[C:39]1([C:45]2[CH:31]=[CH:30][CH:29]=[CH:5][CH:28]=2)[CH:44]=[CH:43][C:42]([N:12]([C:13]2[CH:4]=[CH:3][C:2]([C:2]3[CH:15]=[CH:14][C:13]4[N:12]([C:11]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:16]5[C:17](=[CH:18][C:19]([C:16]6[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=6)=[CH:20][CH:21]=5)[C:5]([CH3:28])([CH3:29])[C:4]=4[CH:3]=3)=[CH:15][CH:14]=2)[C:11]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:41][CH:40]=1
Reactant: Cc1ccccc1
Reactant: CC1(C)c2cc(Br)ccc2N(c2ccccc2)c2ccc(-c3ccccc3)cc21
Reactant: CCO
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: CO
Product: CC1(C)c2cc(-c3ccccc3)ccc2N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(-c5ccccc5)cc4)cc3)cc21
Temperature: 72 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
2-Bromo-9,9-dimethyl-7,10-diphenylacridan (3.2 g), (biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)phenyl]-phenylamine (3.6 g), toluene (40 ml), ethanol (10 ml), and a 2M potassium carbonate aqueous solution (11 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.26 g) and stirred at 72° C. for 7 hours. The mixture was allowed to cool to a room temperature, and methanol (50 ml) was added. A precipitated solid was collected by filtration and washed with water to obtain a red brown crude product. The crude product was dissolved by adding toluene (100 ml) and subjected to adsorptive purification twice using silica gel (3.7 g). The product was then crystallized with toluene/methanol to obtain a white powder of (biphenyl-4-yl)-[4-(9,9-dimethyl-7,10-diphenylacridan-2-yl)phenyl]-phenylamine (3.42 g; yield 68%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.29 g--see Preparation 2), 4-methoxyphenethyl bromide (0.22 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (30 ml) was heated under reflux for 3 hours. The mixture was partitioned between dichloromethane (50 ml) and 5% aqueous sodium carbonate (50 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.22 g.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].Cl[C:9](Cl)(Cl)[CH:10]([OH:12])O.[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[NH2:29])([CH3:18])([CH3:17])[CH3:16].Cl.[NH2:31][OH:32]>O.Cl>[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[NH:29][C:10](=[O:12])/[CH:9]=[N:31]/[OH:32])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc(N)c(C(C)(C)C)c1
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)/C=N/O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 24.8 %

Procedure:
Sodium sulfate (20.75 g, 146 mmol) and chloral hydrate (2.78 g, 17 mmol) were dissolved in water (30 mL). Then a solution of 2,4-di-tert-butyl-phenylamine [prepared according to P. D. Bartlett, M. Roha, R. M. Stiles, J. Am. Chem. Soc. 1954, 76, 2349-2353](3 g, 14.6 mmol) in water (6 mL), 25% HCl (1.9 mL), and a solution of hydroxylamine hydrochloride (3.25 g, 47 mmol) in water (8 mL) were added. The mixture was heated at 100° C. for 1 h. Extraction with ethyl acetate and chromatography on silica gel with a gradient of 0% to 25% of ethyl acetate in heptane afforded a light brown solid (1 g, 25%), which was a 1:1-mixture with formulated starting material. MS: m/z=277 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.CN([CH:15]=[O:16])C.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:28])([F:27])[CH2:25][OH:26]>O>[Cl:9][C:6]1[C:5]([F:10])=[N:4][C:3]([O:16][CH2:15][C:24]([F:28])([F:27])[F:23])=[C:2]([Cl:1])[C:7]=1[O:26][CH2:25][C:24]([F:28])([F:27])[F:23]
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Reactant: OCC(F)(F)F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Fc1nc(OCC(F)(F)F)c(Cl)c(OCC(F)(F)F)c1Cl
Temperature: 30 °C

