Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:3]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][CH2:22]4)[CH:2]([OH:1])[CH3:20])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:3]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][CH2:22]4)[CH:2]([OH:1])[CH3:20])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: CC(O)C(C1CNc2ccccc2C1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MEOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[C:8]([CH2:15]O)=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[Br:6][C:7]1[C:8]([CH2:15][S:2]([CH3:1])(=[O:4])=[O:3])=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=1
Reactant: CSc1ncc(Br)c(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc(Br)c(CS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (5.85 g, 51.0 mmol) was added to a stirred, cooled 0° C. mixture of [5-bromo-2-(methylthio)pyrimidin-4-yl]methanol (INTERMEDIATE 1, 10 g, 42.5 mmol) in CH2Cl2 (200 mL), followed by addition of Et3N (6.46 g, 63.8 mmol). The mixture was stirred at 0° C. for 30 minutes. TLC showed no starting material left. The mixture was quenched with water (30 mL) and the mixture was washed with more water (50 mL). The organic portion was washed with brine (saturated, 50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc/hexane (3/7) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 8.61 (s, 1H), 5.38 (s, 2H), 3.21 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[NH2:12][NH2:13]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH:9]([NH:12][NH2:13])[CH3:10]
Reactant: COc1cccc(C(C)=O)c1
Reactant: NN
Solvent: CCO
Product: COc1cccc(C(C)NN)c1
Reaction time: 48 h
Yield: 41 %

Procedure:
A mixture of 3′-methoxyacetophenone (1.5 g, 10 m mol), anhydrous hydrazine (1.28 g, 40 m mol) and dry ethanol (10 ml) was heated under reflux for 3 hours. Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on silica gel (50 g) using ethyl acetate-hexane (1:1), and eluted with ethyl acetate-hexane (1:1) and then with ethyl acetate. The resulting yellow oily material (1.2 g) was dissolved in ethanol (20 ml). After the addition of 5% palladium-carbon (0.5 g), this solution was stirred in an atmosphere of hydrogen (40 kg/cm2) for 48 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel (30 g) using chloroform-methanol (100:1), and eluted with chloroform-methanol (100:1) and then with chloroformmethanol (10:1). Thus, the desired compound (0.68 g, 41%) was obtained as an oily material.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1.C[CH2:21][N:22](C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1F
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(F)c(F)c1
Yield: 37.3 %

