Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](Cl)[CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:33]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C1COCCN1
Product: COc1cc(-c2nn(-c3ccnc(N4CCOCC4)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.120 g, 0.00023 mol) and morpholine (10 mL) was heated at 100° C. for 6 days. The solvent was removed in vacuo and the residue was slurried in water (25 mL) for 4 hours. The mixture was filtered and the crude solid was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 35%-80% acetonitrile-0.050 M ammonium acetate over 20 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give N2-{4-[4-amino-1-(2-morpholino-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.048 g, 0.00008 mol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Clc1ccc(CN2CCNCC2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)nn12

Procedure:
A mixture of 1-[(4-chlorophenyl)methyl]piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.[Pd]>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2)OC1(C)C
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)C(=O)C(C)(C)O2)cc1
Yield: 85.7 %

Procedure:
4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2 g, 6.7 mol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.43 g, 0.0067 mol), and Cs2CO3 (11 g, 0.034 mol) in toluene (25 mL) and water (8 mL) was degassed, Pd (dppf) Cl2 (1.1 g, 0.0013 mol) was added under an inert atmosphere and the mixture degassed once again. The reaction was heated at reflux for 3 h, upon which the reaction mixture was filtered through a pad of Celite® and the filtrate was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by flash column chromatography using 30% ethyl acetate in hexane and silica gel (230-400 Mesh), Rf=0.30 to afford 4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.3 g, 73%) as solid. 1H NMR (500 MHz, d6-DMSO): δ 8.42 (d, J=7.6 Hz, 1H), 8.06-7.99 (m, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.4 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.79 (s, 3H). 1.42 (s, 6H). MS: [M+H]+: m/z=452.1; [M+Na]+: m/z=474.2.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2>[OH-].[NH4+]>[Cl:3][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c2ncccc2c1Cl
Temperature: 25 °C
Yield: 97 %

Procedure:
To 150 ml of phosphorus oxychloride, at an internal temperature of 80°-85°, was added in portions, with vigorous stirring, during 0.5 hr, 40.5 g (0.184 mole) of 5-hydroxy-6-methoxy-8-nitroquinoline. After completion of addition, the mixture, which had turned from a red solution to a yellow suspension, was heated under reflux for 1.5 hr. The golden yellow solution was allowed to cool to room temperature and the resulting yellow mush was added to a vigorously stirred mixture of 700 ml of conc ammonium hydroxide and ice. The addition rate was regulated to keep the temperature from rising above 25° The pale yellow precipitate was washed with water and air dried to give 43 g (97%) of 5-chloro-6-methoxy-8-nitroquinoline mp 204°-206° (Mp 204° cited by R. C. Fuson et al., J. Org. Chem., 12, 799 (1947).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].Br[CH2:13]C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:13])=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)=O)c(O)c1

Procedure:
2,4-Dihydroxyacetophenone was alkylated with bromoethane in acetone in the presence of potassium carbonate to obtain 2-hydroxy-4-methoxyacetophenone. Using this compound and 2-methoxy-benzoic acid as starting materials, the syntheses according to Examples 1a, b, c, and d yielded the compound (m.p.: 153-154.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[CH:16]=1.[CH2:17](I)[CH3:18].O>C(OCC)(=O)C>[CH2:17]([N:12]1[C:11](=[O:13])[CH2:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]2[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]1=2)[CH3:18]
Reactant: CCI
Reactant: COc1ccc2c(c1)N(C)C(=O)CC(=O)N2
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)CC(=O)N(C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
8-Methoxy-1-methyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (220 mg) was added to the suspension at the same temperature, and stirred at 0° C. for 1 hour. Ethyl iodide (187 mg) was added to the mixture and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was concentrated to dryness under reduced pressure to give the title compound(190.2 mg) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([O-:19])=[O:18]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][CH2:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)CCC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CCC(=Cc1c[nH]c2ncccc12)[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 1.47 g (10 mM) of 1H-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (J. Am. Chem. Soc., 1955, 77, 457-459), 77 mg (10 mM) of ammonium acetate and 2.55 mL (20 mM) of methyl 4-nitrobutyrate (Aldrich) was refluxed in 10 mL of THF for 1 hour. An additional 500 mg of ammonium acetate was added and the mixture refluxed for an additional 3 hours. The reaction was cooled to room temperature, the solvent evaporated, and the residue chromatographed on silica using ethyl acetate as the elutant. Appropriate fractions were combined to yield 410 mg of the desired product as an oil. NMR (D6DMSO) δ12.80 (s, 1H), 8.42 (s, 1H), 8.37 (m, 2H), 8.18 (s, 1H), 7.25 (m, 1H), 3.62 (s, 3H), 3.25 (t, 2H), 2.68 (t, 2H). 13C NMR (D6DMSO) 172.4, 148.7, 144.5, 144.4, 130.0, 127.3, 126.9, 119.9, 117.3, 106.1, 51.6, 30.5, 23.6. Mass Spectrum: m/e=276 (P+1).
Reaction SMILES: C([NH:4][C@@H:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)(=O)C.C1(C)C=CC=CC=1.[ClH:26]>>[ClH:26].[CH3:15][O:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[CH3:13])[CH2:6][C@H:5]([C:16]([OH:18])=[O:17])[NH2:4]
Reactant: COc1cc(C[C@@H](NC(C)=O)C(=O)O)ccc1C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(C[C@@H](N)C(=O)O)ccc1C
Temperature: 25 °C

