Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH2:11]([O:14][C:15]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])[CH2:12][CH3:13]>O>[C:1]([S:24][C:21]1[CH:22]=[CH:23][C:15]([O:14][CH2:11][CH2:12][CH3:13])=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CCCOc1ccc(S)cc1C(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCOc1ccc(SC(C)(C)C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
t-Butanol (16 g.) was added to an aqueous sulphuric acid solution (200 ml.; containing 75% w/w sulphuric acid) cooled in ice-water. The mixture was stirred until all the t-butanol had dissolved, and then 2-propoxy-5-mercaptobenzamide (20 g.; prepared as described in Reference Example 2) was added in small portions with stirring during 15 minutes. After all the solid had dissolved the mixture was allowed to warm up to room temperature and kept at that temperature for 15 minutes. The solution was diluted with water (600 ml.), and the precipitated solid was filtered off and dissolved in chloroform (200 ml.). The chloroform solution was then washed with aqueous sodium hydroxide solution (2N; 40 ml.) and then with water (3 × 20 ml.), and dried over sodium sulphate. The solvent was removed in vacuo and the residue was recrystallised from aqueous ethanol, to give 5-t-butylthio-2-propoxybenzamide (15 g.), m.p. 135.5° - 137.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([O:25]C)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1CCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(Nc2nc(N3CCC(C(=O)O)C3)nc3scnc23)cc1OC
Reaction time: 24 h
Yield: 62.3 %

Procedure:
To a stirred solution of methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylate (160 mg, 0.38 mmol) in 10 mL of methanol was added a solution of sodium hydroxide (154 mg, 3.8 mmol) in 2 mL of water at room temperature. Then the reaction mixture was stirred at this temperature for 24 hours. Then solvent was evaporated at 40° C. at reduced pressure and the residue was suspended in 30 mL of THF, then treated with 2N HCl to pH=2. The solvent was evaporated and the residue was dissolved in 50 mL of THF, then filtered and the filtrate was evaporated to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (95 mg, 61.4%) as a yellow solid. LC-MS: 402.1 [M+H]+, tR=1.33 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[C:5]#[N:6].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:23]=[N:24][NH:25][N:6]=2)[CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH3:18])[C:14]([C:19]([F:20])([F:21])[F:22])=[CH:13][N:12]=1
Reactant: CNc1nc(Nc2ccc(C#N)cc2Cl)ncc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(Nc2ccc(-c3nn[nH]n3)cc2Cl)ncc1C(F)(F)F
Temperature: 125 °C
Yield: 28.3 %

Procedure:
To a solution of 3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile (135 mg, 6.41 mmol) in DMF (2 mL) was added sodium azide (80 mg, 1.24 mmol) and ammonium chloride (66 mg, 1.24 mmol). The mixture was heated at 125° C. for 18 h. The mixture was cooled, filtered and the solid washed with ethyl acetate. The filtrated was concentrated under reduced pressure and the crude residue was diluted with water (5 mL) and diethyl ether (5 mL). A precipitate formed which was filtered and washed with further portions of water and diethyl ether. The solid was co-evaporated with dichloromethane and methanol and then dried in a vacuum oven to yield N2-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (130 mg, 85%). LCMS (ESCI_Formic_MeCN): [MH+]=371 at 3.11 min. 1H NMR (400 MHz, DMSO): δ 8.94 (s, 1H); 8.26-8.19 (m, 2H); 8.14 (d, J=2.0, 1H); 8.03-7.96 (m, 1H); 7.30-7.22 (m, 1H); 2.89 (t, J=4.4, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:24][NH:23][CH2:22]2)=[CH:16][CH:15]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:23]2[CH2:24][CH:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)[CH2:22]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1ccc(NC2CNC2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2)C1
Yield: 78.4 %

Procedure:
The title compound (D84) (79 mg) was prepared according to the experimental procedure described in Description 62 starting from Methyl 2,5-dichloronicotinate (62.06 mg, 0.3 mmol) and N-(4-fluorophenyl)azetidin-3-amine (D54) (60 mg, 0.361 mmol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[O:12][CH2:13][C:14](=[O:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: CCOC(=O)C1=C(Nc2ccc3ncsc3c2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc3ncsc3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 45.2 %

