Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[CH2:17]([CH:20]([CH2:47][CH:48]=[CH2:49])[CH2:21][O:22][SiH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([SiH2:37][O:38][CH2:39][CH:40]([CH2:44][CH:45]=[CH2:46])[CH2:41][CH:42]=[CH2:43])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH:18]=[CH2:19].CC([O-])(C)C.[Na+]>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:44]([CH:40]([CH2:41][CH:42]=[CH2:43])[CH2:39][O:38][SiH2:37][C:34]1[CH:35]=[CH:36][C:31]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([SiH2:23][O:22][CH2:21][CH:20]([CH2:17][CH:18]=[CH2:19])[CH2:47][CH:48]=[CH2:49])=[CH:29][CH:28]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:32][CH:33]=1)[CH:45]=[CH2:46]
Reactant: COc1ccc(Br)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(Nc2ccc([SiH2]OCC(CC=C)CC=C)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCC(CC=C)CO[SiH2]c1ccc(N(c2ccc(OC)cc2)c2ccc([SiH2]OCC(CC=C)CC=C)cc2)cc1
Yield: 49 %

Procedure:
Firstly, dist. toluene (5 mL) and 4-bromoanisole (58 μL, 0.46 mmol) were added dropwise to a mixture of bis[4-(diallylethoxysilyl)phenyl]amine (111 mg, 0.23 mmol), Pd2(dba)3 (1 mg, 0.0011 mmol), (o-biphenyl)P(t-Bu) 2 (2 mg, 0.03 mmol) and NaOt-Bu (33 mg, 0.35 mmol). The resultant mixture was stirred under a nitrogen atmosphere at 80° C. for 24 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with ether. A salt thus formed was removed through a celite filtration process, and the solvent was distilled away from an organic layer with an evaporator to obtain a crude product. The obtained crude product was separated and purified by PTLC (hexane/EtOAc/acetone=20/2/1) to obtain N,N-bis(4-(diallylethoxysilyl)phenyl)-4-methoxyaniline (65.8 mg, 48% yield).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(O[N:41]1N=N[C:43]2[CH:44]=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1N>CN(C=O)C>[N:47]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:41][C:17]([C:15]1[CH:14]=[C:13]([O:20][CH:21]([CH3:22])[CH3:23])[C:11]2[CH2:12][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][C:10]=2[CH:16]=1)=[O:18]
Reactant: CC(C)Oc1cc(C(=O)O)cc2c1CC(Cc1ccccc1)O2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)Nc2ccccn2)cc2c1CC(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A mixture of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.9 mmol), DIPEA (0.37 g, 2.85 mmol) and HATU (0.74 g, 1.94 mmol) in DMF (15 mL) was stirred at room temperature for 1 hr, and then pyridin-2-amine (0.18 g, 1.94 mmol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The mixture was concentrated. The residue was purified by prep. HPLC to give the title compound (73 mg, 21% yield, TFA salt) as a white solid. 1H NMR (400 MHz, CDCl3): δ 11.71 (br, 1H), 8.76 (d, 1H), 8.27 (d, 1H), 8.14 (t, 1H), 7.17-7.46 (m, 9H), 4.96 (d, 1H), 4.78 (t, 1H), 2.82 (m, H), 2.67 (m, 1H), 2.19 (m, 1H), 1.96 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:15]([O-])=O)[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:18])[C:5]2=1>CO.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:15])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([CH3:18])[C:5]2=1
Reactant: Cc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12
Agent: [Pt]
Solvent: CO
Product: Cc1cncc2[nH]c3c(N)cc(Cl)cc3c12
Reaction time: 1.5 h
Yield: 93.3 %

