Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (13.9 g) obtained in Example 2 was suspended in dimethyl sulfoxide (500 ml), and to the suspension was added potassium carbonate (9.5 g), and the mixture was stirred at room temperature for 30 minutes. Ethyl bromoacetate (4.2 ml) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml) and precipitated crystals were recovered by filtration. The thus obtained crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol), and the crude product was re-precipitated from chloroform-hexane and recovered by filtration to obtain the title compound (9.0 g, 53%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH2:30]P(=O)(OCC)OCC)=[N:27]2)=[CH:22][CH:21]=1.C=O>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([CH:30]=[CH2:1])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOP(=O)(Cc1ccc2ccc(Cl)cc2n1)OCC
Reactant: CC(C)NC(C)C
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=Cc1ccc2ccc(Cl)cc2n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
A stirred solution of diisopropylamine (2.24 ml, 15.97 mmol) in tetrahydrofuran (15.0 ml) at -10° C. under nitrogen was treated dropwise with a 2.5 M solution of n-butyllithium in hexane (6.4 ml, 15.97 mmol). After stirring below 0° C. for 30 min the pale yellow solution was cooled to -20° C. and a solution of diethyl 7-chloro-2-quinolylmethylphosphonate (5.0 g, 15.97 mmol) in tetrahydrofuran was added dropwise. The resulting dark green solution was stirred below 0° C. for 1 h, cooled to -10° C. and treated with paraformaldehyde (0.53 g, 17.57 mmol) in portions. Stirred cold for 15 min after which the cooling bath was removed and the mixture was stirred at 25° C. for 90 min. Quenched with brine (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (3×200 ml), dried (Na2SO4) and the solvent was removed in vacuo to give a dark brown solid. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:19) provided the title compound (1.80 g, 59%) as pale yellow crystals. Crystallised from ethyl acetate and light petroleum (b.p. 40-60° C.) as cream crystals, m.p. 79.7-80° C. (Found: C, 69.84; H, 4.15; N; 7.25; Cl, 18.91. C11H8ClN requires C, 69.67; H, 4.25; N, 7.39; Cl, 18.69%); Vmax (nujol)/cm-1 1628, 1609; δH (270 MHz) 5.67 (1H, dd, 2'-H, 3J2',1' =10.89, 2J2',2' =1.0 Hz); 6.29 (1H, dd, 2"-H, 3J2",1' =17.7, 2J2",2' =0.8 Hz); 7.02 (1H, dd, 1'-H, 3J1',2' =17.5, 3J1',2' =10.9 Hz); 7.42 (1H, dd, 7-H, Jo =8.8, Jm =2.1 Hz); 7.53 (1H, d, 3-H, Jo =8.9 Hz); 7.66 (1H, d, 5-H, Jo =8.9 Hz); 8.03 (1H, d, 4-H, Jo =8.3 Hz); 8.05 (1H, s, 8-H). δC (67.8 MHz) 118.6 (2'-C); 120.5 (3-C); 125.7 (4a-C); 135.3 (7-C); 136.0 (4-C); 137.5 (1'-C); 148.3 (8a-C); 156.9 (2-C). Remaining signals fall in the range 127.1-128.5 ppm; m/z 191.0, 189.0 (33.48, 100, M+), 165.0, 163.0 (21.89, 65.87), 154.0 (5.13), 128.1 (9.14).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCCCO
Product: O=C(NCCCO)c1cc2ccccc2[nH]1
Yield: 80 %

