Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16](C(F)(F)F)[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C(C3C=NC=C([Cl:54])C=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:54])[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Reactant: Clc1cncc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)c1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-chloropyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=467, obsd.=467).
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Sc1ccccn1
Product: CCSc1ccccn1

Procedure:
d. 2-Ethylthio-pyridine was prepared by the same method as used for compound (1) c., except that ethyl halide was used instead of methyl halide. The product had a b.p. of 77°-77.5° C./8 mm. Hg. (1) e. (Pyridyl-2)-thiol acetate was prepared by reacting acetic anhydride with 2-mercaptopyridine in alkaline medium according to the method described in Houben-Weyl, 4th ed., vol. 9, 753 (1955) and in J.A.C.S. 59, 1089 (1937). The product has a b.p. of 117°-118° C./9 mm. Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.[Cu]I>[CH3:12][C:4]1[CH:3]=[C:2]([NH:1][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(N)cc1C
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Nc2ccccc2)cc1C
Temperature: 110 °C

Procedure:
To a solution of 1-(4-amino-2,6-dimethylphenyl)ethanone (3.26 g, 20.0 mmol), K3PO4 (9.2 g, 40 mmol), and 1-iodobenzene (4.08 g, 20.0 mmol) in DMF (35.0 mL) was added CuI (761.8 mg, 40 mmol). The reaction was heated at 110° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl-4-(phenylamino)phenyl)ethanone as red-brown syrup: 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2 Hz, 2 H), 7.10 (d, J=7.7 Hz, 2 H), 6.99 (d, J=4.2 Hz, 1 H), 6.71 (s, 1 H), 2.47 (s, 3 H), 2.18 (s, 6 H); ESI-MS: m/z 239.5 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]1[N:15]([CH3:34])[C:16](=[O:33])[C:17]([O:24]C(=O)C2C=CC=CC=2)=[C:18]([C:20]([O:22]C)=O)[N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]1[N:15]([CH3:34])[C:16](=[O:33])[C:17]([OH:24])=[C:18]([C:20]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=2)=[O:22])[N:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1nc(C2COCCN2C(=O)OC(C)(C)C)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: Cn1c(C2COCCN2C(=O)OC(C)(C)C)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The methyl ester 8B in dry MeOH was treated with 4-fluorobenzylamine (2.5 eq.) at reflux for 2 hours. Solvent was removed in vacuo and residue triturated with Et2O to obtain the title product.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN(C)C=O>[CH2:10]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: BrCCCCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(CCOCCCCCCCCCOC2CCCCO2)cc1
Reaction time: 16 h
Yield: 39 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 264 mg, 6.6 mmol) was added at 0° C. to a solution of 2-phenylethanol (807 mg, 6.61 mmol) in tetrahydrofuran (8.6 mL) and N,N-dimethylformamide (3.4 mL), then after 1 h a solution of 2-(9-bromo-nonyloxy)-tetrahydro-pyran (2.44 g, 7.93 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise. The solution was allowed to reach room temperature over 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 2-(9-phenethyloxy-nonyloxy)-tetrahydro-pyran (898 mg, 39%). Colorless oil, m/e=366.2 ([M+NH4]+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1([O:24][C:25](=O)[NH:26][CH:27]([CH3:38])[CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)C=CC=CC=1>O1CCOCC1>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25]([NH:26][CH:27]([CH3:38])[CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[O:24])[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Solvent: C1COCCO1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1

Procedure:
The more polar diastereoisomer of (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (162.7 mg, 0.7 mmole) was added to a solution of [2-(1H-indol-3-yl)-1-methyl-ethyl]-carbamic acid phenyl ester (206 mg, 0.7 mmole) in dioxane (7 ml). The batch was then refluxed for 14 h. A precipitate formed at RT. The precipitate was filtered out, and washed once with cold dioxane (2 ml) and with diethyl ether (3×3 ml). The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea was obtained in this manner as a colorless solid with a melting point of 140-146° C. in a yield of 231 mg (76%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: NCCCc1ccc(CO)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCCc1ccc(CO)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
Palladium on carbon (5%, 0.15 g) was added to a solution of 4-(3-benzyloxycarbonylaminopropyl)benzylalcohol (1.00 g), which is the product of Reference example 50(a) in ethanol (20 ml). The mixture was stirred under an atmosphere of hydrogen at ambient temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford 4-(3-aminopropyl)benzylalcohol as a gum. In a similar manner to that described in Example 5, a reaction was carried out using 4-(3-aminopropyl)benzylalcohol, 4-pyridine-2-ylbenzoic acid (668 mg) and carbonyidiimidazole (650 mg) and the reaction mixture was treated to afford the desired compound (0.74 g) as colorless crystals.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:15]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(O)c1ccc(CCCCO)cn1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(CCCCc1ccc(C(=O)O)nc1)OCc1ccccc1
Temperature: 0 °C
Yield: 90.6 %

