Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])[CH:13]=[CH2:14]
Reactant: C=CCOC(=O)Cc1cccc(O)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OCC)c1
Temperature: 80 °C
Reaction time: 60 h

Procedure:
Allyl 3-hydroxyphenylacetate (5.72 g, 32.9 mmol), potassium carbonate (6.82 g, 49.35 mmol), and ethyl 2-bromoisobutyrate (7.35 mL, 49.35 mmol) were dissolved in dimethylformamide (10 mL), and the mixture was stirred for 60 hours at 80° C. The reaction mixture was added to water, and the resultant mixture was extracted with diethyl ether, followed by washing sequentially with water and saturated brine, drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (6.40 g, 20.90 mmol, 63.5%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2nccc(Cl)c2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A solution of 4.99 g (18.1 mmol) of 4-chloro-6-methoxyquinoline and 50 mL of 48% hydrobromic acid is heated under reflux for seven hours. Upon cooling to room temperature, the reaction solution afforded a dark solid that was then slurried in water. The aqueous mixture was adjusted to pH 10 by the addition of 4N sodium hydroxide. The resulting solid was filtered, washed with water and air-dried to give 1.83 g (56%) of 4-chloroquinolin-6-ol: m.p. 223° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.O[CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Diethyl azodicarboxylate (218 mg, 1.25 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (159 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), 4-hydroxy-1-methylpiperidine (115 mg, 1 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in methylene chloride (5 ml) cooled at 5° C. under nitrogen. The mixture was stirred for 1 hour at ambient temperature, the solvent was removed by evaporation and the residue was partitioned between 2M hydrochloric acid and ether. The aqueous layer was separated, adjusted to pH9 with aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The methylene chloride layer was washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified on neutral alumina eluting with- methylene chloride/methanol (97/3). The purified product was triturated with ether, collected by filtration and dried to give 4-(4chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-yloxy)quinazoline (180 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1>C(#N)C>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:7]=[C:6]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][C:3]=2[N:16]2[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][CH2:21]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)c3ccccc3)cc2N)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)c3ccccc3)cc2NC(=O)c2nc(Br)cnc2N)CC1
Yield: 46 %

Procedure:
Following method 11, tert-butyl 1-(2-amino-4-benzoylphenyl)piperidin-4-ylcarbamate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (1.5 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 1-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-benzoylphenyl)piperidin-4-ylcarbamate (46%). LCMS (m/z): 595.2 (MH+); LC Rt=3.94 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:14][C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.Cl.[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[S:14][C:7]5[C:8](=[O:13])[NH:9][CH2:10][CH2:11][CH2:12][C:6]=5[CH:5]=4)[CH2:28][CH2:29]3)=[N:22][O:23][C:19]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1NCCCc2cc(CCCl)sc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1NCCCc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)sc21
Temperature: 90 °C
Reaction time: 22 h
Yield: 45.1 %

Procedure:
A mixture of 800 mg of 2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, 920 mg of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 1.45 g of potassium carbonate and 580 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel and recrystallized from ethyl acetate to give 0.65 g of 2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, m.p. 192°-194° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][C:21]=1[F:22].S(Cl)(Cl)=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([CH3:28])([CH3:27])[C:24]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:25])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(F)c(Cl)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Diethyl malonate (5.68 mL, 37.6 mmol) was dissolved in ACN (75 mL) at 0° C. MgCl2 (3.93 g, 41.3 mmol) was added to the reaction mixture in one portion and TEA (10.5 mL, 75.1 mmol) was added dropwise. 2-(3-chloro-4-fluorophenyl)-2-methylpropanoic acid (7.73 g, 35.7 mmol) was converted to the acid chloride by reaction with thionyl chloride at 65° C. for 1 hour, and the resulting acid chloride was concentrated under reduced pressure. The acid chloride was then dissolved in ACN and added dropwise via addition funnel to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then quenched with water, acidified with 5N HCl, diluted with 100 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with water (2×50 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (7.17 g) as a light yellow oil after flash chromatography. MS m/e=359 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][CH2:42][CH2:43][O:44][C:45]([CH3:66])([CH3:65])[CH2:46][N:47]1[C:59]2[C:58]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N:52]=[C:51]([NH2:60])[C:50]=2[N:49]=[C:48]1[CH2:61][O:62][CH2:63][CH3:64]>CN(C=O)C>[NH2:60][C:51]1[C:50]2[N:49]=[C:48]([CH2:61][O:62][CH2:63][CH3:64])[N:47]([CH2:46][C:45]([CH3:66])([O:44][CH2:43][CH2:42][NH:41][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH3:65])[C:59]=2[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[N:52]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Nicotinic acid (11.4 mg, 92.3 μmol) was combined with DMF (1.0 mL) to give a colorless solution. To this solution was added TBTU (29.6 mg, 92.3 μmol), and DIEA (54.2 mg, 71.8 μl) were added. Finally 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (30 mg, 83.9 μmol) was added and the reaction mixture was stirred for 1 hour at room temperature. Volatiles were removed in high vacuum at 40° C. The residue was dissolve in a mixture of ethyl acetate (5 mL) and methanol (0.5 mL). 1N sodium hydroxide solution (1.5 mL) was added and after a few minutes stirring the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic phases were combined dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 10% methanol in DCM) to give the title product (33 mg, 85%) as white foam; LC-MS (UV peak area, ESI) 88%, 463.2459 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:10]=1[C:11](O)=[O:12])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:28])=O>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:10]=1[C:11]([Cl:28])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCc1ccc(C#N)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOC(=O)OCc1ccc(C#N)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[(Allyloxycarbonyl)oxymethyl]-5-cyanobenzoic acid (1.6 g, 6.12 mmol) obtained from Example 33-(2) was dissolved in dichloromethane (40 ml), and N,N-dimethylformamide (0.05 ml) and oxalyl chloride (2 g) were added thereto. The mixture was stirred at room temperature for 1 hour, then diluted with toluene, and the solvent was distilled off under reduced pressure to give crude 2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoyl chloride.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[Br:16][CH:3]([C:2](=[O:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)CCCC(=O)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)CCC(Br)C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of methyl 5-oxo-5-phenylpentanoate (16.1 g) in diethyl ether (100 ml) was added bromine (4.01 ml) at room temperature over 30 min. and the mixture was stirred for 30 min. An aqueous sodium sulfite solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine, dried (MgSO4) and concentrated to give methyl 4-bromo-5-oxo-5-phenylpentanoate (22.1 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:16]=[C:17]([NH2:22])[N:18]=[C:19]([NH:21][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:20]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)c1
Reaction time: 0.67 h
Yield: 33.3 %

