Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([C:10]1[C:14]2[CH:15]=[N:16][C:17]([NH:19]C(OCC3C=CC=CC=3)=O)=[CH:18][C:13]=2[N:12]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:11]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[C:1]([O:5][C:6](=[O:49])[N:7]([C:10]1[C:14]2[CH:15]=[N:16][C:17]([NH2:19])=[CH:18][C:13]=2[N:12]([C:30]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:11]=1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ncc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(N)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a 50 mL round bottom flask charged with tert-butyl(6-(((benzyloxy)carbonyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (225 mg, 0.344 mmol) in ethyl acetate (5 ml) and methanol (5 ml) was added palladium on carbon (73.3 mg, 0.069 mmol). The flask was evacuated and back-filled with hydrogen gas using an attached balloon. This procedure was attempted a further two times. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The palladium was filtered off by passing the reaction mixture through celite and washing through with ethyl acetate. The volatiles were removed in vacuo to afford crude tert-butyl(6-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (159 mg, 0.306 mmol, 89% yield) which was taken forward without purification. MS ESI calc'd. For C32H34N5O [M+H]+ 520. found 520.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[C:34](B(O)O)=[CH:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[CH:17]=1)[CH2:13][NH:12][C:4]1[CH:3]=[C:2]([C:34]2[C:35]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[N:32]([S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[CH:33]=2)[N:7]=[CH:6][C:5]=1[CH2:8][C:9]([NH2:11])=[O:10]
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1cc(F)cc(F)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B(O)O)c3cccnc32)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)c3cccnc32)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.7 %

Procedure:
26 mg of 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 20) was dissolved in 0.5 mL of tetrahydrofuran, to which 33 mg of 1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-boronic acid, 10 mg of tetrakis(triphenylphosphine) palladium (0), and 0.5 mL of 2 mol/L sodium carbonate in water were added, and stirred at 80° C. for 14 hours. To the reaction mixture, water was added, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=20:1) to obtain 25 mg (yield 54%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]([F:21])=[C:14]([F:22])[C:12]=2[N:13]=1.O=S(Cl)[Cl:25]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([Cl:25])=[O:19])[C:15]([F:21])=[C:14]([F:22])[C:12]=2[N:13]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid (570 mg, 1.67 mmol) in SOCl2 (10 mL) was added 3 drops of DMF. The suspension was stirred at ambient temperature overnight. The solid was filtered and washed with CH2Cl2 and was dried under reduced pressure to give 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carbonyl chloride.
Reaction SMILES: [CH:1]1([CH2:7][C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[C:18]([NH2:22])=[C:17]([CH3:23])[CH:16]=[CH:15][C:14]=2[N:13]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[C:18]=2[NH:22][C:8](=[O:9])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: Cc1ccc2nc(Cl)ccc2c1N
Reactant: O=C(Cl)CC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(Cl)ccc2c1NC(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyclohexaneacetyl chloride (prepared according to the method of J. Am. Chem. Soc. 1986, 108,7686) (560 mg) in dichloromethane (5 mL) was added a mixture of 2-chloro-6-methyl-5-quinolinamine (prepared according to the method of Journal of the American Chemical Society 1947, 69, 179) (350 mg) and triethylamine (1 mL) in dichloromethane (5 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried, filtered and evaporated to afford the sub-title compound (400 mg).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:6]([F:32])[CH:5]=1.[OH-].[Na+]>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][C:6]=2[F:32])[C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(CN([C@@H]2CC(C)(C)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(C(=O)O)cc2F)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester (0.52 g, 1.1 mmol) was dissolved in THF (20 ml) and treated with 1 N NaOH (2.1 ml) for 2 h. Work-up as for Example 187 yielded crude which was crystallised from acetonitrile to give 4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid: 0.38 g; MS: m/e=481.1 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:15]([O-])=O)[C:6]1=[O:18]>CO.[Pd]>[NH2:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6]2=[O:18]
Reactant: CN(C)CCn1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: CN(C)CCn1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
2-(2-Dimethylamino-ethyl)-5-nitro-2H-isoquinolin-1-one (1.10 g, 0.00358 mol) was dissolved in MeOH (30 mL), Pd/C (10%) was added and the mixture was stirred under an atmosphere of hydrogen at room temperature for 1 h. The mixture was filtered through Celite, and the solvent was removed in vacuo to give the titled product as a light yellow solid (0.82 g). MS m/z (M+H) 232.4.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:6][CH3:7])=[N:4][CH3:5].Cl.[C:9](Cl)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[CH3:7][NH:6][C:3]1[N:4]([CH3:5])[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:1][N:2]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CN=C(NC)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CNc1nnc(-c2cccnc2)n1C

