Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCCOC)=O)=NC(OCCOC)=O.[CH3:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([CH3:27])=[CH:20][C:19]=1[OH:28].[CH:29]1([CH:32](O)[CH3:33])[CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:29]1([CH:32]([O:28][C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[CH3:17])[CH3:33])[CH2:31][CH2:30]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1O
Reactant: CC(O)C1CC1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)cc1OC(C)C1CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
3.10 g of Bis(2-methoxyethyl) azodicarboxylate was added to a mixture of 1.70 g of 2,5-dimethyl-4-nitrophenol, 0.88 g of (1-cyclopropyl) ethanol, 3.20 g of triphenylphosphine and 100 mL of toluene at 0° C., and the mixture was stirred at 80° C. for 4 hours. After cooling, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 1.09 g of 1-(1-cyclopropylethoxy)-2,5-dimethyl-4-nitrobenzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:24](O)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Temperature: 25 °C
Yield: 102.3 %

Procedure:
To a stirred solution of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylcarboxylic acid (1.12 g, 3.13 mmol) in THF (30 ml) was added BH3.DMS (0.63 ml, 6.3 mmol) at 0° C. The mixture was raised to room temperature immediately and then heated at 50° C. for 1.5 h. After cooling to room temperature, the mixture was quenched by the addition of water at 0° C. and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (50/1)], to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (1.10 g, 100%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.45 (m, 1H), 3.58–4.80 (m, 4H), 5.01 (br, 1H), 7.04–7.99 (m, 7H).
Reaction SMILES: [CH2:1]1[CH2:11]C[N:9]2[C:4](=NCCC2)[CH2:3][CH2:2]1.[C:12]([O:16][C:17](=[O:21])CC#N)([CH3:15])([CH3:14])[CH3:13].BrCCCBr>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17]([C:3]1([C:4]#[N:9])[CH2:2][CH2:1][CH2:11]1)=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: BrCCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(C#N)CCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DBU (23.5 mL) was added slowly to a solution of cyano-acetic acid tert-butyl ester (8.84 g) in DMF (100 mL) at rt, followed by addition of 1,3-dibromopropane (13.9 g); then the reaction mixture was stirred in an oil bath (bath temperature=80° C.) overnight. The reaction was cooled, diluted with EtOAc, then washed with cold water, dil. NaCl solution; EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was column purified to give title compound (6.58 g). 1H NMR in CDCl3, δ in ppm: 2.8-2.5 (m, 4H), 2.4-2.2 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1.CCN(CC)CC>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[C:3]([C:4](=[O:5])[NH2:6])[CH:7]=1
Reactant: Cc1cc(Br)cc(C(N)=O)c1N
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C(N)=O)c1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-bromo-3-methylbenzamide (820 mg, 3.55 mmol, 1.0 eq.) in THF (15 mL) and Et3N (0.7 nit) was added nicotinoyl chloride (551 mg, 3.91 mmol, 1.1 eq.) in anhydrous THF (15 mL) dropwise. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the resultant precipitate was filtered and dried in vacuo to give 1.74 g of crude iii-e as a yellow solid. LCMS m/z=333.8, 335.8 (M+1) (Method B) (retention time=1.42 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[C:20]([F:26])([F:25])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][CH:20]([F:26])[O:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(OC(F)F)c2)C1
Temperature: 120 °C
Yield: 69.5 %

Procedure:
(3-Hydroxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 115, 300 mg, 1.19 mmol) and methyl 2-chloro-2,2-difluoroacetate (258 mg, 1.78 mmol) were dissolved in dry DMF (2 mL). Potassium carbonate (328 mg, 2.38 mmol) was added and the reaction was heated to 120° C. under microwave irradiation for 1 hour. The reaction was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of 20% hexanes in ethyl acetate to 100% ethyl acetate to afford the title compound as a yellow oil (250 mg, 67.3%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a suspension of 1.26 g (5.86 mmol) of 4-bromo-2-methylbenzoic acid in 10 mL of CH2Cl2 was added 1.5 mL (17.6 mmol) of oxalyl chloride and two drops of DMF. After stirring at rt overnight, the reaction mixture was concentrated. The residue was dried azeotropically using toluene (3×5 mL) and then dissolved in 10 mL of CH2Cl2, to which 667 μL (6.45 mmol) of benzyl alcohol, 1.23 mL (8.79 mmol) of triethylamine, and catalytic amount of 4-dimethylaminopyridine were added. After stirring at rt for 1 h, the reaction mixture was poured into 20 mL brine. The aqueous layer was extracted with CH2Cl2 (3×10 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant afforded 1.58 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.58 (s, 3H), 5.33 (s, 2H), 7.33-7.44 (m, 7H), 7.81 (d, J=8.5, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:25]>CC(O)C>[NH2:25][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(N)ncnc32)C1
Yield: 78 %

