Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:20]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(Oc2ccc(Cl)cc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-chlorophenoxy)benzaldehyde in an analogous manner to that described in Example 1 to give 9-[3-(4-chlorophenoxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from dimethylformamide/water gave a beige crystalline solid of melting point 238-239° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.FC(F)(F)C(O)=O>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:20]2[N:19]=[C:18]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:17]([CH2:30][CH2:31][CH2:32][CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC1CCCCN1CCCOc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCN1CCCOc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1

Procedure:
The title compound was prepared from (RS) 4-[3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole by standard trifluoroacetic acid deprotection as described supra.
Reaction SMILES: [Si](OCC[N:11]1[C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:13]=[C:12]1[CH2:24][O:25][CH2:26][CH3:27])(C(C)(C)C)(C)C.ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:26]([O:25][CH2:24][C:12]1[NH:11][C:23]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:16]([O-:36])=[CH:15][C:14]=2[N:13]=1)[CH3:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2[nH]1
Reaction time: 2 h

Procedure:
1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.30 g, 5.96 mmol) was dissolved in 30 mL of CH2Cl2 and treated with meta-chloroperbenzoic acid (MCPBA) (1.80 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of 5% Na2CO3 solution and the layers were separated. The organic portion was then washed successively with H2O (20 mL) and brine (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.40 g of 1-2-{[tert-butyl(dimethyl)silyl]oxy)ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridine 5-oxide as a purple syrup.
Reaction SMILES: [CH:1]1(C(Cl)=O)CCCC1.[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26]N=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C1(C)C=CC=CC=1>C(O)C>[CH:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH:9]1([C:14]([NH:16][C:17]([NH:38][C:37]2[CH:39]=[CH:40][C:34]([O:33][C:24]3[C:23]4[C:28](=[CH:29][C:30]([O:31][CH3:32])=[C:21]([O:20][CH3:19])[CH:22]=4)[N:27]=[CH:26][CH:1]=3)=[CH:35][CH:36]=2)=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(Cl)C1CCCC1
Agent: O=C(N=C=S)C1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
1-Cyclopentanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopentanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopentanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 57%).
Reaction SMILES: O1C[CH2:14][NH:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCNCCNCCNCC1>>[N:13]12[CH:14]3[N:10]([CH2:9][CH2:8][N:7]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:11][CH2:12]2
Reactant: C1CNCCOCCOCCNCCN1
Agent: C1CNCCOCCNCCN1
Product: C1CN2CCN3CCN(CCO1)C23

Procedure:
If 1,4-dioxa-7,10,13-triazacyclopentadecane were used in place of 1-oxa-4,7,10-triazacyclododecane in essentially the procedure of Example 1, the product would be ##STR14##
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([Si:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].O>C1COCC1>[CH2:30]([Si:35]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:36][CH2:37][CH:38]([CH:41]2[CH2:46][CH2:45][CH:44]([CH:2]=[O:4])[CH2:43][CH2:42]2)[CH2:39][CH2:40]1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC(C)(C)[O-]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[Si]1(c2ccccc2)CCC(C2CCC(C=O)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g of potassium t-butoxide was added to a mixture of 35 g of methoxymethyltriphenylphosphonium chloride and 200 ml of THF to prepare an orange ylide solution. A solution of 34 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)cyclohexanone in 50 ml of THF was added to the ylide solution and agitated at room temperature for 2 hours. Thereafter, the mixture was poured into iced water and extracted with methylene chloride, followed by washing, drying and concentration by a usual manner. n-Hexane was added to the residue, and the resultant crystals of triphenylphosphine oxide were removed by filtration. The filtrate was concentrated, and the resultant residue was hydrolyzed with 100 ml of 20% hydrochloric acid, followed by washing, drying and concentration by a usual manner to obtain 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)cyclohexane carbaldehyde.
Reaction SMILES: C[CH:2]([C:14]([OH:16])=[O:15])[N:3]([CH2:7][P:8]([O:12]C)([O:10]C)=[O:9])C(C)C.[OH-].[Na+]>O>[P:8]([CH2:7][NH:3][CH2:2][C:14]([OH:16])=[O:15])([OH:12])([OH:10])=[O:9]
Reactant: COP(=O)(CN(C(C)C)C(C)C(=O)O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 300 °C
Yield: 19.2 %