Procedure:
A solution of 6-chloro-4-methyl-8-nitro-9H-β-carboline (80 mg, 0.31 mmol) in MeOH (10 ml) was stirred at RT. Platinum (10% wt. on carbon, 24 mg) catalyst was added thereto and the reaction vessel was capped and vacuum purged 3 times with argon, followed similarly by hydrogen. The reaction mixture was stirred 1.5 hr under 1 atm hydrogen, then vacuum purged with argon, diluted with DCM (10 ml) and filtered through a 0.2 uM syringe filter. The filtrate was concentrated to yield 6-chloro-4-methyl-9H-β-carbolin-8-ylamine (67 mg) as a light brown oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11][C:12]2[NH:16][C:15]([CH2:17][O:18]CC3C=CC(OC)=CC=3)=[N:14][C:13]=2[CH:28]([CH3:30])[CH3:29])[CH:7]=[C:8]([Cl:10])[CH:9]=1.Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>O.C(O)C.O1CCCC1>[Cl:10][C:8]1[CH:7]=[C:6]([S:11][C:12]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:15]([CH2:17][OH:18])=[N:14][C:13]=2[CH:28]([CH3:29])[CH3:30])[CH:5]=[C:4]([Cl:3])[CH:9]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CO)n(CCCc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To dry tetrahydrofuran was added 40 mg of 60% sodium hydride, and under ice-cooling, 200 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b) was added. After 20 minutes, 136 μl of 1-bromo-3-phenylpropane was added. After stirred at room temperature for 3 hours, the mixture was diluted with water and extracted with diethyl ether. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To thus-obtained oil were added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give 80 mg of Compound I-122 (yield 40%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C(Cl)Cl>[F:31][C:32]([F:42])([F:43])[C:33]1[CH:34]=[C:35]([NH:39][C:40]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=3)(=[O:22])=[O:21])[CH2:28][CH2:27]2)=[O:41])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Reaction time: 3 h

Procedure:
To [[4-[(7-trifluoromethyl-4-quinolinyl)amino]-phenyl]sulfonyl]piperazine (prepared in Example 9, part D) in methylene chloride is added dropwise, at room temperature, m-trifluoromethylphenyl isocyanate in methylene chloride solution. The reaction is conducted in an atmosphere of nitrogen at room temperature for 1-5 hours. 1[[(m-Trifluoromethylphenyl)amino]carbonyl]-4-[[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl]sulfonyl]piperazine is isolated by conventional methods, e.g., filtration, chromatography.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Reactant: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2nnn3-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
Sodium hydride (50.1 mg, 1.25 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate AU2) (250 mg, 0.52 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (278 mg, 1.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (15 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-methylpyridin-2-yl)propanamide (335 mg, 91%). 1H NMR (400 MHz, CDCl3) δ0.97 (s, 9H), 2.28 (s, 3H), 3.67-3.84 (m, 4H), 4.26 (d, 2H), 6.15 (t, 1H), 7.30-7.41 (m, 5H), 7.48-7.71 (m, 10H), 8.06-8.14 (m, 2H), 8.68 (s, 1H), 8.76 (s, 1H); m/z (ES+), (M+H)+=708.65; HPLC tR=3.84 min
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A solution of (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (310 mg, 0.576 mmol) and triethylsilane (184 μl, 1.151 mmol) in DCM (5232 μl) were treated with trifluoroacetic acid (2660 μl, 34.5 mmol) and stirred for 1 hr at room temperature. Reaction mixture was evaporated in vacuo, partioned between EtOAc/saturated aqeous NaHCO3 and extracted with EtOAc (2×). Combined organics were washed with saturated aqeous NaHCO3, brine, dried over Na2SO4 and evaporated in vacuo affording crude product which was purified by normal phase column chromotography eluting with MeOH/EtOAc (0-10%) affording (R)-1-(3-amino-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (145 mg, 0.489 mmol, 85% yield) as an off white solid. 1H NMR (500 MHz, dmso) δ 11.42 (s, 1H), 8.87 (s, 1H), 8.57 (s, 1H), 8.07 (s, 1H), 7.39-7.27 (m, 4H), 7.27-7.17 (m, 1H), 5.64 (s, 2H), 4.86 (m, 1H), 1.39 (d, 3H). MS ESI calc'd. For C15H16N6O[M+H]+ 297. found 297.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[N:4]2[N:3]=1.CI.[CH3:18]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:15]=[C:5]2[N:6]([CH3:18])[C:7](=[O:14])[C:8]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[N:4]2[N:3]=1
Reactant: Cc1cc2[nH]c(=O)c3cnccc3n2n1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cc1cc2n(C)c(=O)c3cnccc3n2n1
Temperature: 25 °C

