Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.30) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 58%). MS (ISP) 582.2 [(M+H)+]; mp 193-194° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11](C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]([F:54])([F:53])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:14]=[C:13]([C:43]2[CH:42]=[CH:41][C:40]([C:39]([F:54])([F:53])[F:38])=[CH:45][CH:44]=2)[CH:12]=[C:11]([C:42]2[CH:41]=[C:40]([C:39]([F:54])([F:53])[F:38])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3,5-bis-trifluoromethylphenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:21]=2)[C:17]#[N:18])[CH2:9][CH2:8]1)=[O:6].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:21]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:19]=[C:16]([C:17]3[N:32]=[N:33][NH:34][N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)nc(Nc2nccs2)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(-c3nn[nH]n3)cc(Nc3nccs3)n2)CC1
Temperature: 110 °C
Reaction time: 13 h

Procedure:
A mixture of 25.2 mg of 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-(thiazol-2-ylamino)isonicotinonitrile obtained in Example 104, 17.9 mg of sodium azide, 38.0 mg of triethylamine hydrochloride and 2 ml of N,N-dimethylformamide was stirred at 110° C. for 13 hours, and then the reaction solution was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=5/1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([CH:7]([C:11]([OH:13])=O)[C:8]([OH:10])=O)[CH3:6])[CH3:2].[NH2:15][C:16]([NH2:18])=[O:17].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[O:17]=[C:16]1[NH:18][C:8](=[O:10])[CH:7]([C@@H:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:11](=[O:13])[NH:15]1
Reactant: NC(N)=O
Reactant: CCOC(=O)[C@H](C)C(C(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)[C@H](C)C1C(=O)NC(=O)NC1=O
Temperature: 25 °C

Procedure:
The (R)-2-(1-ethoxy-1-oxopropan-2-yl)malonic acid (3.5 g, 0.017 mol) and the urea (1.03 g, 0.017 mol) was dissolved into Ac2O (20 ml) and then added to the reaction vessel of the microwave reactor and were allowed to react under microwave irradiation at 60° C. for half an hour. After cooled to rt, added NaHCO3 aqueous and extracted with EtOAc. The organic phase was dried and concentrated to afford (R)-ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)propanoate, which was purified by silica gel chromatography (2.0 g, 52%).
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][C:39]=1[F:45].C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[CH:11]1([CH2:16][CH2:17][C:18]([NH:20][C:21]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([O:37][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][CH:29]=3)=[C:39]([F:45])[CH:40]=2)=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:19]2[S:23][CH:22]=[N:21][CH:20]=2)[CH:8]=1)[NH2:5]
Reactant: Brc1cncs1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(N)cc(-c2cncs2)c1
Temperature: 100 °C

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20.98 g, 90 mmol), 5-bromothiazole (8.85 mL, 99 mmol) and sodium carbonate (90 mL, 180 mmol) were combined in a flask. 2-Methyl-THF (326 mL) was added and the mixture was degassed with N2 for 1.5 h before 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.67 g, 4.50 mmol) was added. The reaction was heated to 100° C. overnight and was then cooled to room temperature. The reaction mixture was filtered though a pad of CELITE, washing with ethyl acetate. The layers were separated and the aqueous layer was back-extracted with ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica gel (0-40% ethyl acetate in hexanes). 3-Methyl-5-(1,3-thiazol-5-yl)aniline was isolated as a yellowish brown solid. MS ESI: [M+H]+ m/z 191. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.02 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.50 (s, 1H), 3.71 (s, 2H), 1.79 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][N:23]=4)[N:18]=[CH:17][C:16]=3[NH2:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:26](OC)(OC)(OC)[CH2:27][CH2:28][CH3:29]>Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][N:14]3[C:15]4[C:24]5[N:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:18]=[CH:17][C:16]=4[N:25]=[C:26]3[CH2:27][CH2:28][CH3:29])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCC(OC)(OC)OC
Reactant: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cccnc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Yield: 35.7 %

Procedure:
The methods described in Part A of Example 13 were used to treat N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine (2.6 g, 7.8 mmol) with trimethyl orthobutyrate (1.9 mL, 12 mmol) in the presence of pyridine hydrochloride (0.018 g, 0.16 mmol) and isolated and purify the final product with the modification that the silica column was eluting with 60-90% ethyl acetate in dichloromethane. 1-{[3-(4-Fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.08 g) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40][CH2:41][C:42]#[CH:43]>O1CCCC1.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:43]#[C:42][CH2:41][S:40][CH3:39])=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Reactant: C#CCSC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCSC)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in anhydrous tetrahydrofuran (10 mL); anhydrous triethylamine (20 mL) and a solution of 3-(methylsulfanyl)propyne (130 mg, 1.51 mmol) in anhydrous tetrahydrofuran (2 mL) were added. Resulting solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added under nitrogen atmosphere. Reaction mixture was stirred at ambient temperature overnight, the resulting suspension was filtered through a paddle of silica gel and silica gel was thoroughly washed with ethyl acetate. The filtrate was evaporated in vacuo; the obtained residue was dissolved in dichloromethane and the solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(methyl-sulfanyl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][C:13]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:7]([F:28])[CH:6]=1)(=O)C.O.[OH-].[K+]>CO>[CH2:21]([O:20][C:13]1[CH:14]=[C:15]([CH2:18][CH3:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][C:7]=1[F:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCc1ccc(Oc2ccc(OC(C)=O)cc2F)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(Oc2ccc(O)cc2F)c(OCc2ccccc2)c1
Temperature: 65 °C
Yield: 44.3 %