Procedure:
To a pressure reactor was added 2.09 g (8.3 mmol) of methyl-N-[(dimethoxyphosphinyl)methyl]-N-isopropylglycine, 2.17 g (27.2 mmol) of 50% sodium hydroxide, and 10 ml of water. The reactor vessel was flushed with nitrogen for 15 minutes, sealed, and heated to 300° C. for 3.5 hours while the pressure was controlled to maintain water within the reactor. After cooling and release of residual pressure, the reaction mixture was removed from the reactor and diluted with 5 ml of water. This solution was acidified by the addition of 2.4 ml of hydrochloric acid and purified by ion-exchange chromatography to provide 0.27 g (20% yield) of N-phosphonomethylglycine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:21]3[CH2:30][CH2:29][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:23][CH2:22]3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C1(C2[O:39]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.O>O1CCCC1.C([Li])CCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]3([OH:39])[CH2:30][CH2:29][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:23][CH2:22]3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(C3CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(-c2nc(C3(O)CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decane (Reference Example 95) (734 mg, 1.74 mmol) in tetrahydrofuran (8.7 mL), 1.63 M n-butyllithium/solution in n-hexane (1.17 mL) was added at −78° C., and the obtained solution was stirred at the same temperature for 1 hour. The reaction solution was added at −78° C. to a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (546 mg, 2.09 mmol) in tetrahydrofuran (8.7 mL), and the obtained solution was allowed to warm gradually to room temperature with stirring. Distilled water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (417 mg, 0.954 mmol, 55%) as a colorless amorphous product.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[C:40](=[O:42])[NH2:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON1C(=O)N2C[C@H]1C(C(N)=O)=C[C@H]2CO)C=C.C(ON1C(=O)N2C[C@H]1C(C(N)=O)=C[C@H]2CO[Si](C(C)(C)C)(C)C)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[C:40](=[O:42])[NH2:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON1C(=O)N2C[C@H]1C(C(N)=O)=C[C@H]2CO
Agent: C=CCON1C(=O)N2C[C@H]1C(C(N)=O)=C[C@H]2CO[Si](C)(C)C(C)(C)C
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C(N)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 66.9 %

Procedure:
The title compound (617 mg, 67%) was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-carbamoyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 110, 1.2 g, 1.80 mmol) using the same procedure to prepare Intermediate 109 from Intermediate 108.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[C:8]([CH3:14])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([F:6])[C:8]=1[CH3:14])=[O:4]
Reactant: Cc1c(N)cccc1F
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(F)cccc1NC(=O)CCl
Temperature: 0 °C

Procedure:
A solution of chloroacetyl chloride (38.4 ml, 480 mmol) in ethyl acetate (100 ml) was slowly added to a vigorously-stirred mixture of 3-fluoro-2-methylaniline (60 g, 480 mmol), saturated aqueous sodium bicarbonate (400 ml), ice (ca 100 g) and ethyl acetate (400 ml). Some solid formed then dissolved. After 1 hour the mixture was evaporated to removing the ethyl acetate) and filtered, washing with water. The resulting product was dried in vacuo (94.4 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloropyrdine (4.44 g, 30.0 mmol) and potassium carbonate (8.28 g, 60.0 mmol) in dimethylformamide (60 mL) was purged with nitrogen for 10 min. 4-Aminothiophenol (3.76 g, 30.0 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 h. Water (300 mL) was added and the slurry stirred for 30 min. The resulting solid was filtered, washed with water and vacuum dried at room temperature. Recrystallization from ethyl acetate (35 mL), filtered hot, then cooled gave 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (3.946 g, 56% yield).
Reaction SMILES: BrCC(C1(C2C=CC(Cl)=CC=2)CCC1)=O.[Cl:16][CH2:17][C:18]([C:20]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:23][CH2:22][CH2:21]1)=[O:19].B.CSC.O1CCBN1>>[Cl:16][CH2:17][CH:18]([C:20]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:21][CH2:22][CH2:23]1)[OH:19]
Reactant: COc1ccccc1C1(C(=O)CCl)CCC1
Agent: B
Agent: B1CCON1
Agent: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Solvent: CSC
Product: COc1ccccc1C1(C(O)CCl)CCC1
Yield: 70 %