Procedure:
A mixture of N-acetyl-3-methoxy-4-methyl-D-phenylalanine (2.55 g) in a mixture of 6N hydrochloric acid (25.5 ml) with toluene (18 ml) was stirred under reflux for 4 hours. After cooling to room temperature, the aqueous layer was separated and the organic layer was washed twice with water (10 ml). The aqueous layer and the washings were combined and the solvent was evaporated under reduced pressure. The produced crystals were collected by filtration and washed with ice-water to give 3-methoxy-4-methyl-D-phenylalanine hydrochloride (1.35 g) in the form of colorless crystals. The solvent was evaporated from the filtrate under reduced pressure to give crude 3-methoxy-4-methyl-D-phenylalanine hydrochloride (0.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19]O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1.[Br:28]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:28][CH2:19][CH2:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:6]1[CH2:7][CH2:8][C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([N:2]([CH3:27])[CH3:1])[CH2:4][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCBr)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
2-[2-(4-Dimethylamino-4-phenyl-cyclohexyl)-1H-indol-3-yl]-ethanol (Example 219, 3.20 g, 8.8 mmol) was dissolved in abs. CH2Cl2 (50 ml) at RT and tetrabromomethane (4.39 g, 13.2 mmol) was added. Triphenylphosphine (3.61 g, 12.6 mmol) was then added at RT. The solution was stirred at RT for 2.5 h and then concentrated i. vac. Flash chromatography of the residue with 300 g of silica gel and ethyl acetate/ethanol (1:2) gave 1.98 g of contaminated product, 1 N NaOH was added to this and the mixture was extracted three times with CHCl3. The organic phase was dried over Na2SO4 and concentrated i. vac. Yield: 1.57 g (42%)
Reaction SMILES: Cl.[CH:2]([O:5][NH2:6])([CH3:4])[CH3:3].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:18][C:19](=O)[CH3:20]>C(O)C>[CH:2]([O:5][N:6]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:19]1[CH3:20])([CH3:4])[CH3:3]
Reactant: CC(C)ON
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: Cc1nc2cnc3ccccc3c2n1OC(C)C
Yield: 94.7 %

Procedure:
O-isopropylhydroxylamine hydrochloride (2.14 g, 1.7 eq) was added to a solution of N-(4-chloroquinolin-3-yl)acetamide (2.51 g, 1.0 eq) in ethanol (75 mL). The reaction mixture was heated at reflux for 2 hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 2.60 g of 1-isopropoxy-2-methyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1](O)(=O)C.Cl.[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1.C(=O)C>CO>[CH2:1]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:9]=2[CH2:8][CH2:7][NH:6]1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(=O)O
Agent: CC=O
Agent: Cl
Solvent: CO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 75 °C

Procedure:
Acetic acid was added dropwise to a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (200 mg) in 7 mL of methanol until the pH=4. Acetaldehyde (0.2 mL) was added and the mixture was heated at 75° C. in a sealed tube for 1 h. The tube was cooled to rt and unsealed. The solvent was evaporated yielding 160 mg of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.1 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (I42) (295 mg, 1.04 mmol), (R)-quinuclidin-3-ol (159 mg, 1.25 mmol), HOBt (191 mg, 1.25 mmol), and DCC (258 mg, 1.25 mmol) were dissolved in dry THF and stirred at room temperature for 15 hours. THF was evaporated, and the crude product was dissolved in EtOAc and washed sequentially with NaHCO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (180 mg, 44% yield, mixture of diastereomers).
Reaction SMILES: CC(C)([O-:4])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](F)[C:9]=1[N+:15]([O-:17])=[O:16]>CS(C)=O.S(=O)(=O)(O)O>[F:7][C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([OH:4])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(O)cccc1F
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A solution of potassium tert-butoxide (1.23 g, 11 mmol) in 25 mL of anhydrous DMSO was stirred at room temperature for 30 minutes and treated with 1,3-difluoro-2-nitrobenzene (1.59 g, 10 mmol). After 18 hours, the mixture was diluted with 150 mL of 1 N aqueous sulfuric acid and extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 50 mL of trifluoroacetic acid. After 30 minutes at room temperature, the mixture was concentrated in vacuo, treated with 50 mL of 1 N aqueous sodium hydroxide, and extracted with three 30 mL portions of diethyl ether. The aqueous layer was acidified with 1 N aqueous sulfuric acid and extracted with two 50 mL portions of dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.3 g of 3-fluoro-2-nitrophenol as orange oil (61% yield).
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:15][NH2:16]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[NH:16][N:15]=[CH:4]2
Reactant: NN
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2cn[nH]c12
Yield: 93 %

