Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:13]([O:15]CC)=O.Cl.[NH2:19][C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=1B(O)O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[O:15]=[C:13]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[C:21]2[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:20]=2[NH:19]1
Reactant: N#Cc1ccc(B(O)O)c(N)c1
Reactant: CCOC(=O)c1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Product: N#Cc1ccc2c(c1)[nH]c(=O)c1ccncc12
Temperature: 120 °C
Yield: 78.4 %

Procedure:
Sodium acetate (410 mg, 5 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (complexed with dichloromethane) (36 mg, 0.05 mmol) were added to a mixture of ethyl 3-bromo-4-pyridine carboxylate (230 mg, 1.0 mmol) and 2-amino-4-cyanophenylboronic acid hydrochloric acid salt (179 mg, 0.9 mmol). The mixture was connected to an exit bubbler and heated to 120° C. for 18 hours at which time LCMS analysis indicated that the reaction was done based on the disappearance of starting material. After cooling to room temperature, water was added and the dark solids were filtered and washed with dichloromethane to give 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carbonitrile (156 mg) as a gray solid which was sufficiently pure enough for subsequent chemical transformations. LCMS (ESI) 222.4 (M+1)+. 1HNMR (400 MHz, DMSO-d6) 12.2 (1H, s), 9.96 (1H, s), 8.90 (1H, d, 5.1 Hz), 8.77 (1H, d, 8.2 Hz), 8.13 (1H, d, 5.1 Hz), 7.73 (1H, dd 8.2, 1.6 Hz), 7.70 (1H, d, 1.6 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[C:13]([F:28])[CH:12]=2)[CH:7]=1)=[O:5])C.C1(NC(=O)NC2C=CC(C3C=C(C(O)=O)ON=3)=CC=2)C=CC=CC=1>>[F:28][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=2)[CH:16]=[CH:15][C:14]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:19]
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)c(F)c2)no1
Agent: O=C(Nc1ccccc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1F
Yield: 89 %

Procedure:
The title compound was prepared from 3-{3-fluoro-4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carboxylic acid ethyl ester by using the procedure as described for the preparation of 3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid (Example 76, step 2) and was obtained in 89% yield; MS (m/z): 360 (M++1); 1H NMR (DMSO-d6) δ: 7.13 (t, 2H), 7.46 (m, 2H), 7.76 (m, 2H), 7.84 (m, 1H), 8.32 (t, 1H), 8.78, 9.18 (2×s, 2H, 2×NH).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:22]([O-])(O)=O.[Na+]>CO>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH3:22])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 2,2-diphenylacetic acid (1 gram, 1 equiv) in dry MeOH (50 mL) was added sulfuric acid (0.4 mL) dropwise and heated to reflux. Stirring was then continued for 3 hours. The reaction mixture was then cooled and poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil (1.0 g, 93%) that was not further purified.
Reaction SMILES: C1O[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=2)([CH3:5])[O:3]C1.C(O)(=O)C.O.[OH-].[Na+]>CO>[C:14]([NH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][CH:8]=1)([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C2(C)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
125 g of N-BOC-p-aminomethylacetophenone ethylene ketal are heated for 15 minutes at 65° in 250 ml of methanol and 250 ml of acetic acid as well as 50 ml of water. The reaction mixture is cooled to 0°, adjusted to a pH of 10 with 10N aqueous NaOH, extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. The crude product obtained after drying and concentrating by evaporation is crystallised from hexane. N-BOC-p-aminomethylacetophenone having a melting point of 73°-75° is obtained. IR: 3420, 1707, 1680, 1607, 1500 cm-1 (CH2Cl2). UV: 250 nm (15700) in C2H5OH.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:24][OH:25])=[CH:17][CH:16]=1
Reactant: NO
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
In to a solution of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde (6.5 g, 22.2 mmol) in ethanol (300 mL) were added hydroxylamine hydrochloride (4.62 g, 66.55 mmol) and a solution of sodium acetate (7.27 g, 82.7 mmol) in H2O (40 mL). The mixture was stirred at room temperature for 12 h, then poured into H2O, acidified with 1N HCl and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane, gave a white solid (6.1 g, 89% yield, m.p. 192°-193° C.). Analysis for: C18H16N2O3Calc'd: C, 70.12; H, 5.23; N, 9.09 Found: C, 70.31; H, 5.27; N, 8.82
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].C(N(C(C)C)CC)(C)C.[Br:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[C:8]([C:7]1[CH:6]=[C:5]([CH:12]=[CH:11][CH:10]=1)[O:4][CH2:3][CH2:2][NH:1][C:24](=[O:25])[CH2:23][Br:22])#[N:9]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: O=C(Cl)CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OCCNC(=O)CBr)c1
Reaction time: 8 h