Procedure:
Following the same procedures used for the asymmetric reduction of 2-Bromo-1-[1-(4-chloro-phenyl)-cyclobutyl]-ethanone (See Example 127), 500 mg samples of 2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone were reduced to the enantiomerically enriched alcohols with borane-methyl sulfide in the presence of S-2-methyl CBS-oxazaborolidine or R-2-methyl CBS-oxazaborolidine. Each isomer of 2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanol was obtained in approximately 70% yield and ca. 90% e.e. based on chiral HPLC analysis. 240 mg of each chloroalcohol was converted to the corresponding epoxide using 1.1 equivalents of cesium carbonate in 5 mL of THF at 50° C. for 3 hours. Dilution with 20 mL of water, addition of 30 mL ether, and extractive workup gave in each instance, after concentration of the organic layers in vacuo and chromatography on silica gel, each of the desired epoxides (176 mg and 184 mg, 86% and 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][CH:7]=1.[CH3:14][C:15]1[N:19]=[C:18]([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)[O:17][N:16]=1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:22]([C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:18]3[O:17][N:16]=[C:15]([CH3:14])[N:19]=3)=[N:13][C:4]=2[CH:3]=1
Reactant: Cc1noc(-c2ccccc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(Br)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 4-bromo-N1-tert-butyl-benzene-1,2-diamine (700 mg, 2.8 mmol) in DMF (15 mL) is added 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzaldehyde (813 mg, 4.3 mmol) at room temperature. Oxone (1.7 g, 2.8 mmol) in H2O (4 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (10 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried, (MgSO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the 5-bromo-1-tert-butyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-1H-benzimidazole (900 mg, 76%) as a pale brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.N.O1CCOCC1.CC[N:41]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl.CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH2:41])=[O:26])=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(C(N)=O)cc3)nn3ccnc23)n1
Yield: 28.6 %