Procedure:
To a mixture of 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt (90 mg, 0.25 mmol), 4-chloro-phenylboronic acid (45 mg, 0.29 mmol), copper (II) acetate (218 mg, 1.2 mmol), 4A molecular sieves (5 g) in dichloromethane (20 ml) was added triethylamine (0.3 ml). The mixture was stirred under an oxygen atmosphere for 40 minutes and filtered through a pad of celite under suction. After evaporation of volatiles under reduced pressure, the residue was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (3:5 followed by 1:1 followed by 5:3) to provide the title compound (30 mg, 33% yield). 1H NMR (acetone-d6) δ 3.84 (s, 3H, CH3), 5.33 (d, 2H, J=8.8 Hz, NH2), 6.16 (d, 1H, J=1.1 Hz, Ar), 6.27 (t, 1H, J=1.1 Hz, Ar), 7.12 (d, 1H, J=8.8 Hz, Ar), 7.23 (d, 2H, J=8.9 Hz, Ar), 7.30 (d, 1H, J=2.7 Hz, Ar), 7.36 (dd, 1H, J=8.8 Hz, J=2.7 Hz, Ar), 7.76-7.79 (m, 2H, Ar), 8.05 (s, 1H,
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:30][CH2:29][O:28][CH3:27])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: COCCCl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 0.15 mmol), potassium carbonate (42 mg, 0.30 mmol) and 2-chloroethyl methyl ether (83 μL, 0.91 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 1:1:2 followed by trituration with diethyl ether afforded 24 mg (50%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.45 (s, 1H), 4.27 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH3:10].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[CH3:10][C:6]1[N:5]([CH2:4][CH2:3][OH:2])[CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)Cn1ccnc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Cc1nccn1CCO
Reaction time: 1 h

Procedure:
A solution of (2-methyl-imidazol-1-yl)-acetic acid methyl ester (2.6 g) in diethyl ether (39 ml) is added drop wise to a suspension of LiAlH4 (1.3 g) in 130 ml diethyl ether (130 ml) at 0° C. After 1 hour 1.3 g water, 1.3 g 15% NaOH and 4 g water is added and the slurry stirred for 1 hour. After addition of MgSO4 and filtration the filter cake is washed several times with hot ethyl acetate. After removal of the solvent, the crude product is used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>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>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
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: CCO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 77 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of 4-formyl-phenylboronic acid (5.0 g, 33.0 mmol) and 2-bromopyridine (5.53 g, 35.0 mmol, 1.05 equiv.) in 265 mL of 4:3 toluene/95% ethanol was degassed with nitrogen for 30 minutes and then heated under a nitrogen atmosphere, resulting in a clear solution. A slurry of Pd(PPh3)4 (0.77 g) in 50 mL of a 4:4 mixture of toluene and 95% ethanol was added, followed by 50 mL of 3M aqueous Na2CO3. The resulting mixture was gently refluxed at 77° C. After 16 hours, the reaction mixture was cooled to room temperature, and the solid removed by filtration. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was extracted with toluene (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and dried over sodium sulfate. The solution was filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. Purification by Biotage chromatography (40+M cartridge; gradient, 0 to 5% methanol/dichloromethane) gave 4.13 g (68%) of (3) as a light-yellow solid. TLC Rf (hexane/ethyl acetate, 2:1)=0.25; 1H NMR (CDCl3) δ 10.1 (s, HCO), 8.77 (d, 1H), 8.20 (d, 2H), 8.00 (d, 2H), 7.81 (m, 2H), 7.31 (q, 1H); MS (M)+=184; HPLC tR 1.2 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:34]=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH3:34])[C:10]2=[N:23][C:24]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NCc2ccc(OC)cc2)C1
Reactant: C=O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(N(C)Cc2ccc(OC)cc2)C1