Procedure:
1.50 g (9.26 mmol) of 3-(2-aminoethoxy)benzonitrile and 1.77 ml (10.2 mmol) of diisopropylethylamine were dissolved in 15 ml of tetrahydrofuran. A solution of 0.92 ml (11.1 mmol) of bromoacetyl chloride in 5 ml of tetrahydrofuran was added to the obtained solution at 0° C., and they were stirred for 8 hours. The solvent was evaporated, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[CH:7]([OH:9])[CH3:8].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH:7]([C:6]2[O:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])=[CH:27][C:26]=1[CH3:32]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.15 g, 0.553 mmol) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.12 g, 0.610 mmol) are stirred in 10 mL toluene at 0° C. under a nitrogen atmosphere. Tri-n-butylphosphine (0.21 mL, 0.83 mmol) is added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.21 g, 0.83 mmol). The mixture is allowed to stir at room temperature for 20 hr. The resulting slurry is concentrated under reduced pressure. 50 mL of a 1:1 solution of ethyl acetate:hexanes is added, and the slurry is filtered. The resulting solution is concentrated and purified by silica gel chromatography eluting with a mixture of 8:2 hexanes:ethyl acetate yielding 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic acid methyl ester as a white solid, 0.176 g (71%). MS (M++1) 446.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][NH:4]1.[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16]>CN(C)C=O>[C:18]([CH2:19][N:5]1[NH:4][C:3](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13])([O:17][CH2:15][CH3:16])=[O:21]
Reactant: O=c1[nH][nH]c(=O)c2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1[nH]c(=O)c2ccccc2c1=O
Yield: 10 %

Procedure:
A mixture of sodium hydride (0.05 g; 0.01 mol; 50% suspension in mineral oil); 2,3-dihydrophthalazine-1,4-dione (1.6 g; 0.01 mol); and ethylbromoacetate (excess) in anhydrous dimethylformamide (50 ml) was refluxed for 24 hours. The dimethylformamide solvent was then evaporated affording a gummy material. This gummy material was purified over column silica gel using chloroform: ethyl acetate (1:1) to obtain the product, 2-(1'-carbethoxymethyl)-2,3-dihydrophthalazine-1,4-dione.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH:28]3[C:33](=[O:34])[C:32]([CH3:36])([CH3:35])[O:31][C:30]([CH3:38])([CH3:37])[C:29]3=[O:39])[CH:21]=2)=[CH:16][CH:15]=1.N([O-])=O.[Na+].[I-:44].[K+].C(=O)(O)[O-].[Na+]>C(#N)C.O.C(OCC)(=O)C>[I:44][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[C:22]([CH:28]3[C:33](=[O:34])[C:32]([CH3:36])([CH3:35])[O:31][C:30]([CH3:38])([CH3:37])[C:29]3=[O:39])[CH:21]=2)=[CH:16][CH:15]=1
Reactant: CCc1ccc(-c2ccc(N)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCc1ccc(-c2ccc(I)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
To a solution of para-toluenesulfonic acid monohydrate (1.03 g, 5.40 mmol) in acetonitrile (11 ml) is added 4-(4′-amino-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-pyran-3,5-dione (0.65 g, 1.80 mmol), followed by stirring for 10 minutes at room temperature then cooling to 10° C. To this mixture is then added a second mixed solution of sodium nitrite (0.25 g, 3.60 mmol) and potassium iodide (0.76 g, 4.50 mmol) in distilled water (1.3 ml), and the mixture is then stirred at 10° C. for 20 minutes then at room temperature for 2 hours. Aqueous sodium bicarbonate solution is added until pH 9-10 is achieved, followed by dilution with ethyl acetate and washing with saturated aqueous sodium metabisulfite (20 ml). After additional extraction of the aqueous phase using ethyl acetate (×2) all organic fractions are combined, washed with distilled water and brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo. This crude product is purified by flash column chromatography on silica gel (hexane/ethyl acetate 3:1 ratio) to yield an orange gum, which is triturated with hexanes to afford 4-(4′-iodo-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.413 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCN(C)C)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCN(C)C)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[(2-dimethylamino-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH2:42]([N:44]=[C:45]=NCCCN(C)C)C.CNC>CN(C)C=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:44]([CH3:45])[CH3:42])=[O:22])=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(=O)O)cc1C
Agent: CNC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(=O)N(C)C)cc1C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 4-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-3-methylbenzoic acid (330 mg, 0.775 mmol) in N,N-dimethylformamide (4.0 mL) were added 1-hydroxy-1H-benzotriazole (155 mg, 1.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.853 mmol), and dimethylamine (2.0 M solution in tetrahydrofuran, 0.78 mL, 1.56 mmol). The mixture was stirred at room temperature for 11 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The trifluoroacetic acid salt was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethanol/diisopropyl ether to give the title compound as a colorless crystal (88.8 mg, 0.196 mmol, 25%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH:12]=O)=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH2:19][CH2:18][CH2:17]3)[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:24])[N:3]=1.[C:25](=O)([O-])[O-].[Cs+].[Cs+].[Si](C=[N+]=[N-])(C)(C)C>CO>[O:20]1[C:21]2[C:16](=[CH:15][C:14]([C:10]3[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:24])[N:3]=[C:2]4[NH:1][CH:25]=[CH:12][C:11]=34)=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1c(C)nc(N)c(C=O)c1-c1ccc2c(c1)CCCO2
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cs+]
Solvent: CO
Product: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Temperature: 55 °C
Yield: 96.7 %