Procedure:
A mixture of N-amino-N′,N″-dimethyl-guanidine (500 mg, 2.17 mmol) [J. Amer. Chem. Soc.; 1951; p. 1858] and nicotinoyl chloride hydrochloride (385 mg, 2.17 mmol) in pyridine (10 mL) was refluxed o.n. Aq. sat. K2CO3 was added and the mixture extracted with CHCl3. The organic phase was dried and concentrated. The crude product 240 mg (61%) was used in the next step without further purifications.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2.C([O-])(=O)C.[Na+].Cl.[CH3:37][O:38][NH2:39].O>C(O)C>[CH3:37][O:38][N:39]=[C:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])=[CH:21][C:20]=3[Cl:30])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: CON
Reactant: O=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C1CCCc2cc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)ccc21

Procedure:
1.24 g of 6-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-3,4-dihydro-2H-naphthalen-1-one, 0.23 g of sodium acetate and 0.23 g of O-methylhydroxylamine hydrochloride are stirred in 10 ml of ethanol at 50° C. for 18 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phases and purification over silica gel, the title compound is obtained. M.p. 75-77° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[NH:28][C:27](=O)[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:37])=O>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[N:28]=[C:27]([Cl:37])[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1
Product: COc1cc(OC)c2c(Cl)nc(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1

Procedure:
To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.Cl[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC([O-])(C)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)=[CH:21][CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Reactant: Clc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(Nc5ccccn5)cccc4c3)c2cc1OC
Temperature: 100 °C

Procedure:
To a solution of 6-(6,7-dimethoxyquinolin-4-yloxy)naphthalene-1-amine (150 mg, 0.43 mmol), 2-chloropyridine (45 μl, 0.47 mmol), and NaOtBu (52.0 g, 160 mmol) in dioxane (4 mL) were added Pd2(dba)3 (12 mg, 0.01 mmol) and 2-(dicyclohexylphosphino)-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (25 mg, 0.05 mmol). The resulting mixture was heated at 100° C. for 3 h. After cooling to ambient temperature, the mixture was diluted with EtOAc (25 mL) and poured into sat'd NaHCO3 (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The derived residue was purified by silica gel chromatography (0-10% CH3OH in CH2Cl2) to provide the title compound as a white solid. MS (ESI, pos. ion) m/z: 424.1 (M+1). Mass Calc'd for C26H21N3O3: 423.46.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[C:8]2[C:9]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]=3[CH:17]=[CH:18][CH:19]=2)(=[O:6])=[O:5].[CH2:20](I)[CH3:21]>CN(C)C=O>[CH2:20]([N:12]1[C:13]2[C:9]3[C:8](=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]1=[O:16])[C:7]([S:4]([CH3:3])(=[O:6])=[O:5])=[CH:15][CH:14]=2)[CH3:21]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)c2cccc3c(S(C)(=O)=O)ccc1c23
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 46.8 %

Procedure:
To 25 ml of N,N-dimethylformamide is added 0.48 g of 60% sodium hydride followed by the dropwise addition of a solution of 1.976 g of 6-(methylsulfonyl)-benz[cd]indol-2(1H)-one (Example 3) in 50 ml of N,N-dimethylformamide. Stirring is continued for 20 minutes followed by heating at 50° C. for 10 minutes then cooling at room temperature. A solution of 1.872 g of ethyl iodide in 25 ml of N,N-dimethylformamide is added dropwise and stirring continued for 1.5 hours. The reaction mixture is poured over cracked ice and the solid collected, dried and crystallized from ethyl acetate to give 1.03 g of the desired product as a solid, m.p. 199°-203° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: c1cncc(C2CCNC2)c1
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: Cc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of 3-pyrrolidin-3-ylpyridine (6 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1479.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C([O-])([O-])=O.[Na+].[Na+].[C:15](Cl)([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16].Cl>O.O1CCOCC1.CCOC(C)=O>[C:15]([CH:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])([O:17][CH2:18][CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:16]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCCCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCCCCCC(O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
6-Amino-hexan-1-ol (1.5 g, 12 mmol) was added to a vigorously stirred solution of Na2CO3 in H2O at 0° C. Dioxane (30 mL) was added, providing an opaque mixture. A solution of FmocCl, in dioxane (36 mL) was added dropwise at 0° C. The mixture was then allowed to warm to room temperature and was stirred for 1 hour. AcOEt (300 mL) was added, followed by HCl 0.1M (200 mL). The organic layer was washed with H2O (200 mL) and brine (50 mL), then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH, 97:3 to 90:10) to afford 3 as a white solid (3.95 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Yield: 106.6 %