Procedure:
A solution of 2,4-dichloro-7-(3,4-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (421 mg, 1.398 mmol), methanamine, HCl (283 mg, 4.19 mmol) and DIPEA (1.465 mL, 8.39 mmol) in methanol (10 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(3,4-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (154 mg, 0.521 mmol, 37.2% yield). LC-MS (M+H)+=296.2.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].C([Li])CCC.[CH2:19]([N:26]1[CH2:30][C@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:28][C@H:27]1[CH:39]=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C.O>[CH2:19]([N:26]1[CH2:30][C@H:29]([O:31][Si:32]([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:34])[CH3:33])[CH2:28][C@H:27]1[CH:39]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[OH:40])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C=O)N(Cc2ccccc2)C1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C(O)c2ccncc2)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
A solution of 4-bromopyridine hydrochloride (18.57 g) in ethyl ether (50 ml) and water (50 ml) was neutralized with sodium hydrogen carbonate in water (50 ml). After stirring for 10 minutes, the mixture was extracted three times with ethyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a residue. To a solution of the residue in ethyl ether (300 ml) was added n-butyllithium (1.68N solution in n-hexane) (63 ml) under -60° C. After the addition, the mixture was stirred for 30 minutes at -78° C. Then (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (30.52 g) was added dropwise to the mixture under -60° C. After the addition, the mixture was stirred at -70° C. for 30 minutes and then warmed to room temperature. The raction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel eluting with ethyl acetate:n-hexane=3:7 to 1:1) to give 1-{(2S,4R)-1-benzyl-4-(t-butyl-dimethylsilyloxy)pyrrolidin-2-yl}-1-(4-pyridyl)methanol (14.68 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:12]([N:14]([CH2:32][CH3:33])[CH2:15][CH2:16][NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:19]1)[CH3:13].O>ClCCl>[CH2:32]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][N:17]([C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:19]1)[C:1](=[O:3])[CH3:2])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCN(CC)CCN[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)CCN(C(C)=O)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (2.9 g) was dissolved in 50 ml of dry dichloromethane, mixed with 5.3 ml of triethylamine, and after addition of N,N-diethyl-N′-[(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]-ethane-1,2-diamine (5.8 g), stirred at room temperature for 30 minutes. Subsequently, (LCMS check), water (10 ml) was added to the reaction, and the mixture was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over magnesium sulfate, the solvent was removed, and the crude product was separated by chromatography on silica gel (dichloromethane/methanol 10:1). This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[NH:15])OCC)=[C:5]2[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17].[N:25]#[C:26][NH2:27]>CO>[C:26]([NH:27][C:11]([C:6]1[NH:7][C:8]2[C:4]([C:5]=1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[NH:15])#[N:25]
Reactant: N#CN
Reactant: CCOC(=N)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Solvent: CO
Product: N#CNC(=N)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
Ethyl 5-chloro-3-phenylsulfonylindole-2-carboximidate is reacted with an equimolar amount of cyanamide in absolute methanol (according to the procedure of K. R. Huffman and F. C. Schaefer (J. Org. Chem., 28, 1812 (1963)). After 30-60 minutes the solvent is removed and the residue purified by silica gel chromatography to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]([O:15]C)OC.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].Cl>C1COCC1>[CH2:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[CH:12]=[O:15])[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: COC(OC)c1cc(C(F)(F)F)ccc1Br
Reactant: C=CCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Step AJ (2): To a solution of 1-bromo-2-(dimethoxymethyl)-4-(trifluoromethyl)benzene (1060 mg, 3.544 mmol) in THF (10 mL) at −78° C. was added 1.6N solution of n-butyl lithium in hexanes (4.43 mL, 7.088 mmol). The resulting mixture was stirred at −78° C. for 15 min. 5-Bromopent-1-ene (0.42 mL, 3.544 mmol) was added by drops. The reaction mixture was warmed to rt and stirred overnight. Aqueous hydrochloric acid solution (1N) was added and the reaction mixture was stirred at rt for 3 h. The reaction was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 2-(pent-4-enyl)-5-(trifluoromethyl)benzaldehyde (858.0 mg, 100%) as a brown oil. LC-MS (M+H)+=243.09. 1H NMR (CDCl3, 500 MHz) δ 10.30 (s, 1H) 8.22-7.35 (m, 3H) 7.06 (m, 1H) 5.83 (m, 1H) 5.10-5.00 (m, 2H) 3.84 (s, 3H) 2.16 (m, 2H) 1.75 (m, 2H) 1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]1([CH3:21])[CH:16]=CC(S(Cl)(=O)=O)=C[CH:12]=1>CC(O)(C)C.N1C=CC=CC=1>[C:11]([O:9][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10])([CH3:21])([CH3:16])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ncc(Br)cn1
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
A suspension of 5-bromopyrimidine-2-carboxylic acid (690 mg, 3.40 mmol) in 6.8 mL t-BuOH and 1.9 mL pyridine was stirred at room temperature to 50° C. for 1 hr, and cooled to room temperature. 4-Toluenesulfonyl chloride (1.55 g, 8.12 mmol) was added portion wise. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched with saturated aqueous NaHCO3 slowly, extracted with 3×Et2O, dried over Na2SO4, and concentrated. The residue was purified by Biotage column chromatography with 15-25% EtOAc in hexanes to give a yellow solid (497 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 2 H) 1.64 (s, 9 H).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12.[C:22]1(C)[CH:27]=CC=C[CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12)[CH:22]=[CH2:23]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(Br)cccc3C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cccc2c1CC1CC(=O)N(C(=O)OC(C)(C)C)C21

Procedure:
A solution tert-butyl 5-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Step 3, 500 mg), Pd(PPh3)4 (80 mg, 0.1 equiv.), allyltributylstannate (0.56 g, 1.20 equiv.) in toluene (17 mL) was degassed and stirred at reflux overnight. The solvent was removed under vacuum. The residue was taken up in acetonitrile (40 mL) and washed twice with n-hexane. The acetonitrile was removed in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate and cyclohexane (1 to 25%) to give 210 mg of the desired product E1; LCMS (Method B), RT: 1.05 min; ES+ 649 (2M+Na+).
Reaction SMILES: Br[CH:2]1[CH2:17][CH2:16][C:5]2=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:7][C:8]([S:9][CH3:10])=[C:4]2[C:3]1=O.[C:19]([NH2:27])(=[S:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C>C(OCC)(=O)C.O1CCCC1>[CH3:10][S:9][C:8]1[O:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[C:4]=1[C:3]1[N:27]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:26][C:2]=1[CH2:17][CH2:16]2
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)c1oc(SC)c2c1CCC(Br)C2=O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1oc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 57.6 %

Procedure:
A fixture of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]furan-1-carboxylate (2.60 g), thiobenzamide (2.14 g) and ethanol (60 ml) was refluxed under heating for 5 hours, after which it was diluted with ethyl acetate-tetrahydrofuran (3:1, v/v, 400 ml), washed with water and dried (MgSO4), after which the solvent was distilled off to yield ethyl 4,5-dihydro-8-methylthio-2-phenylfuro[3,4-e]benzothiazole-6-carboxylate (1.67 g, 57.6%), which was then recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 170-171° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])=[CH:9][C:8]=1[Br:33].C(N(CC)CC)C.[C:41](Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>ClCCl>[Br:33][C:8]1[CH:9]=[C:10]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCCCN)c(OCC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCCCNC(=O)C(C)C)c(OCC)c1
Reaction time: 17 h