Procedure:
A solution of (R)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.0 g, 4.32 mmol) in IPA saturated with NH3 (20 mL) was stirred at 100° C. for 12 h in a 100 mL of autoclave. The organic layer was concentrated and purified on silica gel chromatography (eluted with PE:EtOAc=1:1) to afford (R)-tert-butyl 3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.5 g, 78% in yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.C(O)(=O)C>C(O)C.O.[Zn]>[CH3:11][S:10][C:4]1[N:5]=[CH:6][C:7]([C:8]#[N:9])=[CH:2][N:3]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CSc1ncc(C#N)cn1
Reaction time: 3 h

Procedure:
To a stirred mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (0.843 g, 4.54 mmol) and zinc dust (1.48 g, 22.71 mmol) in ethanol (7.5 mL) and water (1.4 mL) was slowly added acetic acid (0.29 mL, 5.13 mmol). The resulting reaction mixture was vigorously stirred for 3 h. The solids were removed by filtration and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel 60 (35 g), eluting with 10:1-20:89-70 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 152.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][NH:13][NH2:14]>C(O)(=O)C.O>[OH:6][C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[N:13]([CH3:12])[N:14]=1
Reactant: CNN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(O)c2ccccc2c1=O

Procedure:
Phthalic anhydride (7.4 g) was dissolved in hot acetic acid (50 ml) and a solution of methylhydrazine (2.7 ml) in water (50 ml) was added. The mixture was heated under reflux for 15 minutes and left to cool overnight. The precipitate that formed was filtered off, washed with water and dried under reduced pressure at 65° C. to yield 1,2-dihydro-4-hydroxy-2-methyl-1-oxophthalazin (7.6 g) as a white solid. m.p. 243-244° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[F:25][C:26]([F:34])([F:33])[CH2:27][CH:28]([OH:32])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:25][C:26]([F:34])([F:33])[CH2:27][CH:28]([OH:32])[C:29]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:30]
Reactant: O=C(O)C(O)CC(F)(F)F
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)C(O)CC(F)(F)F)CC3)nc(-c3ccccc3O)nc2c1
Yield: 69.2 %