Procedure:
By analogy with the method described in example 12 using 9-(4-methoxy-benzylamino)-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 9) in place of 9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester and formaldehyde (37%) in place of benzaldehyde, the compound was obtained as a solid oil. The compound was used as such in the next step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1.[CH3:10][C@@H:11]([CH2:30][CH3:31])[C@H:12]([NH:17][C:18]([O:20]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:10][C@@H:11]([CH2:30][CH3:31])[C@H:12]([NH:17][C:18]([N:2]([CH3:1])[CH2:3][C:4]1[N:5]=[C:6]([CH3:9])[S:7][CH:8]=1)=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC[C@H](C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: CNCc1csc(C)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)OC
Yield: 0.1 %

Procedure:
A solution containing the product from Example 109B (0.200 g, 1.4 mmol) in THF (6 mL) was treated with the product from Example 109C (0.415 g, 1.4 mmol), triethylamine (0.196 mL, 1.4 mmol), and DMAP (0.020 g, 0.16 mmol) at 25° C., stirred at reflux for 1 hour, cooled and concentrated. The residue was partitioned between ethyl acetate and 5% K2CO3. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated to give the title compound (0.38 mg, 86% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13](=[O:15])[CH3:14])=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Product: CC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: -35 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Treat a −35° C. solution of fuming nitric acid (32.3 mL, 723 mmol) with 4-fluorophenylacetone (1.756 ml, 13.14 mmol) and stir at −35° C. for 1 h. Pour the mixture onto ice, extract with DCM (2×), dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (1.07 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 7.97 (dd, J=7.4, 2.2 Hz, 1H), 7.58 (ddd, J=8.6, 4.6, 2.2 Hz, 1H), 7.52 (dd, J=11.3, 8.6 Hz, 1H), 3.95 (s, 2H), 2.17 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13](Cl)=[O:14])[CH3:11])([O-:3])=[O:2].[CH:16]([NH:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]([N:19]([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])=[O:14])[CH3:11])([O-:3])=[O:2]
Reactant: CC(C)NC(C)C
Reactant: CC(OC(=O)Cl)c1ccccc1[N+](=O)[O-]
Product: CC(OC(=O)N(C(C)C)C(C)C)c1ccccc1[N+](=O)[O-]
Yield: 57 %

Procedure:
1-(2-Nitrophenyl)-1-ethoxycarbonyl chloride (XIV; R3=H, R4=CH3; 1.4 g; 6 mmol) was dissolved in diisopropylamine (30 ml) under an inert atmosphere and the solution was refluxed for 48 hr. The resulting diisopropylammonium chloride was filtered off and excess of diisopropylamine was removed by evaporation under vacuum to give an oil, which was purified by flash chromatography on silica, eluting with dichloromethane to afford the required compound as a colourless solid. Recrystallization from toluene-petroleum ether (bp 60-80° C.) 2:1 gave colourless crystals (1.0 g; 57% yield), mp 40-41° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:9]=2[NH:8][C:7](=[O:19])[CH2:6]1)C.Cl.[C:21]([NH2:26])(=[NH:25])[CH2:22][CH2:23][CH3:24]>>[CH3:17][C:15]1[C:14]([CH3:18])=[CH:13][C:10]2[C:11]3[N:26]=[C:21]([CH2:22][CH2:23][CH3:24])[N:25]=[CH:4][C:5]=3[CH2:6][C:7](=[O:19])[NH:8][C:9]=2[CH:16]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(=CN(C)C)CC(=O)N2
Reactant: CCCC(=N)N
Agent: Cl
Product: CCCc1ncc2c(n1)-c1cc(C)c(C)cc1NC(=O)C2
Yield: 67 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7,8-dimethyl-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 67%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:15][CH:14]3[CH2:16][N:10]4[CH2:11][CH:12]([CH2:17][CH:8]2[CH2:9]4)[CH2:13]3)=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:15][CH:14]4[CH2:16][N:10]5[CH2:11][CH:12]([CH2:17][CH:8]3[CH2:9]5)[CH2:13]4)=[N:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: Brc1cnc(N2CC3CC4CC2CN(C4)C3)s1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cnc(N3CC4CC5CC3CN(C5)C4)s2)cc1

Procedure:
The title compound was prepared from the product of Example 105A and 4-methoxyphenylboronic acid according to General Method C: 1H NMR (500 MHz, CDCl3) δ ppm 7.35 (d, 2 H), 7.28 (s, 1 H), 6.88 (d, 2 H), 4.75-4.71 (m, 1 H), 3.64-3.59 (q, 2 H), 3.48-3.40 (q, 2 H), 3.08-3.05 (m, 4 H), 2.29-2.18 (m, 3 H), 1.88-1.80 (m, 3 H); LC-MS Method D (ESI+) m/z 342.0 (M+H)+, retention time 1.44 minutes.