Procedure:
To a solution of 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl acetate (1.6 g, 4.2 mmol) in MeOH:H2O (35 ml:35 ml), was added KOH (0.83 g, 14.8 mmol). The mixture was heated at 65° C. for 4.5 hours, concentrated in vacuo, then extracted with EtOAC (25 ml*2). Combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by column chromatography, (pet ether: EtOAC 95:5), to yield the title compound as a white solid (630 mg; 44%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:44]=[CH:43][C:35]([O:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][C:33]=1[O:45][CH3:46])=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:44]=[CH:43][C:35]([O:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:34][C:33]=3[O:45][CH3:46])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(OCCCC(=O)O)ccc1C=O
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cc(OCCCC(=O)O)ccc1CNc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(4-formyl-3-methoxy-phenoxy)-butyric acid according to the procedure of Example 66. MS (ESI) m/z 613.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.[OH-].[NH4+]>ClCCl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[C:15]([CH3:21])=[CH:14][N:13]=3)=[O:32])=[N:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3ncc(C)c(OC)c3C)nc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 2.5 °C
Reaction time: 0.21 h

Procedure:
To a solution of 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole (30 g) in dichloromethane (165 mL) at 0-5° C., under an inert atmosphere, was added meta-chloroperbenzoic acid (0.95 eq) over 10 minutes. The mixture was stirred for 10-15 minutes. To the reaction was added 12% ammonium hydroxide (180 mL). The layers were separated. The organic layer was extracted with 12% ammonium hydroxide (2×180 mL). The combined aqueous layers were washed with toluene (90 mL). To the aqueous layer was added dichloromethane (120 mL) and the mixture was cooled to 0-5° C. The pH was adjusted to pH=8.5-9.5 using 50% aqueous acetic acid. The layers were separated. The aqueous layer was extracted with dichloromethane (2×90 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered through celite and vacuum distilled to 150 mL to give a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]1H-benzimidazole in dichloromethane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:10]([CH2:27][OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:10]([CH2:27][O:28][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1COS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a vigorously stirred solution of Example 45E (1 g, 2.59 mmol) in dichloromethane (5.19 mL) was added triethylamine (0.542 mL, 3.89 mmol) and methanesulfonyl chloride (0.253 mL, 3.24 mmol). The reaction was stirred for 10 minutes and then quenched with brine, extracted twice with dichloromethane, dried over sodium sulfate, and the solvent was evaporated to afford the title compound. MS (ESI+) m/z 464.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][N:19]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[Cl:32])=[O:21])[CH:7]=1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42](B(O)O)[CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.ClCCl.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>[Cl:32][C:23]1[C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:20]([N:19]([CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][C:6]1[CH:7]=[C:2]([C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)[CH:3]=[CH:4][C:5]=1[O:38][CH3:39])[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:21]
Reactant: COc1ccc(Br)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2cccnc2)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
Temperature: 85 °C
Yield: 89.7 %

Procedure:
A solution of 61 mg (0.1 mmol) N-({3-[(5-bromo-2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in 2 mL toluene is treated with 4 mg (0.003 mmol) tetrakis(triphenylphosphine)palladium(0), 15 mg (0.12 mmol) pyridine-3-boronic acid and 0.2 mL 2M potassium carbonate. The solution is heated to 85° C. for 18 hr and cooled to room temperature. The solution is diluted with 10 mL dichloromethane, washed with 10 mL brine, dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 55 mg (89%) (2-chloro-3,4-dimethoxyphenyl)-N-({3-[(2-methoxy-5-(3-pyridyl)phenyl)methyl](imidazol[1,2-a]pyridin-2-yl)}methyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 613.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1.O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO>[CH3:2][C:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:17][CH2:18]3)=[N:7][C:6]=2[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1nn(-c2ccccc2)c2nc(C3CCNCC3)[nH]c(=O)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-6-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrochloride (500 mg, 1.45 mmol, 1.00 equiv) in methanol (50 mL) at room temperature. To the resulting mixture was then added tert-butyl 4-oxopiperidine-1-carboxylate (865 mg, 4.35 mmol, 3.00 equiv), in portions at room temperature, followed by NaBH3CN (460 mg, 7.30 mmol, 5.00 equiv), in portions at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in water (50 mL). The resulting solution was extracted with ethyl acetate (3×50 mL), the organic layers combined and concentrated under vacuum to yield tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=3)[C:3]=12.Cl.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:21]([C:23]3[O:24][C:25]4[C:30]([C:31](=[O:40])[C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(=O)Nc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Yield: 27.3 %

Procedure:
To a solution of Example 107 (0.080 g, 0.149 mmoles) in ethanol (5 ml), Con.HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixture was basified with sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.020 g, 27% yield). MP: 91-94° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.04(dd, J=8.3,1.5 Hz, 1H), 8.02(s,1H), 7.85(m,1H), 7.67(d, J=8.4 Hz, 1H), 7.53(t, J=7.6 Hz, 2H),7.29(m,3H), 7.06(dt, J=8.7,2.3 Hz, 1H), 6.91(br s,1H), 6.68(d, J=8.4 Hz, 2H), 6.00(q, J=7.0 Hz, 1H), 5.42(s,2H), 1.87(d, J=7.0 Hz, 3H). Mass: 492.83(M+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[O:15]=[C:16]1[CH2:20][CH2:19][S:18][CH2:17]1>>[O:15]=[C:16]1[CH2:20][CH2:19][S:18][C:17]1=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCSC1
Reactant: COC(=O)C(C)c1cccc(C=O)c1
Product: COC(=O)C(C)c1cccc(C=C2SCCC2=O)c1
Yield: 11.6 %

Procedure:
By using methyl 2-(3-formylphenyl)propionate (720 mg) obtained in Example 66 and 3-oxothiolane (580 mg), the title compound (120 mg, 12%) was obtained in the same manner as that of Example 1.