Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:23]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:24]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 300 mg (1.19 mmol) of ethyl (1R,2S)-2-aminocyclohexanecarboxylate HBr 10 salt (Xu, Daquiang et al., Tetrahedron: Asymmetry (1988), 9(10) 1635) dissolved in 8 mL DMF was added 192 mg (1.19 mmol) of indole-2-carboxylic acid, 228 mg (1.19 mmol) of EDCI, 161 mg (1.19 mmol) of HOBT and 0.458 mL (4.16 mmol) of N-methylmorpholine. The reaction mixture was stirred at room temperature overnight, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to provide ethyl (1R,2S)-2-[(1H-indol-2-ylcarbonyl)amino]cyclohexane-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24](Cl)=[O:25])[N:23]=1>>[CH3:18][C:19]1[S:20][C:21]([CH3:27])=[C:22]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])[N:23]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: Cc1nc(C(=O)Cl)c(C)s1
Product: Cc1nc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)c(C)s1

Procedure:
Beginning with 0.34 gm (1.6 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.44 gm (2.50 mMol) 2,5-dimethyl-4-thiazolecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclobutane-1,1′-naphthalen]-3′-carboxylate (155 mg, 505 μmol) and glycine tert-butyl ester hydrochloride (102 mg, 606 μmol) were mixed in dioxane (4 mL). DIPEA (106 μL, 606 μmol) was added, and the reaction mixture was stirred at 75° C. for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting yellow solid was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a white solid (151 mg). MS (m/e)=336.1 (M+H-tBu)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][N:26]=[C:25]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:25]2[C:24]3[C:28](=[C:20]([F:19])[CH:21]=[CH:22][CH:23]=3)[NH:27][N:26]=2)[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=1
Reactant: Nc1n[nH]c2c(F)cccc12
Reactant: Clc1ccccc1-c1nc(Cl)c2ccncc2n1
Product: Fc1cccc2c(Nc3nc(-c4ccccc4Cl)nc4cnccc34)n[nH]c12

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (48.7 mg, 22% yield). HPLC-Method A, Rt 3.35 min; 1H NMR (DMSO, 500 MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.70-7.35 (5H, m), 7.25(1H, m), 6.95 (1H, m),; MS (m/z), MH+ 391.08.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:17][CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][C:21]=2[F:32])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.[SH:33][C:34]1[S:35][CH2:36][CH2:37][N:38]=1.C(N(CC)CC)C>CN(C)C=O.O>[F:32][C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:20]=1[CH2:19][CH2:18][CH2:17][C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][S:33][C:34]3[S:35][CH2:36][CH2:37][N:38]=3)[CH2:7][CH2:8]1)=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCCl)CC1
Reactant: SC1=NCCS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSC2=NCCS2)CC1
Temperature: 80 °C
Reaction time: 23 h
Yield: 21 %

Procedure:
A mixture of 0.7 g of ethyl 1-(2-chloroethyl)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate dihydrochloride, 0.18 g of 2-mercaptothiazoline and 0.63 cm3 of triethylamine in 10 cm3 of dimethylformamide was stirred under an inert atmosphere for 23 hours at a temperature in the region of 80° C. After cooling to about 20° C., the reaction mixture was taken up in water, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was added to a solution of 0.18 g of 2-mercaptothiazoline and 0.06 g of 10% sodium hydride in 10 cm3 of dimethylformamide, and the mixture was then heated at a temperature in the region of 80° C. for 15 hours. After cooling to about 20° C., the reaction mixture was taken up in water, extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure on a column of silica gel (particle size 70-200μ; diameter 2 cm; mass 40 g), eluting with a mixture of dichloromethane/ethanol (95/5 by volume) and collecting 10-cm3 fractions. Fractions 11 to 24 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.15 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(4,5-dihydrothiazol-2-ylthio)ethyl]piperidine-4-carboxylate was obtained in the form of a brown oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].[H-].[Na+].Br[CH2:9][CH:10]([N:17]1[C:21]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=2[N:19]=[C:18]1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(OCC)(=O)C>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]2[N:17]([CH:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:9][O:4][C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[F:26])[C:21]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=3[N:19]=2)=[CH:33][CH:32]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3F)C3CCCCC3)c2cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
To a solution of 27 mg (0.24 mmol) 2-fluorophenole in 2 mL N,N-dimethylformamide 11 mg (0.24 mmol, 55% dispersion in mineral oil) sodium hydride were added and the reaction mixture stirred for 10 min. at room temperature. To the suspension 100 mg (0.22 mmol) 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole were added. The reaction mixture was stirred for 18 h at room temperature, and then poured on 30 mL 1N hydrochloric acid and 30 mL ethyl acetate. The phases were separated and the aqueous layer extracted a second time with 30 mL ethyl acetate. The combined organic layers were washed twice with 30 mL water and once with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate 100:0 to 70:30) to give the desired compound as white solid (9%). MS (Turbo Spray): m/z=485.3 [M+H].
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13](=S)[NH:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:23]([NH:26][NH2:27])(=O)[CH3:24]>C(O)C>[CH2:1]([S:3][C:4]1[C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:11][CH2:12][C:13]3[N:14]([C:23]([CH3:24])=[N:26][N:27]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1cccc2c1C(c1ccccc1Br)=NCC(=S)N2
Reactant: CC(=O)NN
Solvent: CCO
Product: CCSc1cccc2c1C(c1ccccc1Br)=NCc1nnc(C)n1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6-ethylthio-1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 7-ethylthio-1-methyl-6-(o-bromophenyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl.N[CH2:3][CH2:4][CH2:5][CH:6]=[C:7]([CH3:11])[C:8]([NH2:10])=[O:9].C(OC(=O)CC)(=O)CC.C(N(CC)CC)C>CO>[C:8]([NH2:10])(=[O:9])[CH2:7][CH3:6].[CH2:5]([CH:6]=[C:7]([CH3:11])[C:8]([NH2:10])=[O:9])[CH2:4][CH3:3]
Reactant: CC(=CCCCN)C(N)=O
Agent: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(N)=O
Product: CCCC=C(C)C(N)=O
Yield: 95 %