Procedure:
To a solution of ethyl 2-(benzo[d]thiazol-6-ylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.070 g, 0.23 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.034 g, 0.23 mmol) in ethanol (6.0 mL), L-proline (0.0030 g, 0.023 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.045 g, y. 45%).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:33])(=[O:32])[NH:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[C:30]([CH2:29][CH2:28][CH2:27][NH:26][S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:33])=[O:32])#[N:31]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCCC#N)C4(CC4)C3)ncnc21
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N#CCCCNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[4-(3-Cyano-propylsulfamoyl)-4,7-diaza-spiro[2.5]oct-7-yl]-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 18) was dissolved in THF (1 mL), added TFA (0.5 mL) and then stirred at rt for 2 h.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]=[C:20]=[O:21].O>CC(C)=O>[CH3:18][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:9][CH2:10][C:11]([CH2:16][CH3:17])([CH2:14][CH3:15])[CH2:12][O:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)COC(c2cccc(N)c2)OC1
Reactant: CN=C=O
Solvent: CC(C)=O
Solvent: O
Product: CCC1(CC)COC(c2cccc(NC(=O)NC)c2)OC1

Procedure:
Nine and four tenths grams (9.4 g) of 2-(m-aminophenyl)-5,5-diethyl-1,3-dioxane was reacted with 3 g of methyl isocyanate in 75 ml of acetone. The mixture was refluxed for between one and two hours and poured into water and the product collected by filtration. The yield was 11.7 g of the title compound, m.p. 112°-125° C. Trituration with diethyl ether raised the melting point to 135°-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][C:5]([CH3:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1N
Reaction time: 16 h
Yield: 80.5 %

Procedure:
1-Bromo-2-(2,4-difluoro-phenoxy)-4-methyl-5-nitro-benzene (87.0 g, 253 mmol) was dissolved in THF (300 mL) and diluted with MeOH (900 mL). Zinc dust (82.7 g, 1.26 mol) was added and 1 L of saturated NH4Cl was added slowly so that the reaction temperature never exceeded 42° C. The reaction was mechanically stirred vigorously for 16 hours. The reaction was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was then concentrated with 1.2 L of saturated NH4OAc. When the THF/MeOH was removed, the solids were collected and washed with water. The solids were then stirred in 1 L water for 30 min, then collected via filtration and rinsed with water (1 L) in three portions. The resulting solid was dried under high vacuum for 48 hours to produce 64 g of the desired product (81% yield). MS (ESI+) m/z 314, 316 (M+1, Br pattern) detected; 1H NMR (400 mHz, CDCl3) δ 6.92 (m, 1H), 6.91 (s, 1H), 6.75 (m, 2H), 6.70 (s, 1H), 3.57 (br. s, 2H), 2.08 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O1CCCC1.[Cl-].[Na+].O>[C:25]([O:13][CH:11]1[CH2:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10]1)(=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: OC1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OC1CC(c2ccccc2)NC(c2ccccc2)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a -70° C. solution of 2.50 g (9.9 mmol) of 2,6-diphenyl-4-hydroxypiperidine in 80 ml of dry tetrahydrofuran (THF), 4.2 mL (10.5 mmol) of n-butyllithium (2.5M in hexanes) is added dropwise. The mixture is warmed to -20° C. and stirred for 30 minutes. The solution is then cooled again to -70° C. and a solution of 2.2 g (9.9 mmol) of lauroyl chloride in 20 mL of dry THF is then added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is added to 250 mL of brine and then extracted with 2×200 mL of ether. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by liquid chromatography (LC) (silica gel, ethyl acetate/hexane) to give 3.2 g (74%) of the title compound as a white solid: mp 40°-42° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH2:14][O:13]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[CH:31][NH:30][N:29]=2)=[CH:24][CH:23]=1.[H-].[Na+]>C(O)(C)(C)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:32]=[CH:31][N:30]([CH2:14][C:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[OH:13])[N:29]=2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(-c2nc[nH]n2)cc1
Reactant: Fc1cc(C(F)(F)F)ccc1C1(Cn2cncn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: OC(Cn1cncn1)(Cn1cnc(-c2ccc(F)cc2)n1)c1ccc(C(F)(F)F)cc1F