Procedure:
A reaction flask was loaded with 3,5-dichloro-2,4,6-trifluoropyridine (5.6 g), DMF (15 ml), and potassium carbonate (9.2 g), and heated up to 30° C. with stirring. To this, a mixture of 2,2,2-trifluoroethanol (5.6 g) and DMF (10 ml) was dropwise added in one hour. After the dropwise addition was ended, the temperature was raised to 50° C., followed by stirring for three hours. The heating was stopped and left to cool. Thereafter, water (100 ml) was added to the reaction mixture, followed by extraction with ether. The ether layer was condensed to give 3,5-dichloro-2-fluoro-4,6-bis(2,2,2-trifluoroethoxy)pyridine (9.7 g). By GC/MS analysis, a molecular ion peak of 362 was confirmed.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([B:7]([OH:9])[OH:8])[CH:2]=1.[Mn]([O-])(=O)(=O)=[O:12].[K+].[OH-:17].[Na+]>>[C:10]([C:1]1[CH:2]=[C:3]([B:7]([OH:9])[OH:8])[CH:4]=[CH:5][CH:6]=1)([OH:12])=[O:17]
Reactant: Cc1cccc(B(O)O)c1
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of m-Tolylboronic acid (8.0 g, 0.059 mol) in 10% sodium hydroxide (250 ml) was added potassium permanganate (20 g) in small portions. The reaction mixture was stirred at room temperature for 48 hours. The precipitated manganese dioxide was filtered and the filtrate was acidified with 10% sulfuric acid and cooled. The white precipitate that formed was filtered and recrystallized from water. M.P. 250°-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][N:20]3[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A suspension of 2-chloro-4-{[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (87.8 mg, 0.206 mmol) in methanol (1 mL) was cooled to ˜0° C. and 1 M sodium hydroxide (0.206 mL, 0.206 mmol) was added. The cooling bath was removed and the reaction mixture was allowed to stir overnight. A further portion of sodium hydroxide (1 M; 0.2 mL, 0.2 mmol) was added and the mixture was stirred at room temperature for 7 h. The solvent was evaporated and the residue was dissolved in water (25 mL) and washed with ethyl acetate (2×10 mL). The aqueous layer was made acidic with 1 M HCl and extracted with ethyl acetate (2×20 mL). These extracts were combined, washed with brine (10 mL), dried (MgSO4), filtered, and concentrated to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid (77.3 mg, 91%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:44]([NH:43][CH:40]([CH3:42])[CH3:41])=[O:45])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NC(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 12.2 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (52 mg, 0.6 mmol) in dichloromethane (1 mL) was added isopropylisocyanate (36.5 mg, 0.51 mmol). Triethylamine (60 mg, 0.60 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 40.8 mg (52%) of the title compound as off white solid. MS (ES) m/e 654.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]#[N:25])[CH:20]=[C:19]([CH3:26])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]2[NH:29][N:28]=[N:27][N:25]=2)[CH:20]=[C:19]([CH3:26])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:16][CH2:17]2)(=[O:12])=[O:13])[CH:10]=1
Reactant: Cc1cc(NC#N)cc(Cl)c1Oc1ccc(O)c(S(=O)(=O)NC2CC2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(Nc2nnn[nH]2)cc(Cl)c1Oc1ccc(O)c(S(=O)(=O)NC2CC2)c1
Temperature: 165 °C

Procedure:
5-[2-Chloro-6-methyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-N-cyclopropyl-2-hydroxy-benzenesulfon-amide was prepared from 5-[2-chloro-4-cyanoamino-6-methyl-phenoxy]-N-cyclopropyl-2-hydroxy-benzenesulfonamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.2 equiv) and ammonium chloride (10 equiv) were used, and the reaction was heated to 165° C. for 3 hours. After the reaction had been acidified, the aqueous mixture was washed with ethyl acetate (3×10 ml). The combined organic extracts were extracted with aqueous 1N HCl (3×50 ml), and brine (50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane 25:3:72) to afford the title product of Example 5. MS (APCI+) Calc.: 436.1, Found: 436.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][S:7]([NH:10][C:11]2[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20]O)[C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:45]>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][S:7]([NH:10][C:11]2[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20][Br:45])[C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(Cl)cc2)c(=O)n1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(Cl)cc2)c(=O)n1CCCBr
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
3-(4-Chlorobenzylsulfonylamino)-6-methyl-1-(3-hydroxypropyl)pyridone (3-8) (292 mg, 0.8 mmol) was dissolved in 8 mL methylene chloride under a nitrogen atmosphere. Triphenylphosphine (250 mg, 0.96 mmol) was added, followed by 370 mg (1.12 mmol) carbon tetrabromide. The reaction mixture was cooled to 0° C. and held at that temperature for 16 hours. The solvent was evaporated in vacuo and the product purified by flash chromatography (50:50 ethyl acetate: hexanes) to afford 227 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.25 (m, 2H), 2.39 (s, 3H), 3.50 (t, 2H), 4.28 (t, 2H), 4.27 (s, 2H), 5.93 (d, 1H), 7.20-7.31 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:88])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:74][C:75]1[N:76]([CH2:80][C:81](=[O:87])[O:82][C:83]([CH3:86])([CH3:85])[CH3:84])[CH:77]=[CH:78][N:79]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:19]([C:38](=[O:73])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][C@@H:44]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[NH:45][C:46](=[O:65])[NH:47][C@H:48]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CN(C=O)C>[NH2:20][C@H:19]([C:38](=[O:73])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][C@@H:44]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[NH:45][C:46](=[O:65])[NH:47][C@H:48]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:49][CH2:50][C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])[CH2:18][CH2:17][CH2:16][CH2:15][N:14]([CH2:13][C:9]1[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:88])[CH:12]=[CH:11][N:10]=1)[CH2:74][C:75]1[N:76]([CH2:80][C:81]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:87])[CH:77]=[CH:78][N:79]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@@H](N)CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (84 mg, 0.069 mmol) in DMF (0.50 mL) was added piperidine (0.50 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with 5% MeOH to 25% MeOH in DCM to afford (7S,14S,18S)-tri-tert-butyl 7-amino-1-(1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (59 mg, 86%). 1H NMR (400 MHz, 6.96 (d, J=0.8 Hz, 2H), 6.85 (d, J=0.8 Hz, 2H), 5.55 (brs, 1H), 5.43 (brs, 1H), 4.59 (s, 4H), 4.37-4.28 (m, 2H), 3.61 (s, 4H), 3.35-3.27 (m, 2H), 3.18-3.12 (m, 1H), 2.53 (t, J=7.4 Hz, 2H), 2.34-2.28 (m, 2H), 2.10-2.00 (m, 2H), 1.85-1.26 (m, 55H); MS (ESI), 503.0 (M/2+H)+.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.P(OCCCC)(OCCCC)OCCCC>>[CH3:19][C:15]1[CH:14]=[C:13]([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(N)c1
Reactant: Oc1cccc2ccccc12
Agent: CCCCOP(OCCCC)OCCCC
Product: Cc1cccc(Nc2cccc3ccccc23)c1
Yield: 88 %