Procedure:
In the same manner as in Reference Example 34 and using tert-butyl {3-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (16.4 g, 49.5 mmol), palladium carbon (50% water-containing product, 1.50 g) and methanol (100 mL) as starting materials, the title compound (15.9 g, quant.) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH:37]=2)=[O:34])=[C:4]([F:49])[CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[CH:37]=2)=[O:34])=[C:4]([F:49])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCCC4)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCCC4)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea (135 mg, 0.196 mmol) in TFA (3 mL) was stirred at RT for 3 h. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3 and stirred for 15 min. The resulting solid was collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea (98 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (br s, 1H), 8.71 (br s, 1H), 8.41 (s, 1H), 8.13 (m, 1H), 7.73 (s, 1H), 7.54-7.48 (m, 2H), 7.27 (m, 1H), 7.04 (m, 2H), 6.23 (s, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 2.86 (s, 3H), 2.42 (m, 4H), 1.66 (m, 4H), 1.20 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 567.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10].N1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([NH:9][NH2:10])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: Clc1nccnc1Cl
Solvent: c1ccncc1
Product: NNc1nccnc1Cl
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 63.9 %

Procedure:
A mixture of 2,3-dichloropyrazine (6.26 g, 42.0 mmol) and anhydrous hydrazine (5 mL, 159 mmol) in pyridine (22 mL, 272 mmol) was stirred at 60° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The obtained residue was triturated with water. The resulting slurry was filtered, and the collected solid air dried to yield the first crop of the title compound (3.88 g) as a white solid. The filtrate was concentrated in vacuo, the obtained residue was treated by repeating above process to afford additional amount of the product (1.73 g). (total 5.61 g, 92% yield). HPLC/MS (Method C): retention time=0.30 min, [M+H]+=144.8. 1H NMR (500 MHz, DMSO-d6): δ 8.27 (s, 1H), 8.05 (s, 1H), 7.56 (s, 1H), 4.32 (s, 2H); 13C NMR (500 MHz, DMSO-d6) δ 152.62, 140.67, 132.60, 130.01.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[N-:13]([C:16]#[N:17])[C:14]#[N:15].[Na+]>CN(C)C=O>[C:14]([N:13]=[C:16]([NH2:17])[NH:12][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([I:2])[CH:4]=1)[NH:10][CH:9]=[CH:8]2)#[N:15]
Reactant: Nc1cc(I)c2[nH]ccc2c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CN=C(N)Nc1cc(I)c2[nH]ccc2c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A solution of 7-iodo-1H-indol-5-ylamine hydrochloride IV (24.6 g, 83.7 mmol) in N,N-dimethylformamide (400 mL) at 25° C. was treated with sodium dicyanamide (18.6 g, 209 mmol). The reaction mixture was warmed to 50° C. for 2 h, concentrated in vacuo, and the residue treated with water (500 mL). The resulting mixture was allowed to stand at 25° C. for 2.5 h during which time a yellow precipitate formed. The precipitate was collected by filtration and washed with water to afford N″-cyano-N-(7-iodo-1H-indol-5-yl)guanidine V (22.59 g, 83%) as a light yellow solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.02 (broad s, 1H), 8.89 (broad s, 1H), 7.46 (d, J=1.83 Hz, 1H), 7.37 (d, J=1.83 Hz, 1H), 7.35 (t, J=2.56 Hz, 1H), 6.85 (broad S, 2H), 6.56(dd, J1=1.83 Hz, J2=3.10 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH2:19][CH3:20])[CH:9]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N+:11]([O-:13])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=O)C=CC(N=C=O)=CC=1.[CH3:34][CH:35]([CH3:38])[C:36]#[CH:37].O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]([CH:9]([C:10]1[CH:37]=[C:36]([CH:35]([CH3:38])[CH3:34])[O:13][N:11]=1)[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CC(C)C
Reactant: CCC(NC(=O)OC(C)(C)C)C(C[N+](=O)[O-])O[Si](C)(C)C
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O[Si](C)(C)C)c1cc(C(C)C)on1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of (1-Ethyl-3-nitro-2-trimethylsilanyloxy-propyl)-carbamic acid tert-butyl ester (918 mg, 2.86 mmol), 1,4-Phenylene diisocyanate (1.38 g, 8.5 mmol) and 3-methyl-1-butyne (586 mg, 8.5 mmol) in dry toluene (15 mL) under N2 is added triethylamine (10 drops). The mixture is heated to 50° C. in a sealed vial for 28 h, and then cooled to room temperature Water (1 mL) is added and the mixture is stirred for an additional 2 h, then filtered. The filtrate is concentrated in vacuum and the residue is purified over 35 g silica gel, eluted with ethyl acetate: heptane (1:5) to afford {1-[(5-Isopropyl-isoxazol-3-yl)-trimethylsilanyloxy-methyl]-propyl}-carbamic acid tert-butyl ester (764 mg, 72%) as an oil.