Procedure:
A mixture of methyl 6-amino-4-(chroman-6-yl)-5-formyl-2-methylnicotinate (4.5 g, 13.79 mmol) and cesium carbonate (8.99 g, 27.6 mmol) in methanol (180 mL) was heated to 55° C. and then treated with TMSCHN2, 2.0 M solution in hexanes (27.6 mL, 55.2 mmol). The mixture was heated to 60° C. for several minutes until LCMS and TLC showed the reaction was complete. The mixture was cooled in an ice-bath and then quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude product (4.3 g, 13.34 mmol, 97% yield) as a pale yellow solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 (br. s., 1 H), 7.28-7.21 (m, 2 H), 6.93-6.87 (m, 1 H), 6.48 (d, J=2.9 Hz, 1 H), 4.30-4.25 (m, 2 H), 3.72-3.68 (m, 3 H), 2.90-2.83 (m, 2 H), 2.74 (s, 3 H), 2.12-2.05 (m, 2 H); LC/MS (m/z) ES+=323.24 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[N+:14]([C:6]1[C:5]2[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:13])[C:3]=3[CH:12]=[CH:11][CH:10]=2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2cccc3cccc1c23
Solvent: CC(=O)O
Product: O=C1Nc2ccc([N+](=O)[O-])c3cccc1c23
Temperature: 25 °C
Yield: 51.8 %

Procedure:
To a mixture of 33.9 g (0.200 mol) benz[cd]indol-2(1H)-one in 150 ml glacial acetic acid was added dropwise 16.5 ml (0.260 mol) nitric acid. At first, there was a very minor exotherm and then, over the course of one hour, the reaction temperature rose to 50° C. The reaction mixture was gradually cooled to room temperature with a cold water bath. A thick dark green paste resulted. This mixture was filtered, washed with 50% aqueous acetic acid, and pulled as dry as possible. The resulting wet filter cake was refluxed in 600 ml methanol and then cooled to 0° C. The mixture was filtered, washed with cold methanol and dried in vacuo to yield 22.2 g (51% theory) of 6-nitrobenz[cd]indol-2(1H)-one. TLC (CHCl3 :MeOH 95:5) showed the product to be essentially one spot material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:17][CH:18]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>C([O-])([O-])=O.[Na+].[Na+].CCO.C1(C)C=CC=CC=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>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=C(c1cccc(CNCCNc2ccccc2Br)c1)N1CCCCC1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccccc1-c1ccccc1NCCNCc1cccc(C(=O)N2CCCCC2)c1
Yield: 31.6 %