Procedure:
A solution of 2-fluoro-3-trifluoromethylbenzaldehyde (5 g, 26 mmol)), hydrazine hydrate (8.3 mL, 260 mmol) and DMAP (3.17 g, 26 mmol.) in 10 mL pyridine was heated at 100° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried with anhydrous sodium sulfate (Na2SO4). The organic phase was concentrated in vacuo to give 4.5 g of product. The crude product was recrystallized from Et2O/hexane to give the title compound (3.6 g, white solid, mp 90° C.).
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][CH:12]([CH2:16][C:17]([O:19]C)=[O:18])[C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:17]([CH2:16][CH:12]([CH3:11])[C:13]([C:8]1[CH:9]=[CH:10][C:4]2[N:3]=[C:2]([OH:1])[NH:6][C:5]=2[CH:7]=1)=[O:14])([OH:19])=[O:18]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: Oc1nc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(CC(=O)O)C(=O)c1ccc2nc(O)[nH]c2c1

Procedure:
Carbon disulfide (90 ml), 2-hydroxybenzimidazole (4.1 g) and 2-methyl-3-carbomethoxy propionyl chloride (5 g) are added to aluminum chloride (20.3 g) under nitrogen. The resulting mixture is refluxed for about 45 hours, quenched with ice cold 6N HCl and the acidic mixture filtered. The filtered solid is washed with water and dried in vacuo, affording the desired product as a solid, M.P. 223° C. (dec).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:12])=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O.[NH2:14][NH2:15]>O1CCOCC1>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:14][NH2:15])=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=1
Reactant: NN
Reactant: CS(=O)(=O)c1cc(Cl)nnc1Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cc(Cl)nnc1NN
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,6-Dichloro-4-methanesulfonylpyridazine(W4.126; 660 mg, 2.9 mmol) was dissolved in 1,4-dioxane (5 ml) and hydrazine hydrate (295 μl, 5.8 mmol) was added. The mixture was stirred at RT for 4 h, then concentrated, and the residue was purified by flash chromatography (dichloromethane:ethyl acetate). Yield: 200 mg
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[NH:34][C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[NH:34][C:35](=[O:37])[O:36][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
275 mg (1.00 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 289 mg (1.00 mmol) 6-(6-chloropyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.348 mL (2.00 mmol) DIPEA were stirred overnight in 10 mL DMF at RT. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was eliminated i. vac. and the aqueous phase remaining was neutralised with 4N aqueous NaOH solution. The precipitate was suction filtered, washed with water and dried in the CAD.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:32])=[CH:4][C:5]([Cl:31])=[C:6]([C:8]2[C:9](=[O:30])[N:10]([CH2:28][CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:12]=3)[CH:7]=1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1>[Cl:31][C:5]1[C:6]([C:8]2[C:9](=[O:30])[N:10]([CH2:28][CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:40]([NH:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:41])=[C:3]([F:32])[CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCCN3CCOCC3)cc21
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NCCCN3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)amino)-1,6-naphthyridin-2(1H)-one (0.140 g, 0.304 mmol) in pyridine (4 mL) was treated with phenyl isocyanate (0.040 g, 0.336 mmol) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with MeOH and the resulting solid was collected via filtration to afford 1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.52 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 7.10 (t, J=5.6 Hz, 1H), 6.97 (t, J=7.4 Hz, 1H), 6.28 (s, 1H), 4.06 (m, 2H), 3.56 (t, J=4.5 Hz, 4H), 3.34 (m, 2H), 2.34 (d, J=6.8 Hz, 6H), 1.70 (t, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 579.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:23]3[CH2:24][CH2:25][NH:20][CH:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: CCOC(=O)C1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonylchloride (1.1 g) in dichloromethane (12 ml) is added dropwise, taking 30 minutes while stirring under ice-cooling, to a mixture of ethyl piperazine-2-carboxylate hydrochloride (1.0 g), triethylamine (0.5 g) and dichloromethane (20 ml). The reaction mixture is stirred for one hour at 0 ° C, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=1:1:1) to afford ethyl 4-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine-2-carboxylate as crystals (1.2 g). This product is recrystallized form ethyl acetate and hexane to give colorless prisms, m.p. 105-106° C.