Procedure:
0.8 g of 3-aminopropyl methacrylamide hydrochloride was dissolved in a methanol solvent and 1.0 g of propionic anhydride and 0.9 g of triethylamine (TEA) were added thereto. The resultant mixture was stirred under ice-cooling for 4 hours. After the completion of the reaction, the solvent was distilled off with an evaporator and the precipitate was filtered off. The filtrate was recovered and introduced into a silica column. Thus, the eluate fraction containing the target product was taken up and subjected to recrystallization to thereby purify the target propionamide-propyl methacrylamide (yield: 95%). FIG. 2 shows the result of the mass spectrometry of the purified product while FIG. 3 shows the result of 1H-NMR thereof.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([C:16]#[N:17])=[CH:4]1)[CH3:2].[Li+].CC([N-]C(C)C)C.[Cl:26]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:26][C:4]1[N:3]([CH2:1][CH3:2])[C:11]2[C:6]([C:5]=1[C:16]#[N:17])=[CH:7][CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=2
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCn1cc(C#N)c2ccc(C(F)(F)F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c(Cl)c(C#N)c2ccc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure 1A, in anhydrous THF (20.0 mL), at −78° C. is added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture is continued for 0.5 hr after the addition, followed by the addition of hexachloroethane and the mixture is then brought to room temperature slowly and stirred for 0.5 hr. The solvent is then evaporated and the residue is treated with water. The organics are extracted with dichloromethane, washed with water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (silica gel, dichloromethane/hexanes, 3/2) to provide 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g, 64%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH:6]([O:8][CH2:9][CH3:10])=[CH2:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:6]([O:8][CH:9]([O:5][CH2:1][CH2:2][C:3]#[CH:4])[CH3:10])[CH3:7]
Reactant: C=COCC
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCOC(C)OCC
Reaction time: 2 h
Yield: 85.4 %

Procedure:
3-Butyn-1-ol (46.33 g, 0.661 mole) in methylene chloride (700 mL) was treated with ethyl vinyl ether (0.661 mole, 63.2 mL) and pyridinium p-toluenesulfonate (0.033, 8.31 g) (note: upon addition of pyridinium p-toluenesulfonate an exothermic reaction takes place). After stirring 2 hours, the reaction mixture was concentrated and filtered through a pad of silica gel (ethyl acetate:hexane, 1:1) to provide the title compound as a colorless liquid (80.29 g, 85.5%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[C:37]([O:44][CH3:45])[C:36]=3[F:46])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1)=O.[CH3:47][NH2:48]>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:47][NH:48][CH2:15][C:17]1[N:18]=[C:19]([NH:22][C:23]([C:25]2[C:26]3[N:27]=[CH:28][CH:29]=[N:30][C:31]=3[C:32]([C:35]3[C:36]([F:46])=[C:37]([O:44][CH3:45])[CH:38]=[C:39]([O:42][CH3:43])[C:40]=3[F:41])=[CH:33][CH:34]=2)=[O:24])[NH:20][CH:21]=1
Reactant: CN
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3nc(C=O)c[nH]3)c3nccnc23)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCc1c[nH]c(NC(=O)c2ccc(-c3c(F)c(OC)cc(OC)c3F)c3nccnc23)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
Sodium triacetoxyborohydride (72.4 mg, 0.341 mmol, 1.5 equiv) was added to a suspension of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (4-formyl-1H-imidazol-2-yl)-amide (100 mg, 0.228 mmol) (Example 185) and methylamine (40% wt in H2O, 40 μL, 0.455 mmol, 2 equiv) in DCM (4 mL) at rt, under an argon atmosphere. The reaction mixture was stirred for 4 h at rt. After further addition of sodium triacetoxyborohydride (72.4 mg, 0.341 mmol, 1.5 equiv), the reaction mixture was stirred for additional 16 h at rt. Then, methylamine (50 μL) and sodium triacetoxyborohydride (150 mg) were added. The reaction mixture was stirred for 4 h at rt, diluted with EtOAc/saturated aqueous solution of NaHCO3 and extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91.5:7.5:1) to afford 41 mg of the title compound as a yellow solid: ES-MS: 455 [M+H]+; tR=3.00 min (System 1); TLC: Rf=0.10 (DCM/MeOH/NH3aq, 91.5:7.5:1).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH3:11])[CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([OH:12])[CH:6]=[C:5]([CH3:4])[CH:3]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(C)c(C(C)C)c(O)c1
Reaction time: 3 h
Yield: 23.2 %