Procedure:
3.92 g of 5-(4-hydroxybutyl)picolinic acid was dissolved in 20 ml of pyridine, and with stirring under ice cooling, a solution of 4.6 g of carbobenzyloxy chloride in 20 ml of toluene was added dropwise. Under ice cooling, the mixture was reacted for 2 hours. Then, the reaction mixture was poured into ice water, and extracted with toluene. The extract was washed successively with water, 1 N hydrochloric acid and then with water, and the toluene was distilled off to give 5.7 g of 5-(4-carbobenzyloxybutyl)picolinic acid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>OS(O)(=O)=O>[N+:1]([C:14]1[C:9]2[N:8]=[CH:7][S:6][C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: c1ccc2scnc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2scnc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
KNO3 (1.95 g, 19.3 mmol) was added portionwise to an ice-cold solution of 1,3-benzothiazole (2.0 g, 14.8 mmol) in H2SO4 (5 ml) while maintaining the temperature below 10° C. and the mixture was stirred at 0° C. for 2 h. The mixture was poured onto ice and the aqueous phase was extracted with DCM. The organic phase was washed with sat NaHCO3 solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was diluted with MeOH (15 ml) and heated under stirring at 65° C. for 1 h, on cooling the resulting precipitate was collected by filtered and washed with MeOH to give the title compound (500 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:8]=2[CH:9]=1)=[O:4].Br[CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:16]([O:14][C:10]1[C:8]2[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[O:6][C:7]=2[CH:13]=[CH:12][CH:11]=1)([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: COC(=O)c1cc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC(C)C)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 0.41 g (2.13 mmol) of 4-hydroxy-2-benzofurancarboxylic acid methyl ester in 7 mL of DMF was added 0.80 mL (8.54 mmol) of 2-bromopropane and 1.18 g (8.54 mmol) of potassium carbonate. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was extracted with ethyl acetate. The organic layer washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 0.49 g of methyl 4-isopropoxy-1-benzofuran-2-carboxylate. Yield ˜100%; m.p. 43-45° C.; MS: 235.1 (M+H)+.
Reaction SMILES: [N+:1]([CH2:3][CH2:4]C(S(C1C=C(C=CC=1)N)(=O)=O)C)#[C-:2].[N+:17]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])([O-:19])=[O:18].CCOC(C)=O>CO>[CH3:4][C:3]1[N:1]=[CH:2][O:24][C:23]=1[C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: [C-]#[N+]CCC(C)S(=O)(=O)c1cccc(N)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ncoc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 3-{[1-(isocyanoethyl)ethyl]sulfonyl}aniline (60 g, 0.287 mol) in dry MeOH (800 mL), was added dry powdered K2CO3 and stirred at rt for 1 h. The reaction mixture was re-cooled to 0° C. and 3-nitro benzaldehyde (43 g, 0.287 mol) added. The reaction mixture was warmed to rt, followed by heating at 55° C. overnight with stirring. The excess solvent was removed under reduced pressure, the residue was dissolved in water (100 mL) and extracted with EtOAc (3×350 mL). The combined organic layers were washed with brine, water, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica get (60-120 mesh) column chromatograph using 15% EtOAc in petroleum-ether to yield product as yellow solid. Yield 50 g (86%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>O.CO>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: OCCCCCCBr
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Yield: 78.7 %

