Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:55])([CH3:54])[C:48]([NH:50][CH2:51][CH2:52][OH:53])=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48](=[O:49])[NH:50][CH2:51][CH2:52][OH:53])([CH3:55])[CH3:54])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(=O)NCCO
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)NCCO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-(2-amino-2-methylpropionylamino)ethanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:11]=[C:12]([NH:16][NH2:17])[CH:13]=[CH:14][CH:15]=1.[CH:18]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]1>ClCCl>[Br:9][C:10]1[CH:11]=[C:12]([NH:16][NH:17][C:22]([CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:23])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NNc1cccc(Br)c1)C1CCC1
Reaction time: 1.5 h
Yield: 59.8 %

Procedure:
Triethylamine (6.90 mL, 49.22 mmol) was added dropwise to a suspension of 3-bromophenylhydrazine hydrochloride (5.00 g, 22.37 mmol) in dichloromethane (60 mL) to give a solution. The mixture was cooled in an ice-salt bath and then cyclobutanecarbonyl chloride (2.68 mL, 23.49 mmol) in dichloromethane (10 mL) was added dropwise at such a rate that the internal temperature did not exceed −10° C. After the addition, the mixture was stirred at −5° C. to −10° C. for 1.5 hours. The cooling bath was removed and the mixture was stirred for a further 2 hours at room temperature. The mixture was evaporated in vacuo and 4% aqueous sodium hydrogen carbonate solution was added. The mixture was filtered and the semi-solid was washed with 4% aqueous sodium hydrogen carbonate solution, water and diethyl ether and dried in vacuo to give the title compound (3.60 g, 60%) as a white solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:26]([C:30]1[CH:31]=[C:32]([CH:38]=[C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:40]=1[OH:41])[CH:33]=[CH:34][C:35](O)=[O:36])([CH3:29])([CH3:28])[CH3:27].[NH2:46][C:47]1[CH:48]=[N:49][C:50]2[C:55]([C:56]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:63])=[CH:54][C:53]([CH3:64])=[CH:52][C:51]=2[CH3:65]>CN(C=O)C>[C:42]([C:39]1[CH:38]=[C:32]([CH:31]=[C:30]([C:26]([CH3:28])([CH3:27])[CH3:29])[C:40]=1[OH:41])[CH:33]=[CH:34][C:35]([NH:46][C:47]1[CH:48]=[N:49][C:50]2[C:55]([C:56]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:63])=[CH:54][C:53]([CH3:64])=[CH:52][C:51]=2[CH3:65])=[O:36])([CH3:44])([CH3:45])[CH3:43]
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
1-Hydroxybenzotriazole (154 mg) and dicyclohexylcarbodiimide (272 mg) were added to a solution of 3,5-di-tert-butyl-4-hydroxycinnamic acid (331 mg) in DMF (5 ml). The mixture was stirred at room temperature for minutes, and then, 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (288 mg) was added thereto. The resultant mixture was further stirred at room temperature for 24 hours. The insoluble materials were filtered off, while the filtrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was purified by a silica gel chromatography with benzene-acetone (9:1), then, crystallized from isopropyl ether to give 3-(3,5-di-tert-butyl-4-hydroxycinnamoylamino)-4-(2-chlorophenyl)-6,8-dimethylquinoline (257 mg, 47.5%) as colorless needles.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=[O:11])[CH2:2]1)[CH2:8]2.[NH2:12]OS(O)(=O)=O>C(O)=O>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([NH:12][C:4]3=[O:11])[CH2:2]1)[CH2:8]2
Reactant: NOS(=O)(=O)O
Reactant: O=C1C2CC3CC1CN(C3)C2
Solvent: O=CO
Product: O=C1NC2CC3CC1CN(C3)C2
Temperature: 25 °C

Procedure:
A solution of azaadamantan-4-one (2.0 g, 13.2 mmol; Synthesis 1992, 1080) in formic acid (10 mL) at room temperature was treated with a solution of hydroxylamine-O-sulfonic acid (2.24 g, 19.8 mmol; Aldrich) in formic acid (7 mL) added dropwise. The resulting mixture was then heated at reflux for 3.5 hours. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, and the resulting oil was diluted with 1 NNaOH and extracted with chloroform (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (115 g), eluting with 5-10% methanol (containing 1% ammonium hydroxide)-chloroform to afford the title compound: MS (DCI/NH3) m/z 167 (M+H)+, 184 (M+NH4)+.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)([O:5][CH2:4][C@H:2]1[O:3][CH2:1]1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Temperature: 2.5 °C
Yield: 78.4 %

Procedure:
To a solution of 6.7 g of (R)-glycidol (0.09 mol)(optical purity: 99.4% ee) and 50 ml of water, 0.17 g of N,N-dimethylaminopyridine (0.0014 mol) and 17.2 g of p-toluenesulfonyl chloride (0.09 mol) in 50 ml of toluene, and then 18.1 g of 24% sodium hydroxide (0.11 mol) were added under stirring at 0-5° C. And the solution was stirred for one hour. After separation with a separating funnel, the organic layer was washed with 50 ml of 1% hydrochloric acid and 50 ml of water. The excess solvent was removed under vacuo. The chemical purity by HPLC and optical purity at that time were 99.5%, 99.5% ee respectively. The residue was recrystallized from isopropyl alcohol/hexane=1/1 (V/V) to give 16.1 g of (S)-glycidyl tosylate (yield 78%). Chemical purity: 99.9%, Optical purity: 99.6% ee
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][NH:9][C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH3:27])[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=1.[H-].[Na+].O>CC(N(C)C)=O>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:17]([CH3:27])[CH:16]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Reactant: Cc1cc2c(c(Cl)n1)CNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc2c(c(Cl)n1)CN(Cc1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 4-chloro-6-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (91 mg, 0.50 mmol, Step-1), 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (119 mg, 0.50 mmol, Step-3 in Amine-3) and sodium hydride (40 mg, 0.99 mmol) in DMA (1.7 mL) is stirred for 1 hour at rt. The reaction mixture is poured into water and extracted with EtOAc. The organic layer is dried over sodium sulfate. After filtration, the filtrate and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1) to give 65 mg (34% yield) of the title compound as colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:24][C:25]([O:28][C:29]([NH:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34])=[O:30])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C>[C:25]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:2][C@H:3]([C:10]1[CH:11]=[C:12]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:15]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CCOC(=O)C[C@H](N)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
To a solution of a mixture of (S)-ethyl 3-amino-3-(3,5-di-tert-butylphenyl)propionate hydrochloride (112.0 mg, 0.33 mmol) and Boc-Gly-Osu (95.0 mg, 0.35 mmol) in anhydrous DMF was added triethylamine (62 μL, 0.45 mmol) and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight to give a colorless solution. The solvent was evaporated in-vacuo and the residue was partitioned between ethyl acetate (25 mL), water (25 mL) and saturated NaHCO3 solution (10 mL). The organic layer was removed, washed with water (1×10 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford a cream foamy solid (163.4 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 463 (M+H) and m/.z 485 (M+Na); Calcd for C26H42N2O5: 462.62. The above product will be used as such for the Boc-deprotection. (step #5).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:13][N:12]([CH3:14])[N:11](C)[CH2:10]2)=[O:7])=[C:4]([O:19][CH3:20])[CH:3]=1.Cl[O-].[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:13][N:12]([CH3:14])[N:11]=[CH:10]2)=[O:7])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CN(C)N(C)C1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1C=NN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of 1.44 g (0.00482 mole) of 4-amino-5-chloro-2-methoxy-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide in 100 ml of methanol, cooled to -30° C. and under nitrogen atmosphere was added dropwise 10.5 ml (0.007 mole) of 5% aqueous sodium hypochlorite over a 15 minute period. The mixture was slowly warmed to 0° C. at which temperature it was stirred for 1 hr. The mixture was diluted with 250 ml of chloroform and extracted successively with 100 ml of water and 100 ml of saturated sodium chloride solution. The chloroform layer was dried over sodium sulfate and concentrated in vacuo. The concentrate was filtered through silica gel (eluted with ethyl acetate:hexane:methanol, 4.5:4.5:1). The filtrate was concentrated and the residue was triturated with cold diethyl ether to give 0.58 g (43%) of the title product as white powder, m.p. 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:33][C:34]([F:37])([F:36])[F:35].[N:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45](=O)[O:46]C2C=CC=CC=2)=[CH:40][CH:39]=1>O1CCOCC1>[F:27][C:24]([F:25])([F:26])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:45]([NH:44][C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)=[O:46])=[C:3]([O:33][C:34]([F:36])([F:37])[F:35])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1)([OH:32])[C:28]([F:29])([F:30])[F:31]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Temperature: 80 °C
Yield: 4.8 %

Procedure:
(4-Amino-3-(trifluoromethoxy)phenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.367 mmol, 200 mg) and phenyl pyridin-4-ylcarbamate (0.550 mmol, 118 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (11.7 mg). MS (ESI) m/z 666.3 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-chloro benzene-1-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([C:34]([F:37])([F:36])[F:35])[CH:23]=2)=[O:20])=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([C:34]([F:36])([F:35])[F:37])[CH:23]=2)=[O:20])=[CH:38][C:39]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:153-155° C.; 1H NMR (300 MHz, CDCl3) δ: 10.34 (1 H, s), 8.36 (1 H, s), 8.24-8.27 (1 H, d, J=8.1 Hz), 8.03 (1 H, s), 7.82-7.85 (1 H, d, J=8.1 Hz), 7.48 (1 H, s), 7.41-7.44 (1 H, d, J=8.7 Hz), 7.34-7.37 (2 H, t, J=9.3 and 8.7 Hz), 6.80 (1 H, s), 6.61-6.64 (1 H, d, J=9.6 Hz), 5.57-5.59 (1 H, d, J=6.0 Hz), 4.22-4.29 (1 H, m), 2.45-2.48 (2 H, m), 2.28 (3 H, s), 1.76-2.01 (4 H, m). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C28H24ClF3N6O: 276.0821. found: 276.0817.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]2[N:5]([CH:10]=[CH:11][N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1.[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Br:2][C:3]1[C:4]2[N:5]([C:10]([F:14])=[CH:11][N:12]=2)[N:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Fc1cnc2c(Br)cc(Cl)nn12
Reaction time: 6 h
Yield: 24.2 %

Procedure:
In a 20 ml reaction vial was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine hydrochloride salt (0.33 g, 1.4 mmol) from Example I(1), step 1b, CH3CN (7.0 ml) and selectflor (0.5 g, 1.4 mmol). The reaction was stirred at 50 C for 6 hrs, then concentrated to dryness. Purification was done by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to give 0.085 g of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23].Cl>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[O:3][CH2:1][CH3:2])[CH:8]=[O:9]
Reactant: ClCCCBr
Reactant: CCOc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1OCCCCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Ethoxy-3-hydroxybenzaldehyde (74.3 g) and potassium carbonate (111.3 g) were suspended in N,N-dimethylformamide (350 mL). To the mixture was added dropwise 1-bromo-3-chloropropane (79.6 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid (300 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (69.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:21][CH2:22][C@@H:18]([NH:17][C:16](=[O:23])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19]2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cc2C=O)C1
Temperature: 120 °C
Yield: 83.3 %

Procedure:
5-Bromo-2-fluorobenzaldehyde (1.55 mL, 13.0 mmol) and tert-butyl-(3R)-pyrrolidin-3-ylcarbamate (2.90 g, 15.6 mmol) in DMF (70 mL) were treated with potassium carbonate (2.25 g, 16.3 mmol). The solution was heated to 120° C. for 18 h under nitrogen. The solution was allowed to cool to ambient temperature and was diluted with ethyl acetate (150 mL) and washed with water (100 mL). The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (30% ethyl acetate/hexanes) to afford product 22-A as a yellow solid (4.00 g, 83%). 1H NMR (500 MHz, CD3OD): δ 10.02 (s, 1H), 7.81 (d, J=2.9 Hz, 1H), 7.51 (dd, J=11.2, 2.4 Hz, 1H), 6.88 (d, J=9.27 Hz, 1H), 4.20 (m, 1H), 3.60–3.51 (m, 2H), 3.42 (m, 1H), 3.21 (m, 1H), 2.22 (m, 1H), 2.00 (m, 1H), 1.46 (s, 9H); LCMS found for C16H21N2O3Br (M+H)+: m/z=370.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[C:3]1=[O:13].[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][N:27]([CH:2]4[CH2:10][C:9]5[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=5)[C:3]4=[O:13])[CH2:26][CH2:25]3)[C:18]=2[O:17][CH2:16][CH2:15]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: COc1ccc2c(c1)C(=O)C(Br)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(N1CCN(c3cccc4c3OCCO4)CC1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A suspension prepared from 25.3 g (100 mmol) of the compound obtained in Step 1, 22.0 g (100 mmol) of (2,3-dihydro[1,4]benzodioxin-5-yl)piperazine, 13.8 g (100 mmol) of potassium carbonate and 140 ml of dimethylformamide is stirred at room temperature for 20 hours. The mixture is then poured into 1.5 litres of water, and the solid that forms (violet) is filtered off, rinsed with water and dried in vacuo to obtain 28.1 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:27][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:26])[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)c(C)nn23)ccc1F
Yield: 74.9 %

Procedure:
A mixture of 0.046 g (0.38 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 92 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [F:1][C:2]([F:17])([S:13][CH2:14][CH2:15][OH:16])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[Cl:18][CH:19]([CH2:23][Cl:24])[C:20](O)=[O:21]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:18][CH:19]([CH2:23][Cl:24])[C:20]([O:16][CH2:15][CH2:14][S:13][C:2]([F:1])([F:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])=[O:21]
Reactant: OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)C(Cl)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: O=C(OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(Cl)CCl
Yield: 96.5 %

Procedure:
1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (138.4 g (400 mmol)) was dissolved in a mixture liquid of DMF (400 ml) and water (80 ml), and mercaptoethanol (32.2 g (400 mmol)) was added. Further, sodium formate (27.2 g (400 mol)), sodium sulfite heptahydrate (100.9 g (400 mmol)) were added, and stirred at room temperature (23° C.) for one night. Water (1 L) and isopropyl ether (1 L) were added to the reaction liquid, which was separated. A water layer was further extracted with isopropyl ether (500 ml×2). The organic layer was washed with 10% hydrochloric acid (500 ml), water (500 ml) and a saturated saline solution (500 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 2-(perfluorobutylthio)ethanol. Then, p-toluene sulfonic acid monohydrate (2.5 g (13.1 mmol)) was added to a solution of 2-(perfluorobutylthio)ethanol (50 g (equivalent to 158 mmol)) and 2,3-dichloropropionic acid (22.5 g (157 mmol)) in cyclohexane (500 ml), and was subjected to dehydration condensation reaction (bath temperature: 90° C.) for one night by using a Dean-Stark method. The reaction liquid was filtered with celite. An organic layer was washed with water three times and with saturated saline solution, and dried over anhydrous magnesium sulfate. The filtration and concentration under reduced pressure gave crude 2-(perfluorobutylthio)ethyl 2,3-dichloropropionate (63.8 g). Yield: 96.5%.