Procedure:
To a solution of (3-{[2-(2-bromo-phenylamino)-ethylamino]-methyl}-phenyl)piperidin-1-yl-methanone (Example 17; 0.051 g, 0.12 mmol) and 2-methoxybenzeneboronic acid (0.037 g, 0.25 mmol) in 2 M Na2CO3/EtOH/toluene (1:1:4, 6 mL) was added Pd(PPh3)4 (0.014 g, 0.012 mmol), and the resulting solution was stirred at reflux for 16 h. The solution was partitioned with EtOAc (20 mL) and satd aqueous NaHCO3 (20 mL), and the aqueous layer was back-extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (10% CH3OH/CH2Cl2) to provide a tan oil (0.0168 g, 28%). MS (ESI): mass calculated for C28H33N3O2, 443.26; m/z found, 444.2 [M+H]+, 466.2 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.38-7.22 (m, 7H), 7.08-6.97 (m, 3H), 6.78-6.72 (br s, 2H), 4.15 (br s, 1H), 3.69-3.76 (br m, 4H), 3.68 (s, 3H), 3.29-3.24 (br m, 4H), 2.86-2.76 (m, 2H), 1.75-1.49 (br m, 8H). 13C NMR (100 MHz, CDCl3): 170.2, 156.8, 145.8, 140.4, 136.5, 131.9, 130.7, 129.0, 128.9, 128.6, 128.4, 128.0, 126.4, 125.3, 124.9, 121.1, 116.8, 111.2, 110.5, 55.6, 53.2, 48.7, 47.8, 43.5, 43.6, 26.5, 25.6, 24.5.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[C:11]([OH:13])=O.[CH:14]([NH2:16])=O>>[NH:8]1[C:9]2[C:5]([CH:4]=[C:3]3[C:2]([CH:10]=2)=[N:1][CH:14]=[N:16][C:11]3=[O:13])=[CH:6][NH:7]1
Reactant: Nc1cc2[nH]ncc2cc1C(=O)O
Reactant: NC=O
Product: O=c1ncnc2cc3[nH][nH]cc3cc12
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
450 mg (2.5 m-mol) of 6-amino-indazole-5-carboxylic acid (formula 20, prepared according to Example XIII) in 3 ml of formamide were heat-melted and kept at a temperature of 140° during a period of 4.5 hours and then at a temperature of 180° during another period of 1.5 hours. The mass obtained was cooled to room temperature. The product was filtered under suction, washed well with water until the filtrate became clear, and then washed with a small amount of ethanol. The target product (formula 3) was recovered in an amount of 167 mg (36%) in the form of a greyish-brown, finely crystalline material, m.p. 330°. The product was uniform as evidenced by chromatography; pmr (DMSO-d6): δ 7.78, 8.10, 8.44, 8.76 (4 broad s, 4, H3, H4, H7, H9), 11.92, 13.36 (2 with D2O exchangeable broad m, 2, N1H, N6H), (DMSO-d 6 /D2O): δ 7.83, 8.10, 8.45, 8.78 (4 sharp s, 4, H3, H4, H7, H9); ms (70 eV): m/e 186 (100%, M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=1[F:23])[O:24][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]
Reactant: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(O)c2F)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 3-[(2,3-dimethyl-5-phenyl-phenyl)methylamino]-2,4-difluoro-phenol (120 mg, 0.4 mmol, 1.0 eq) in acetone (4 mL) was added Cs2CO3 (173 mg, 0.5 mmol, 1.5 eq) and the reaction was stirred at room temperature for 30 min. Isopropyl bromoacetate (76 mg, 0.42 mmol, 1.2 eq) was added and the reaction was stirred at room temperature for 1 h. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a colorless oil (117 mg, 75%).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([CH2:19][N:20]([CH3:22])[CH3:21])[N:10]=1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[C:15]([C:13]1[CH:12]=[C:11]([CH2:19][N:20]([CH3:22])[CH3:21])[N:10]=[C:9]([NH2:8])[CH:14]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)cc(NCc2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(C)Cc1cc(C(C)(C)C)cc(N)n1
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
Add concentrated sulfuric acid (20 mL) to benzyl-(4-tert-butyl-6-dimethylaminomethyl-pyridin-2-yl)-amine (0.88 g, 2.96 mmol) at ambient temperature and stir for 1.5 hours. Adjust the pH of the aqueous solution carefully with saturated sodium bicarbonate solution. Extract the aqueous phase with ethyl acetate (3×75 mL) and pool, desiccate, filter and concentrate to a residue. Dissolve the residue in methanol and subject the material to SCX chromatography. Concentrate the methanolic ammonia eluent and plug chromatograph the amine to provide the title compound (0.56 g, 2.7 mmol). MS(ES), m/z 208 (M+1).