Procedure:
1H Indole-2-carboxylic acid (5.0 g, 31 mmol) and 3-amino-1-propanol (2.2 ml, 40.3 mmol) were coupled according to the procedure of Example 17 to 5.46 g (80% yield) of an off-white solid. MP 152-156° C.; 1H NMR (DMSO-d6): δ 1.6-1.7 (m, CH2),3.31-3.37 (q, CH2), 3.41-3.51 (q, CH2), 4.52 (t, NH), 7.0-7.19 (m, 3 Ar H), 7.40 (d, 1 Ar H), 7.58 (d, 1 Ar H), 8.46 (t, NH), 11.9 (s, NH) Electrospray Mass Spec: m/z 217.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:26][CH2:27]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:26][CH2:27][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CCBr)cc1OC
Product: COc1ccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1OC
Yield: 36 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3,4-dimethoxyphenethyl bromide. Yield: 36%. MS M+H calculated 440.19; found 440.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.26 μM.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>>[N:15]1([CH2:14][CH2:13][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][C:2]2=[NH:10])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: ClCCN1CCOCC1
Reactant: Nc1nc2ccccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Product: N=c1sc2ccccc2n1CCN1CCOCC1
Yield: 25.9 %

Procedure:
Benzothiazol-2-ylamine (1.0 g, 6.6 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.2 g, 6.6 mmol) and triethylamine (2.8 mL, 20 mmol) were heated at 80° C. for 16 hours. The solid was recrystallized from ethyl acetate, collected by filtration, dried under vacuum to provide 0.45 g (26%) of the title compound. MS (DCI/N3) m/z 264 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-acetamidophenol (20.0 g; 132.3 mmol), 2-bromopyridine (41.8 g; 265 mmol), potassium carbonate (28.3 g; 205 mmol) and Cu° (4.2 g; 66 mmol) in 130 mL pyridine was heated at reflux for 2 days. The reaction was cooled to ambient temperature and filtered through celite. The filtrate was diluted with ethyl acetate and washed with water. The extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The material was partially purified by flash chromatography (3% methanol in dichloromethane) and then recrystallized from ethyl acetate/hexane to give N-acetyl-4-(pyrid-2-yloxy)aniline.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]Cl)(=[O:3])[CH3:2].[I-:14].[Na+]>CC(C)=O>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][I:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCCOCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OCCOCCOCCI
Yield: 109 %

Procedure:
A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6.23 g) and sodium iodide (22.2 g) in acetone (60 mL) was refluxed for 4 hours. The mixture was further refluxed for 4 hours after adding sodium iodide (11.0 g). The solvent was evaporated off, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with 10% sodium thiosulfate and brine, dried over MgSO4, and evaporated to give 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate as a pale yellow oil (9.74 g).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][C:20]2[N:21]([CH3:25])[N:22]=[CH:23][N:24]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)CCC>O1CCOCC1.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.[Cu]I>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[N:5]2[N:4]=[C:3]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)[C:2]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:10]2[CH:9]=[N:8][N:7]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccccn1
Temperature: 100 °C
Yield: 76.8 %

Procedure:
A mixture of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (81.8 mg, 0.202 mmol) and 2-(tributylstannyl)pyridine (0.1520 g, 0.413 mmol) in anhydrous 1,4-dioxane (8 ml) was degassed using three freeze-pump-thaw cycles. Tetrakis(triphenylphosphine)palladium(0) (32.5 mg, 0.0281 mmol) and copper(I) iodide (4.5 mg, 0.024 mmol) were added and the mixture was further degassed with one freeze-pump-thaw cycle before heating at 100° C. under nitrogen for 18 h. The mixture was filtered through glass fibre paper, washing well with ethyl acetate (25 ml). The filtrate was washed with saturated aqueous NaCl (10 ml), and the aqueous layer was further extracted with ethyl acetate (25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified bar flash chromatography (silica gel, 4% MeOH/CH2Cl2 and silica gel, 0-4% MeOH/EtOAc) to give 62.4 mg (77%) of the title compound as a white solid, mp=186-187° C. (CH2Cl2-EtOAc); 1H NMR (400 MHz, CDCl3) δ 3.79 (3H, s), 5.61 (2H, s), 7.20 (1H, m), 7.29 (1H, t, J=9.4 Hz), 7.40 (1H, td, J=7.6 and 0.8 Hz), 7.64 (1H, mn), 7.73 (1H, td, J=7.8 and 1.8 Hz), 7.80 (1H, m), 7.89 (1H, s), 7.94 (1H, d, J=8.0 Hz), 8.70 (1H, m), 10.30 (1H, s); MS (ES+) m/e 403 [MH]+. Anal. Found C, 59.76; H, 3.65; N, 27.65%. C20H15FN8O requires C, 59.70; H, 3.76; N, 27.85%.
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[Br:21])[CH:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Br:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:4]([CH:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[C:3]2=[O:2]
Reactant: CCCC(CCC)N(CCc1ccc(F)cc1Br)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(Br)cc(F)cc2C1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 96.6 %