Procedure:
2-(2-Fluoro-4-trifluoromethylphenyl)-2-(1,2,4-triazole-1-ylmethyl)oxirane (0.4 g.) and 3-(4-fluorophenyl)-1,2,4-triazole (0.3 g.) were added to a solution of sodium hydride (0.1 g. of a 50% dispersion in oil) in tert-butyl alcohol (10 ml.) and the mixture was heated at 80° for 16 hours. The reaction mixture was evaporated to dryness and the residual gum was partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated to dryness. The residual gum was chromatographed on a K60 silica column, eluting successively with chloroform/petroleum ether (b.p. 60°-80° C.) 60/40 v/v, 70/30 v/v and 80/20 v/v, to give 2-[3-(4-fluorophenyl)-1,2,4-triazole-1-yl]-1-(2-fluoro-4-trifluoromethylphenyl)-1-(1,2,4-triazole-1-ylmethyl)-ethanol, m.p. 96°-100°.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>CN(C=O)C.CCOC(C)=O>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: N#Cc1cccc(CCN)c1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)C(NCCc2cccc(C#N)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 8.7 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.525 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 3-(2-Aminoethyl)benzonitrile (78 mg, 0.530 mmol) was added followed by TEA (53 mg, 0.525 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (18 mg, 56.3%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 2.60 (t, 2H), 3.17 (q, 2H), 4.37-4.46 (m, 1H), 5.49 (bs, 1H), 6.88 (s, 1H), 7.02 (d, 1H), 7.30-7.34 (m, 1H), 7.47-7.57 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 20.38, 35.75, 44.70, 47.90, 107.72, 113.00, 118.70, 125.17, 129.19, 129.67, 130.36, 130.77, 131.95, 132.20, 133.23, 135.11, 139.03, 158.60; Mass Spectrum: M+H+ 396.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[C:18]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:19]2[N:20]([C:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][N:24]=2)[N:21]=1>CO.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:16]2[CH:17]=[C:18]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:19]3[N:20]([C:22]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)=[O:26])=[CH:23][N:24]=3)[N:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCCN(Cc2ccccc2)C1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(Cl)nn12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(N[C@H]3CCCN(Cc4ccccc4)C3)nn12
Temperature: 170 °C
Yield: 7.1 %

Procedure:
A vial containing a mixture of (S)-1-benzylpiperidin-3-amine (0.385 g, 2.021 mmol) and 6-chloro-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 37A (0.08 g, 0.135 mmol) was heated to 170° C. overnight. The mixture was dissolved in 3 mL methanol and 3 mL Solvent B (90% MeOH, 10% water, 0.1% TFA). One drop of TFA was added to the solution, the sample was split into 4 equal volumes and purified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 20-100% solvent B gradient, 20 mL/min, 220 nM UV detection to provide (S)-6-(1-benzylpiperidin-3-ylamino)-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.0082 g, 9.52 μmol, 7.06% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.42 (2H, m), 8.02-7.68 (5H, m), 7.49 (1H, m), 7.29-6.76 (9H, m), 4.2-3.95 (2H, m), 3.73-3.58 (1H, m), 3.37 (1H, m), 3.06-2.64 (2H, m), 2.32-1.78 (3H, m). LC/MS: HPLC Retention time: 2.15 min, MS: 520 (M+1) (Shimidazu LC, Waters Sunfire C-18 column (4.65×50 mm, 5 um, 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection. Solvent A: 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:38]=[CH:37][C:8]([C:9]([N:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:38]=[CH:37][C:8]([C:9]([N:11]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(O)c2)cc1
Reaction time: 12 h
Yield: 74.1 %