Procedure:
A solution of 4.4 g of NaOH in 20 ml of distilled water was added to a solution of 7.5 g of 4-hydroxy cinnamic acid in methanol, 0.02 g of Kl was added thereto, and then 10.0 g of 6-bromo-1-hexanol was slowly added dropwise for reaction at 65° C. for 24 hours. 100 ml of distilled water was added thereto to complete the reaction, and then the mixture was cooled to normal temperature. A 10% aqueous HCl solution was added thereto, and the obtained precipitants were filtered to obtain 9.5 g of 4-((6-hydroxyhexyl)oxy)cinnamic acid. (Yield: 60%)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:24][CH:25]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4cccnc4)ccc3n2C)cc1
Yield: 35 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 35% of theory, C36H45N7O5 (655.8) Rf value: 0.28 (silica gel; dichloromethane/ethanol=19:1) ##EQU87##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:32]1C=CC=CC=1.[OH-].[NH4+]>CC#N>[NH2:32][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: c1ccncc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A mixture of (S)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid (1.8 g), di-tert-butyl dicarbonate (CAN:24424-99-5, 12 mmol) and pyridine (3 mL) in CH3CN (50 mL) was stirred at room temperature for 20 min. Ammonium hydroxide solution (25%-28% NH3, 15 mL) was added dropwise during 30 min. The resulting reaction mixture was stirred overnight. During the removal of solvents, the product precipitated, was collected by filtration and dried to give the target compound as a white solid (1.55 g, 86%). MS (D): m/e=253.2 [M+Na]+.
Reaction SMILES: [NH:1]1[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([C:21]([N:1]2[CH2:3][CH:2]2[C:4]([O:6][CH3:7])=[O:5])=[O:22])=[CH:18][CH:17]=1
Reactant: COC(=O)C1CN1
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.40 g (43.5 mmol) methyl aziridine-2-carboxylate and 13.5 ml (97.3 mmol) triethylamine in 30 ml methylene chloride is combined with 8.80 g (48.6 mmol) 5-chlorothiophenecarboxylic acid chloride in 30 ml methylene chloride while cooling with ice and subsequently after removal of the cooling bath stirred for 3 h at room temperature. Then the mixture is diluted with water, extracted with methylene chloride, dried with sodium sulphate, concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/15->80/20) to obtain the slightly contaminated title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a 50 ml round-bottomed flask, 3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.6 mmol) was dissolved in dichloromethane 912 ml). The colorless solution was cooled to 0° C. and triethylamine (0.34 ml, 2.44 mmol) and methanesulfonyl chloride (0.14 ml, 1.8 mmol) were added. The reaction mixture was stirred at 0° C. for 1.5 h then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]([CH2:24][C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of the compound of step 1 (2.52 g, 6.66 mmol) in 45 ml of acetone were added potassium carbonate (5.522 g, 39.96 mmol) and iodomethane (1.24 ml, 19.98 mmol) and the solution was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in EA, washed twice with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 85:15) to give 2.334 g of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>NC1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1cccc2c(N)cccc12
Temperature: 20 °C
Yield: 55.2 %

Procedure:
60 g (0.275 mol) of 1,5-dinitro naphthalene were suspended, in a 700 ml stirrer autoclave, in 340 ml of aniline and treated with 8 g of water-moist, 5% strength catalyst of palladium on activated charcoal, corresponding to 2.8 g of dry catalyst. Hydrogenation was performed at a temperature of about 100° C. and an initial hydrogen pressure of about 10 bars. As soon as the hydrogen pressure dropped to 5 bars, the hydrogen supply was stepped up until the original value of 10 bars was reattained. After 104 minutes the hydrogen uptake was finished and the reaction over. The catalyst was separated off at about 70° C. by filtration and the filtrate cooled to 20° C. whereupon 1,5-diamino naphthalene crystallized out. The crystallate was then filtered off and washed twice with 50 ml of methanol; 24 g of 1,5-diamino naphthalene were obtained with a m.p. of 189°-190° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9](F)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: C1COCCN1
Reactant: Cc1cc2cn[nH]c2cc1-c1cc(F)cc2c(N)c(C(N)=O)nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc2cn[nH]c2cc1-c1cc(N2CCOCC2)cc2c(N)c(C(N)=O)nnc12
Temperature: 140 °C
Yield: 25.2 %

Procedure:
A mixture of 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide (200 mg, 0.59 mmol), DIPEA (1000 mg), morpholine (500 mg,) and DMA (4 mL) was heated at 140° C. in a microwave under N2 for 3 hours. The mixture was cooled, concentrated, and purified via preparative HPLC to give the title compound (60 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1H, s), 8.93 (1H, br s), 8.30 (1H, d, J=2.4 Hz), 8.03 (1H, s), 7.81 (1H, br s), 7.60 (1H, s), 7.54-7.51 (3H, m), 7.35 (1H, s), 3.79 (4H, t, J=4.8 Hz), 3.42 (4H, t, J=4.8 Hz), 2.00 (3H, s); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 3.053 minutes); ESI+APCI m/z [M+H]+ 404.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:39]1([CH:17]2[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([O:4][C:3]4[CH:21]=[CH:22][C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[S:27])=[CH:24][C:2]=4[F:1])[CH:10]=[CH:9][N:8]=3)=[O:13])[CH2:15][CH2:16]2)[CH2:42][CH2:41][CH2:40]1
Reactant: C1CNC1
Reactant: O=C1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC4)CC3)c2)c(F)c1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 4-{2-fluoro-4-[3-(2-phenylacetyl)thioureido]phenoxy}-2-[(4-oxopiperidin-1-yl)carbonylamino]pyridine (38 mg) in dichloromethane (2.0 ml) were added azetidine hydrochloride (17 mg) and sodium triacetoxyborohydride (40 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was dried in vacuum to provide the titled compound (31.9 mg, 78%) as white powder.