Procedure:
A mixture of the product of step b (117 mg), triethylamine (81 μl) and isobutyrylchloride (24 μl) in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/EtOAc (from 1/0 to 0/1) as eluent. Yield: 69 mg. MS-ESI: [M+H]+=610.4/612.4; HPLC: Rt=19.45 min. (method 1). Diast. ratio: 5:1
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(=O)OC(C)(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 75.7 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.51 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (100 mg, 0.51 mmol), sodium triacetoxyborohydnde (162 mg, 0.75 mmol) and acetic acid (30 mg, 0.5 mmol) in tetrahydrofuran (20 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92.3:6.7:0.33) to give the title compound (260 mg) as a solid. R 0.66 in dichloromethane:methanol:ammonia (80:20:1).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]([F:18])([F:17])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:8][C:9]([F:17])([F:18])[C:10]1[CH:11]=[C:12]([NH:13][C:1]([CH3:2])=[CH:4][C:5](=[O:7])[CH3:6])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Acetylacetone (15.53 g, 155 mmol), 3-trifluoromethylaniline (5.00 g, 31 mmol), and 4-toluenesulfonic acid (0.53 g, 3.1 mmol) are dissolved in toluene (50 ml). The reaction mixture is refluxed overnight with a Dean-Stark trap to remove water. After cooling to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Reactant: CN(C)CCn1ncc2cc(N)ccc21
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)CCn1ncc2cc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)ccc21
Reaction time: 6 h

Procedure:
A mixture of 1-(2-dimethylamino-ethyl)-1H-indazol-5-ylamine (42 mg, 0.20 mmol), 4-phenoxy-phenylacetic acid (47 mg, 0.21 mmol), ethyldimethylpropylcarbodiimide hydrochloride (43 mg g, 0.22 mmol), N-hydroxybenzotriazole (30 mg, 0.22 mmol), N-methyl morpholine (46 mg, 0.44 mmol) in 2 mL of DMF was shaken for 6 hours. The mixture was concentrated under reduced pressure, the residue taken up in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.84 (s, 6H), 3.65 (s, 2H), 3.62 (t, J=6.24, 2H), 4.76 (t, J=6.24, 2H), 6.97–7.00 (m, 4H), 7.11–7.14 (m, 1H), 7.36–7.40 (m, 4H), 7.64 (m, 1H), 7.69 (m, 1H), 8.12 (m, 1H), 8.15 (m, 1H), 9.58 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](I)=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[BrH:13].O>C(O)(=O)C>[Br:13][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Brc1cc(Br)c2nccn2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 5.0 (14.0 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c, 30 mL of hydrogen bromide solution in acetic acid (33%) was stirred at 120° C. for 1 hour under microwave irradiation. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium thiosulfate and sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 3.0 g (78%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([NH:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]2=[N:4][C:3]=1[CH3:22].N1C=CC=CC=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([N:19]([CH3:20])[S:29]([CH3:32])(=[O:31])=[O:30])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]2=[N:4][C:3]=1[CH3:22]
Reactant: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2c(OCc3cc(N(C)S(C)(=O)=O)ccc3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 34.6 %

Procedure:
To a solution of 3-bromo-8-(2-chloro-5-methylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (60 mg), pyridine (16 mg) and 4-dimethylaminopyridine (10 mg) in methylene chloride (2 ml) was added mesyl chloride (22 mg) in one portion at 5° C., and the mixture was stirred for 9 hours at ambient temperature. The precipitate was filtered off and the residue was washed with methylene chloride and diethyl ether respectively. The filtrate was concentrated in vacuo and the residue was purified by preparative thin-layer chromatography on silica gel (methanol:methylene chloride=1:10, V/V) to give 3-bromo-8-[2-chloro-5-(N-methyl-N-methylsulfonylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (25 mg).
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C:3]([OH:5])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[NH:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:31]=1[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>O1CCCC1>[C:7]([NH:6][C@H:2]([C:3]([NH:29][C:30]1[C:31]([C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[NH:33][N:34]=1)=[O:5])[CH3:1])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
Under a stream of argon gas, 421 mg of Z-L-alanine and 306 mg of carbonyldiinidazole (CDI) were dissolved in 10 ml of tetrahydrofuran, followed by stirring at room temperature for 10 minutes. Then, 150 mg of 5-amino-3-(4-fluorophenyl)-4-(4-pyridyl)pyrazole and 287 mg of 1,8-diazabicyclo[5.4.2]undec-7-ene (DBU) were added thereto, followed by stirring at room temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography using 20 g of silica gel [with an elution solvent comprising chloroform-methanol (50:1)]. Thus, 88 mg (32% yield) of the title compound was obtained as a white powder.