Procedure:
216 parts of α-naphthol, 214 parts of m-toluidine and 10 parts of tributyl phosphite are mixed. The reaction is carried out using the method described in Example 17. After removing 24 parts of water, the reaction has ended. After distilling off excess m-toluidine 309 parts of N-m-tolyl-α-naphthylamine, corresponding to a yield of 88% of theory, are obtained at a boiling point of 203° - 206° C/5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CCO>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH2:17][N:18]5[C:19](=[O:28])[C:20]6[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:26]5=[O:27])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:30]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: OCCCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1

Procedure:
A mixture of 2-[1-(3-bromophenyl)-1H-benzimidazol-5-ylmethyl]-isoindole-1,3-dione (1.10 g, 2.54 mmol), 3-pyridineboronic acid (0.47 g, 3.82 mmol), potassium carbonate (1.06 g, 7.63 mmol), 1,3-propanediol (0.92 ml, 12.72 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g) in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred at reflux in a nitrogen atmosphere for 20 min. The resultant mixture was cooled and volatile material was removed in vacuo. The product precipitated from the residual solvent and was filtered off, washed with water and dried in the air to afford 0.56 g.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1
Reactant: c1ccc(-c2cc(OCC3CO3)no2)cc1
Reactant: C1COCCN1
Solvent: CCO
Product: OC(COc1cc(-c2ccccc2)on1)CN1CCOCC1
Yield: 89.2 %

Procedure:
To a solution of 40.0 g of 3-(2,3-epoxypropoxy)-5-phenylisoxazole dissolved in ethanol (400 ml) was added 17.6 g of morpholine and the mixture was refluxed by heating for 5 hours, followed by concentration under reduced pressure. The resulting solid was recrystallized from ethyl acetate to afford 50.0 g of the title compound with melting point 123°-124° C. as colorless columns.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[NH:33]N>>[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cccc(NN)c1C
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: Cc1cccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)c1C

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (2,3-dimethyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=421.3 (M+H)+
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:4][CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)NCc1ccnc(Br)c1
Temperature: 25 °C

Procedure:
After a mixture of isopropylamine (2.8 mL), 2-bromopyridine-4-carboxaldehyde (3.00 g), and chloroform (60 mL) was stirred at room temperature, sodium triacetoxyborohydride (10.00 g) was added thereto and the mixture was stirred for 21 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was then stirred for a while and extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=88:12-0:100) and (NH silica gel cartridge, hexane:ethyl acetate=90:10-0:100) to afford the title compound (2.64 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[CH2:8][CH2:9][O:10][CH3:11].[H-].[Na+]>CN(C=O)C.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:11][O:10][CH2:9][CH2:8][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCn1ccnc1C
Temperature: 80 °C
Yield: 66.1 %

Procedure:
To a solution of 2-methyl-1H-imidazole (1.0 g, 12.2 mmol) and 1-chloro-2-methoxyethane (1.34 ml, 14.62 mmol) in DMF (15 ml) was added sodium hydride (0.49 g, 12.2 mmol). The reaction mixture was heated to 80° C. for 18 hrs. The reaction mixture was transferred to a microwave vial and heated to 80° C. under microwave conditions for 1 hr. The reaction mixture was diluted with DCM (40 ml) and aq. 2M Na2CO3 (30 ml) and water (40 ml). The aqueous layer was re-extracted with DCM several times. The residue was purified by reverse phase chromatography (C18, 100% water) to afford the title compound (1.13 g, 66%).