Procedure:
540 mg of methyl[2-(2-bromo-4-fluorophenyl)ethyl](1-propylbutyl)carbamate are dissolved under an inert atmosphere in 40 cm3 of dichloromethane at a temperature close to 20° C. 529 mg of 4-dimethylaminopyridine are added to the reaction mixture. The latter is cooled to a temperature in the vicinity of 0° C. 1.91 cm3 of trifluoromethanesulfonic anhydride in solution in 15 cm3 of anhydrous dichloromethane are poured into the reaction mixture over 30 min. The suspension is kept stirring for 15 h at a temperature close to 20° C. 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction medium. This stirring is continued for 30 min, then 20 cm3 of dichloromethane are added to the mixture. The organic phase is decanted then washed successively with 100 cm3 of a 0.1M aqueous solution of hydrochloric acid and 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. Next, the organic phase is dried then concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual brown oil is then taken up in ethyl acetate and purified by filtration through silica (silica 60—particle size 15-40 μm). The organic phase is concentrated under reduced pressure (5 kPa). 477 mg of 5-bromo-7-fluoro-2-(1-propylbutyl)-3,4-dihydroisoquinoline-1(2H)-one are obtained in the form of a dark orange oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH2:27][CH2:28][NH:29]3)[CH:20]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15](=[O:17])[N:29]3[C:30]4[C:26](=[C:25]([C:21]5[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=5)[CH:33]=[CH:32][CH:31]=4)[CH2:27][CH2:28]3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1cncc(-c2cccc3c2CCN3)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3cccnc3)cccc21
Yield: 71.9 %

Procedure:
The product is prepared by following the procedure described in example 10d using 26.7 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) and 25 mg of 4-pyridin-3-yl-2,3-dihydro-1H-indole in place of 4-pyridin-4-yl-2,3-dihydro-1H-indole. 30.7 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)[C:27](OC)=[O:28].COC1C=CC=CC=1S>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:28][CH3:27])=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: COc1ccccc1S
Product: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 2-methoxythiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH3:16]C1C=CC(N[C@H](C(O)=O)C(C)C)=CC=1>>[CH3:16][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: Cc1ccc(N[C@H](C(=O)O)C(C)C)cc1
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Product: CC(C)[C@@H](C(=O)O)N(C)c1ccc(Cl)cc1

Procedure:
Each of the m-phenoxybenzyl ester of N-(4-chlorophenyl)valine and N-(4-methylphenyl)valine is methylated using the procedure of Example 2 to yield the m-phenoxybenzyl ester of N-methyl,N-(4-chlorophenyl)valine, MS m/e 423 (M+), and the m-phenoxybenzyl ester of N-methyl,N-(4-methylphenyl)valine, MS m/e 403.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[N:30]=[C:31]=[O:32]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: COc1ccc(OC)c(N=C=O)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: COc1ccc(OC)c(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
33.1 mg of yellow lyophilizate 3-{4-[3-(2,5-dimethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2,5-dimethoxyphenyl isocyanate.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=1)[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:18]1[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=1)[C:7]([NH:9][NH2:10])=[O:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200.1 %