Procedure:
A mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (45 mg, 0.11 mmol), 0.5 M ammonia in dioxane solution (23 mg, 1.3 mmol), EDCI (32 mg, 0.163 mmol) and HOBt (22 mg, 0.163 mmol) in dichloromethane (3 mL), DMF (0.5 mL) and Et3N (22 mg, 0.22 mmol) was stirred at room temperature for 16 h. The solution was concentrated in vacuo, washed with water (10 mL×3), and purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=30:1) to give 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (13 mg, 29%) as a yellow oil. 1H NMR (300 MHz, DMSO): δ 9.68 (s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.12-7.99 (m, 5H), 7.68 (s, 1H), 7.48-7.43 (m, 2H), 6.74 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.26-4.21 (m, 1H), 3.58-3.40 (m, 2H), 2.09-2.00 (m, 3H), 1.74-1.70 (m, 1H), 1.15 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 414, tR=1.547 min, HPLC: 99.34% at 214 nm, 99.33% at 254 nm, tR=5.357 min.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([N:8]([CH:9]2[CH2:10][CH2:11]2)[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C2CC2)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (3.0 ml), 4-chloro-N-cyclopropyl-2-nitroaniline (0.40 g (1.88 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.38 g (1.99 mmol)) was added. After one hour's stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.42 g (61%) of the title compound as yellow crystals
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]=2[F:17])[NH:10][CH:11]2[CH2:13][CH2:12]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH:11]1([N:10]([CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]2[C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]([F:17])=[C:7]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:12][CH2:13]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1c(F)c(N2CCNCC2)cc(NC2CC2)c1[N+](=O)[O-]
Product: CCOC(=O)C(=CN(c1cc(N2CCNCC2)c(F)c(C)c1[N+](=O)[O-])C1CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
To 3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitro-N-cyclopropylaniline (1.57 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and the mixture is heated at 150° C. for 25 hours. After cooling, the reaction product is purified by silica-gel column-chromatography (dichloromethane:methanol=100:1) to give diethyl [N-cyclopropyl-N-[3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitrophenyl]amino-methylene]malonate (1.50 g). The product is dissolved in acetic anhydride (7.9 ml) and thereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C., followed by stirring for 30 minutes. The resultant mixture is poured into ice-water, neutralized, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure. Purification by silica-gel column-chromatography (dichloromethane:methanol=10:1) to give ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (26 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[CH:6][CH:5]=1.[CH3:20][NH:21][C:22]([C:24]1[N:25]([CH3:30])[N:26]=[CH:27][C:28]=1[NH2:29])=[O:23]>>[CH3:30][N:25]1[C:24]([C:22](=[O:23])[NH:21][CH3:20])=[C:28]([NH:29][C:10]([C:8]2[C:7]([NH:13][C:14]3[CH:15]=[N:16][CH:17]=[N:18][CH:19]=3)=[CH:6][CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:9]=2)=[O:12])[CH:27]=[N:26]1
Reactant: COCc1ccc(Nc2cncnc2)c(C(=O)O)n1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(COC)ccc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 6-methoxymethyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (30 mg, 0.12 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (23 mg, 0.15 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as off-white solid (28 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][CH2:21][O:22][C:23](C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:20][CH2:21][O:22][CH3:23])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 100 °C

Procedure:
2,6-Dichloro-4-hydroxybenzaldehyde (0.5 g, 2.62 mmol), 1-bromo-2-methoxyethone (0.3 mL), sodium iodide (0.4 g, 0.4 mmol) and potassium carbonate (0.9 g, 6.55 mmol) were added in DMF (5 mL) and heated at 100° C. for 1 h under stirring. When the reaction was done, the reaction mixture was diluted with EtOAc and extracted three times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The resulting solid was purified by normal phase chromatography (hexanes:EtOAc 3:1) to afford 2,6-dichloro-4-(2-methoxyethoxy)benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][C:3]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.[CH3:22][O:23][CH:24]([O:33][CH3:34])[CH2:25][NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:33][CH3:34])[O:23][CH3:22])[C:11](=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[C:3]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(CNC1CCCCC1)OC
Reactant: Cn1cc(-c2cc(CCOCCC(=O)O)ccc2F)cn1
Product: COC(CN(C(=O)CCOCCc1ccc(F)c(-c2cnn(C)c2)c1)C1CCCCC1)OC

Procedure:
The subtitled compound (3.3 g) was prepared from 3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 13, Step v)] and N-(2,2-dimethoxyethyl)cyclohexanamine using a similar method to that described in Example 12, Step iii). MS [M+H-MeOH]+=430 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.99 and 7.98 (2×s, 1H), 7.86 (and 7.85 (2×s, 1H), 7.47 (m, 1H), 7.09-6.97 (m, 2H), 4.51 and 4.36 (2×t, J=5.4 Hz, 1H), 4.00 and 3.62 (tt, J=3.2 and 12.0 Hz, 1H), 3.920 and 3.918 (2×s, 3H), 3.75-3.63 (m, 4H), 3.34 (s, 3H), 3.33 (d, J=5.6 Hz, 1H), 3.32 (s, 3H), 3.25 (d, J=5.2 Hz, 1H), 2.86-2.79 (m, 2H), 2.65 and 2.63 (2×t, J=6.1 Hz, 2H), 1.79-1.01 (m, 10H); a ˜1:1 mixture of rotamers is observed.