Procedure:
63 g of propylene are introduced into 244 g of 3,5-dimethylphenol and 22 g of p-toluene sulphonic acid at 120° C. Thereupon the mixture is stirred at this temperature for 3 h. The catalyst is removed by washing with sodium hydrogen carbonate solution. Then the mixture is fractionated. At boiling point 120° C (12 mm Hg) 57 g of 3,5-dimethyl-2-isopropylphenol are obtained.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][C:6]([F:12])([F:11])[C:7]([O:9]C)=[O:8].CCOCC>O>[Br:2][CH2:3][CH2:4][CH2:5][C:6]([F:12])([F:11])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(F)(F)CCCBr
Agent: Br
Solvent: CCOCC
Solvent: O
Product: O=C(O)C(F)(F)CCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HBr gas was introduced into 48% HBr in H2O (100 ml) with occasional cooling in an ice bath until the weight became 180 g. The HBr solution was then added to Part (5) compound (8.4 g, 36.3 mmole) at room temperature and the reaction was stirred for 5 hours at room temperature. The reaction was cooled to 0° C. and poured into Et2O (900 ml) in an ice bath. The products were extracted into the Et2O layer. The water layer was further extracted with Et2O (200 ml and 100 ml). The combined ether layers were washed with H2O (200 ml). The H2O wash was backwashed with Et2O (100 ml). The Et2O layers were combined and dried over MgSO4. Filtration and evaporation of solvent gave the title compound (7.8 g, quant.) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20]OS(C)(=O)=O)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[OH:33][CH2:34][C:35]1[O:39][C:38]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:37][CH:36]=1>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][C:38]4[O:39][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: OCc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(CO)o4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[O:29])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(OCC)(=O)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:29])[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC2CCN(C(=O)C3CCNCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A solution of 4-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-ylmethyl)phenylamino]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylcarbonyl]piperidine (0.311 g, 0.54 mmol) obtained in Step 1 in chloroform (5.0 mL) was added with a 4 mol/L hydrogen chloride-ethyl acetate solution (2.0 mL) followed by stirring at room temperature for 1 hour. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution to control the pH to 12 and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were added with diisopropyl ether followed by stirring under reflux for 1 hour. The crystals were collected by filtration and dried under reduced pressure to obtain Compound 147 (0.153 g, 0.32 mmol, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:35])[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42](Br)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:35][C:4]1[C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=[C:2]([Cl:1])[CH:3]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(O)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(OCc5ccccc5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of tert-butyl {1-[4-(6-chloro-8-hydroxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was in a manner analgous to that described for Intermediate Example Int-16 (1.90 g, 3.87 mmol) in DMF (50 mL) was added cesium carbonate (6.88 g, 11.6 mmol, 3.0 equiv.) and benzyl bromide (0.58 mL, 4.84 mmol, 1.25 equiv.), and the resulting mixture was irradiated in a microwave apparatus at 140° C. for 90 min. The resulting mixture stirred at room temperature for 16 h. The resulting mixture was added to ice water 100 mL). The aqueous mixture was extracted with a 4:1 DCM/isopropanol solution (3×50 mL). The combined organic phases were dried (Na2SO4 anh.), and concentrated under reduced pressure. The resulting oil was triturated with ethanol to give tert-butyl (1-{4-[8-(benzyloxy)-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate as a powder (0.93 g, 41%):
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:11][C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[CH:4]=[CH:3][CH:2]=[N:1]5)=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Oc1cccc2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccc5ncccc45)ncnc32)CC1
Temperature: 160 °C
Yield: 46.6 %

Procedure:
A mixture of quinolin-5-ol (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 26 mg, 0.178 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tertbutyl ester (Intermediate 19; 60 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.391 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to afford 4-[4-(quinolin-5-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (37 mg, 47%) as a white solid. Mass spectrum MH+=447.