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (2 mL) was added to a solution of tert-butyl N′-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (300 mg) in ethyl acetate (2 mL), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 250 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7](N)[C:6]=1[CH3:13])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:15].N([O-])=O.[Na+].NC(N)=O.[Cl-].[Na+]>O>[C:1]([NH:4][C:5]1[C:6]([CH3:13])=[C:7]([OH:15])[CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1c(C)ccc(N)c1C
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Product: CC(=O)Nc1c(C)ccc(O)c1C
Yield: 67 %

Procedure:
1-Acetamido-3-amino-2,6-dimethylbenzene (4.77 g; 26.8 mmol) was dissolved in a diluted acid prepared from concentrated sulfuric acid (3 ml) and water (30 ml). To the resulting solution was added dropwise a solution of sodium nitrite (2.40 g; 34.8 mmol) in water (5 ml) in a manner such that the temperature of the reaction mixture did not exceed 10° C. Then, the mixture was stirred under ice-cooling for 15 minutes. After addition of 1.00 g of urea (16.6 mmol), the mixture was dropwise added gradually into 75 ml of boiling water and the whole mixture was refluxed for 30 minutes. After cooling, sodium chloride was added, followed by extraction with ether and chloroform. The organic layer was washed with water and dried over magnesium sulfate (dehydration), and the solvent was distilled off to give 3.2 g (67%) of the title compound as colorless needles, m.p. 190°-195° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([CH3:14])[N:3]=1.C1COCC1.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][N:6]1[C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[C:4]([CH3:14])[N:3]=[C:2]1[C:27]#[C:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1noc(-c2c(C)nc(Br)n2C)n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2c(C)nc(C#Cc3ccccc3)n2C)n1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a stirred solution of 5-(2-bromo-3,5-dimethyl-3H-imidazol-4-yl)-3-methyl-[1,2,4]oxadiazole (0.52 g, 2.02 mmol) in THF (10 mmol) was added at RT bis(triphenyl-phosphin)palladium(II)chloride (71 mg, 0.1 mmol), phenylacetylene (0.31 g, 3.03 mmol), triphenylphosphine (27 mg, 0.1 mmol) and triethylamine (0.61 g, 6.07 mmol). Through the reaction mixture was bubbled argon for 10 min and stirring was continued at 55° C. for 16 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (40 ml), dried (MgSO4) and evaporated to give the crude product as yellow oil (0.81 g). Purification by column chromatography on silica gel (ethyl acetate/toluene 5:1) gave the title compound (0.31 g, 55%) as a light yellow solid, m.p. 137° C. and MS: m/e=278.1 (M+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.12 g) with acryloyl chloride (39 μl) and N,N-diisopropylethylamine (0.21 ml) in tetrahydrofuran (10 ml) was performed according to the method described in example 6.
Reaction SMILES: ClC1C=C(CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CC[O:26][CH2:25][C@@H]2O)C3=O)C=CN=1.Cl[C:32]1[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[CH:34][N:33]=1>>[CH3:25][O:26][C:32]1[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[CH:34][N:33]=1
Reactant: O=c1c2cc(Cc3ccnc(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: OCc1ccnc(Cl)c1
Product: COc1cc(CO)ccn1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one in Example 15, substituting (2-methoxypyridin-4-yl)methanol for 2-chloropyridine-4-methanol. The resultant orange solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 418.1779 for [M+H]+ [Calc'd for C24H24N3O4, [M+H]+=418.1761]: 1H NMR (400 MHz, d6-DMSO) δ 9.01 (d, J=7.7 Hz, 1H), 8.71 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 7.81-7.74 (m, 2H), 7.56-7.54 (m, 1H), 5.32 (d, J=5.5 Hz, 1H), 4.64 (br s, 1H), 4.37 (s, 2H), 4.17 (br 5, 1H), 4.18-3.97 (m, 2H), 3.51-3.43 (m, 1H), 3.34 (s, 3H), 3.15 (t, J=10.3 Hz, 1H), 2.25 (br s, 1H), 1.91 (d, J=12.0 Hz, 1H).