Procedure:
2 g. of 2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin5(4H)-one are treated with 2 g. of methyl iodide in 20 ml. of dimethylformamide in the presence of 2 g. of potassium carbonate at 70° with stirring for 12 hours. The mixture is cooled to room temperature, 20 ml. of water are added and the precipitated 2,4-dimethylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one is filtered off, yield: 1.5 g. (70%); m.p. > 300° (DMF).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][C:26]([F:32])=[C:27]([F:31])[CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[CH:28][C:27]([F:31])=[C:26]([F:32])[CH:25]=3)[CH2:30][CH:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC1Cc2cc(F)c(F)cc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Agent: [Na+]
Product: CC1Cc2cc(F)c(F)cc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 40.9 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 80 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 46 mg of (−)-2-methyl-5,6-difluoro-2,3-dihydro-1H-indole (reference example 3a). After silica column purification: eluent 98/02 dichloromethane/methanol, 47 mg of 5-fluoro-2-[2-((+)-5,6-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C@H:9]1[C:16]([O:18]CC1C=CC=CC=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:12][CH2:13]2)[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 5-benzyl ester 6-tert-butyl ester (intermediate 16, 110 g, 0.32 mol, ee:66%) in anhydrous methanol (1 L) was added Pd/BaSO4 (50 g) under hydrogen, the reaction mixture was stirred at room temperature for overnight. The resulting mixture was filtered and the liquid phase was evaporated to give 68 g of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 6-tert-butyl ester (light white solid, yield:85%) which was recrystallized with PE/EtOAc (4:1) to give 38 g of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 6-tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.Cl.Cl[CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:29][CH2:30][N:31]([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc2c(c1)C(c1ccc(OCCN(C(C)C)C(C)C)cc1)c1c-2ccc2ccccc12

Procedure:
A 7 g portion of the compound of Example 1 was reacted with 6.6 g of 2-chloroethyl-bis(isopropyl)amine hydrochloride in the presence of 12.2 g of potassium carbonate in 75 ml of methyl ethyl ketone. The mixture was stirred under reflux for 72 hours, and was then worked up as described in Example 5. The impure product was chromatographed over silica gel with a gradient solvent proceeding from toluene to 9:1 toluene:ethyl acetate. Concentration of the product-containing fractions gave 4.16 g of the desired product, m.p. 106°-115° C.
Reaction SMILES: C1C(CCC(C2C(O)=CC(O)=CC=2O[C@@H:18]2O[C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@H:20](O)[C@H:19]2[OH:28])=O)=CC=C(O)C=1.C([O-])(=[O:34])C.[Na+]>C(OC(=O)C)(=O)C>[CH3:18][C:19]([CH2:20][C:21]([CH2:22][C:24]([OH:34])=[O:25])=[O:26])=[O:28]
Reactant: CC(=O)[O-]
Reactant: O=C(CCc1ccc(O)cc1)c1c(O)cc(O)cc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)CC(=O)O
Yield: 181.7 %

Procedure:
1 g of phlorizin, 10 mL of acetic anhydride, and 0.82 g (0.01 mol) of sodium acetate were reacted at 100° C. for 6 hrs. The reaction mixture was cooled and the triacetate derivative of phlorizin precipitated from the solution in the form of a crystalline solid. The crystalline solid was separated by filtration, dissolved in 50 mL of hot methanol, and re-crystallized twice from hot methanol. The reaction yielded 0.6 g of the triacetate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].C([O:12][B:13](OC(C)C)[O:14]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[C:7]([C:3]1[N:2]([CH3:1])[C:6]([B:13]([OH:14])[OH:12])=[CH:5][CH:4]=1)#[N:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1cccc1C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C#N)ccc1B(O)O
Temperature: 13 °C
Yield: 80.3 %