Procedure:
2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (87 mg, 0.27 mmol), 4,4,4-trifluoro-2-hydroxybutanoic acid (43 mg, 0.27 mmol), HATU (0.12 g, 0.33 mmol) and triethylamine (45 μL, 0.33 mmol) were stirred in DMF (3 mL) at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4 and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in 1:1 CH2Cl2: hexanes gave 4,4,4-trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one as an off-white solid (86 mg, 66%). 1H NMR (400 MHz, CDCl3) d 8.46 (dd, J=8.0, 1.7 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.41-7.37 (m, 1H), 7.31 (dd, J=8.5, 1.5 Hz, 1H), 7.05-7.03 (m, 1H), 6.97-6.93 (m, 1H), 4.80-4.75 (m, 1H), 4.07-3.68 (m, 9H), 2.56 (s, 3H), 2.50-2.39 (m, 2H) ppm; LC/MS: m/z 461.3 (M+H)+ at 2.49 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15](Br)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=O)(C)(C)C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].ClCCl.[CH:51]1([C@H:57]([NH:62][C:63]([C:65]2[O:66][C:67](Br)=[CH:68][CH:69]=2)=[O:64])[C:58](=[O:61])[NH:59][CH3:60])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:51]1([C@H:57]([NH:62][C:63]([C:65]2[O:66][C:67]([C:15]3[CH:14]=[CH:13][C:12]4[N:8]=[C:9]([CH2:18][C:19]5[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=5)[NH:10][C:11]=4[CH:16]=3)=[CH:68][CH:69]=2)=[O:64])[C:58](=[O:61])[NH:59][CH3:60])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CC(C)(C)OC(=O)n1c(Cc2ccncc2)nc2cc(Br)ccc21
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(Br)o1)C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2ccc3nc(Cc4ccncc4)[nH]c3c2)o1)C1CCCCC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A pressure vial is charged with 5-bromo-2-pyridin-4-ylmethyl-1H-benzimidazole-1-carboxylic acid tert-butyl ester (100 mg, 0.26 mmol), bis(pinacolato)diboron (72 mg, 0.28 mmol), KOAc (99 mg, 1.01 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (PdCl2(dppf)*CH2Cl2) (8.2 mg, 0.01 mmol). After flushing with nitrogen, DME (2 mL) is added and the reaction stirred at 100° C. for 2 h. The mixture is cooled to room temperature before 5-bromo-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (88 mg, 0.26 mmol), PdCl2(dppf)*CH2Cl2 (8.2 mg, 0.01 mmol), and 2M Na2CO3 solution (0.84 mL, 1.68 mmol) are added. The mixture is stirred at 110° C. for 8 h. Water is added and the mixture is extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the residue was purified by reversed phase (HPLC). The product is obtained as a pale yellow solid. 19 mg, 15%, LC/MS ESI m/z (M+H)+=472.46
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrBr>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1cccc(F)c1
Reactant: Fc1ccccc1
Agent: BrBr
Product: CC(=O)C(c1ccc(F)cc1)c1cccc(F)c1
Reaction time: 1 h

Procedure:
A solution of 16.5 g. of m-fluorophenyl-2-propanone [Z. Eckstein and J. Plenkiewicz, Rocznik, Chem., 37, 907 (1963)]in 70 ml. of p-fluorobenzene is cooled and stirred as 5.5 ml. of bromine are added dropwise. Argon gas is bubbled through the mixture for one hour. The solution is then added dropwise to a mixture of 29.6 g. of aluminum chloride and 70 ml. of p-fluorobenzene, stirred at 80°-90° C. Stirring is continued at this temperature for one hour then the mixture is poured into ice and 45 ml. of concentrated hydrochloric acid. Toluene is added, the organic layer is separated, washed with dilute sodium hydroxide and then water and distilled, giving the desired product as a liquid, b.p. 106°-112° C. (0.15 mm.).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:14]=1[F:15])#[N:8].ClCCl.Br[C:23]1[N:27]2[N:28]=[C:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH:33]3[C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[CH:30]=[CH:31][C:26]2=[N:25][CH:24]=1>O1CCOCC1.O>[CH3:44][C:38]1[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:37]=1[CH:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:29]1[CH:30]=[CH:31][C:26]2[N:27]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([F:15])=[C:9]([CH:10]=3)[C:7]#[N:8])=[CH:24][N:25]=2)[N:28]=1
Reactant: Cc1ccc(C)c(C2CCCN2c2ccc3ncc(Br)n3n2)c1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(C)c(C2CCCN2c2ccc3ncc(-c4ccc(F)c(C#N)c4)n3n2)c1

Procedure:
In step 4-2, sodium carbonate (30 mg, 0.30 mmol), 3-cyano-4-fluoro phenylboronic acid (30 mg, 0.24 mmol) and Pd(DPPF)-dichloride catalyst (1,1′ bis(diphenylsphosphino-ferrocene)-dichloropalladium (II) adduct with dichloromethane) (10 mg, 0.012 mmol) was added into in a microwave vessel containing a solution of 3-bromo-6-(2-(2,5-dimethylphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine (50 mg, 0.13 mmol) and 2.5 mL of 1,4-dioxane/water (3:1). The reaction mixture was subjected to the following microwave conditions using a laboratory microwave instrument (conditions: 150° C., 200 W max threshold, 20 atm. Max pressure, 20 minute reaction time). The resulting solution was purified using preparatory LC/MS (reverse phase C-18 chromatography) to yield 5-(6-(2-(2,5-dimethylphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile (4-2). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.50-8.10 (m, 2H), 7.80 (br s, 1H), 7.50 (app d, J=8.5 Hz, 1H), 7.20 (app t, J=6.5 Hz, 1H), 7.06 (d, J=6.5 Hz, 1H), 6.93 (d, J=6.6 Hz, 1H), 6.81 (br s, 1H), 6.60 (br s, 1H), 5.22 (app dd, J=6.2, 2.1 Hz, 1H), 4.05-4.00 (m, 1H), 3.76 (app q, J=6.4 Hz, 1H), 3.36 (app d, J=2.2 Hz, 1H), 2.58-2.43 (m, 1H), 2.24 (br s, 6H), 2.19-2.08 (m, 2H). LCMS observed m/z 412.2.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[C:12]1([CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[S:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(O)C>O>[C:12]1([CH2:18][CH2:19][NH:20][C:21]2[S:22][CH:3]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[N:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)NCCc1ccccc1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(CCNc2nc(-c3ccccn3)cs2)cc1
Yield: 67.6 %

Procedure:
A mixture of 2-bromo-1-pyridin-2-ylethanone hydrobromide (4.00 g), N-(2-phenylethyl)thiourea (3.60 g), sodium acetate (1.60 g) and ethanol (30 mL) was stirred with heating under reflux for 1 hr. After cooling, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-2:1 in volume ratio) to give the title compound (2.71 g, yield 48%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4].[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 93.1 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(toluene-4-sulfonyloxy)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (0.9 g, 1.55 mmol), 4-(methanesulfonyl)phenylboronic acid (930 mg, 4.6 mmol) and dichlorobis(triphenylphosphine)palladium (II) (110 mg, 0.15 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.3 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (815 mg, 73%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.1.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[N:9]1([CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:5]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)([CH3:20])[CH3:19])=[CH:22][CH:23]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Oc1ccc(C(C)(C)NCCCn2ccnc2)cc1

Procedure:
In a similar manner to Example 71, a solution of butanesulphonyl chloride (0.45 g) in dichloromethane (5 ml) was added in portions over 5 minutes to a solution of 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenol (0.75 g) and triethylamine (0.29 g) in dichloromethane (5 ml) at 0° C. with stirring, to give 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl 1-butanesulphonate as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:16][CH2:17][F:18].[Cl-].[NH4+]>C(OCC)(=O)C.CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([O:14][CH2:16][CH2:17][F:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCCF)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
60% Sodium hydride (0.18 g) was added to a DMF (5.0 mL) solution of 3-hydroxyazetidine-1-carboxylic acid t-butyl ester (0.52 g) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. 1-Bromo-2-fluoroethane (0.45 mL) was added under ice cooling, and the mixture was stirred for 2 hours at room temperature, then for 1.5 hours at 50° C., and further for 1.5 hours at 70° C. The reaction mixture was cooled to room temperature, and ethyl acetate and a saturated aqueous solution of ammonium chloride were added, whereafter the organic layer was isolated. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=80/20→70/30) to obtain 3-(2-fluoroethoxy)azetidine-1-carboxylic acid t-butyl ester (colorless oil) (0.30 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:18](=[O:19])[CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[NH:14][C:13]2=[O:24])[CH2:7][CH2:6]1)=[O:4].[C:25]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][N:12]2[C:18](=[O:19])[CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[N:14]([CH3:25])[C:13]2=[O:24])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3NC2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3N(C)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-(2,4-Dioxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexanecarboxylic acid methyl ester (1 mmol, 0.35 g) in DMF dry (6 mL) under argon was sequentially added K2CO3 (1.6 mmol, 0.22 g) and MeI (2.2 mmol, 140 μL). The mixture was stirred at room temperature overnight. Then H2O (10 mL) was added and the solution was loaded on a C18 cartridge, wash with water (3×5 mL) and then the desired product was eluted with MeOH. The solvent was removed under reduced pressure to give the pure titled compound (0.29 g, yield 80%).