Procedure:
4-Acetylamino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (50.0 mg, 0.10 mmol) was dissolved in methylene chloride (3.0 ml) to which was subsequently added a methylene chloride solution (1 ml) of boron tribromide (0.018 ml, 0.19 mmol) at 0° C. After 12 hours of stirring at 0° C. to room temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, and dried on anhydrous sodium sulfate. Thereafter, the solvent was distilled off under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (ethyl acetate-chloroform:methanol=10:1) to obtain 37.3 mg (76.7%) of the title compound in a light yellow amorphous form.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.Cl.CCCCCC>C(Cl)Cl>[ClH:16].[N+:23]([C:22]1[C:17]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 8.2 %

Procedure:
A mixture of 56.0 g (0.28 mole) of 2-aminobenzophenone and 49.6 g (0.31 mole) of 2-chloro-3-nitropyridine was heated in an oil bath with stirring at 150° C. for 45 minutes. After cooling, an 8.7 g portion of the product was dissolved in 45 ml of methylene chloride, hydrogen chloride gas was added for 15 min and 100 ml of hexane was added. After stirring for 20 min, solid was collected and washed twice with 1:3 mixture of methylene chloride to hexanes. After drying in air, 8.2 g (81.6%) product was obtained.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.Br[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1>>[CH3:27][C:24]1[N:25]=[CH:26][C:21]([CH2:20][CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=2)[NH2:16])=[CH:22][CH:23]=1
Reactant: Cc1ccc(NN)cc1
Reactant: Cc1ccc(CCBr)cn1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by General Method 1. Triethylamine (13.0 mL, 94.5 mmol) was added dropwise to p-tolylhydrazine hydrochloride (5.0 g, 31.5 mmol) over a period of 5-min. The reaction mixture was stirred for additional 10 min. 5-(2-bromoethyl)-2-methylpyridine (6.3 g, 31.5 mmol) was added dropwise at 25° C. over a period of 10-15 min. The reaction mixture was stirred at RT for 1 h and the subsequently heated at 90° C. for 2-3 h at which point the reaction was found complete by TLC and LC-MS. Reaction mixture was concentrated under reduced pressure and diluted with water (50 mL) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain crude product as dark brown oil (16.7 g). Purification of crude product by column chromatography (silica gel, 100-200 mesh, eluent: 0-40% ethyl acetate-Hexane) furnished 1.92 g of pure product as brown liquid. Yield: 25%.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:22]([NH:24]O)=[NH:23])[CH3:18]>>[CH:1]1([C:6]2[CH:7]=[C:8]([C:9]3[O:11][N:24]=[C:22]([C:21]4[CH:26]=[C:27]([CH3:34])[C:28]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:19]([CH2:17][CH3:18])[CH:20]=4)[N:23]=3)[CH:12]=[C:13]([O:15][CH3:16])[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)cc(C2CCCC2)n1
Reactant: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1NS(C)(=O)=O
Yield: 48.4 %

Procedure:
The title compound (48 mg) is prepared in analogy to Example 11 starting from 2-cyclopentyl-6-methoxy-isonicotinic acid (48 mg, 217 μmol) and 3-ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (62 mg, 228 mmol); LC-MS**: tR=0.91 min, [M+H]+=457.05; 1H NMR (CDCl3): δ1.35 (t, J=7.5 Hz, 3H), 1.71-1.80 (m, 2H), 1.84-1.95 (m, 4H), 2.06-2.16 (m, 2H), 2.56 (s, 3H), 2.93 (q, J=7.5 Hz, 2H), 3.18 (s, 3H), 3.21-3.30 (m, 1H), 4.02 (s, 3H), 5.88 (s, 1H), 7.31 (s, 1H), 7.51 (s, 1H), 7.97 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(#N)C>[F:12][C:11]1[C:2]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:5][CH2:4]2)[CH:10]=1
Reactant: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2Cc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2Cc1ccccc1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
50 mg of compound (182) obtained in Example 59, 26 mg of pyrrolidine and 10 mg of triethylamine were added to 3 ml of acetonitrile, and the solution was heated at 80° C. for 3 hours. The solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with ethanol and ether in this order to obtain 33 mg of the subject compound (183).