Procedure:
The solution of 1-methylpyrrole-2-carbonitrile (0.131 g, 1.23 mmol), triisopropylborate (250 μL, 1.08 mmol), and THF (4 mL) was cooled to about −4° C. and 2M LDA (0.6 mL, 1.2 mmol) was added dropwise from a syringe. The bath was removed and the suspension was allowed to warm to about 13° C. within about 2 hours. After cooling and quenching with water and 5% aqueous HCl, the product was extracted with diethylether. The organic layer was evaporated to give an oil which solidified upon standing to give 0.130 g (70% yield) of (5-cyano-1-methyl-1H-pyrrol-2-yl) boronic acid. 1H-NMR (DMSO-d6): δ 8.38, 6.87, 6.77, and 3.88.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=S)[C@H:15]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[O:22])[CH2:14][CH2:13]1>CO>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][NH:17][C:16](=[N:2][NH2:3])[C@H:15]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[O:22])[CH2:14][CH2:13]1
Reactant: NN
Reactant: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Solvent: CO
Solvent: O
Product: NN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
Hydrazine monohydrate (1.46 mL, 30.1 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (502 mg, 1.00 mmol) in methanol (20 mL). After 30 min, the reaction was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound (515 mg). MS 499.1 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2[N:18]([CH2:31][CH2:32][CH3:33])[N:19]=[C:20]3[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=[C:21]3[NH2:30])[CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:17]2[N:18]([CH2:31][CH2:32][CH3:33])[N:19]=[C:20]3[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=[C:21]3[NH2:30])[CH2:12][CH2:13]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
Methanesulfonyl chloride (0.30 g, 0.20 mL, 2.58 mmol) was added to a stirring suspension of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride (1.0 g, 2.35 mmol) and triethylamine (0.59 g, 0.82 mL, 5.88 mmol) in dichloromethane (10 mL). The resulting suspension was stirred at ambient temperature 16 hours. Additional dichloromethane (90 mL), triethylamine (4.2 g, 5.7 mL, 41.1 mmol) and methanesulfonyl chloride (0.19 g, 0.13 mL, 1.66 mmol) were added to the mixture and the resulting cloudy suspension was stirred at ambient temperature 3 days. The reaction mixture was concentrated and the resulting brown solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-20% methanol in dichloromethane). The resulting oil was crystallized from acetonitrile and isolated by filtration to yield 169 mg of N1-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine as an off-white solid, mp 204-207° C. Anal. calcd for C21H30N6O2S: C, 58.58; H, 7.02; N, 19.52. Found: C, 58.77; H, 6.92; N, 19.54.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10](CO)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[C:28]([Br:32])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:28][Br:32])[C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(CBr)c1-c1ccccc1C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a stirred solution at −10° C. under N2 of N-[4-hydroxymethyl-2-(2-methylphenyl)benzoyl]methionine methyl ester (200 mg, 0.517 mmol ), prepared as in Example 403F, and carbon tetrabromide (189 mg, 0.568 mmol) in CH2Cl2 (5 mL) was added triphenylphosphine (163 mg, 0.620 mmol). Reaction stirred one hour at −10° C., and then, solvents concentrated in vacuo to produce a colorless glass. The residue could not be stored, and so, was used directly in the reaction in Example 1188B.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:37])([F:36])[C:10]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]2[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].C(N(CC)CC)C.[Cl:45][C:46]1[N:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(Cl)Cl>[Cl:45][C:46]1[N:51]=[CH:50][C:49]([S:52]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][C:16]([C:10]([OH:15])([C:9]([F:8])([F:36])[F:37])[C:11]([F:14])([F:13])[F:12])=[CH:17][CH:18]=3)[C@@H:23]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@H:30]3[CH3:35])[CH2:24]2)(=[O:54])=[O:53])=[CH:48][CH:47]=1
Reactant: C[C@H]1COCCN1C[C@H]1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 1,1,1,3,3,3-hexafluoro-2-(4-((2R)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (115 mg, 0.172 mmol) was dissolved in CH2Cl2 (30 mL) and was chilled to 0° C. To this solution was triethylamine (96 μl, 0.687 mmol) followed by 6-chloropyridine-3-sulfonyl chloride (40.1 mg, 0.189 mmol, Organic Process Research & Development 2009, 13, 875). The mixture was warmed slowly to room temp and stirred for 2 h. Afterwards, the mixture was concentrated to give 2-(4-((S)-4-((6-chloropyridin-3-yl)sulfonyl)-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol.